WO2025251084A1

WO2025251084A1 - Methods of treating a disease or condition associated with weight gain

Info

Publication number: WO2025251084A1
Application number: PCT/US2025/031950
Authority: WO
Inventors: Kristen Patricia FORTNEY; Eric Kim MORGEN; Paul David RUBIN; Yong Pan; Yan Wang; Peng Khun LEONG; Justin REBO; Shijun Yan
Original assignee: Bioage Labs Inc
Current assignee: Bioage Labs Inc
Priority date: 2024-05-31
Filing date: 2025-06-02
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30

Abstract

This disclosure provides methods for treating a condition or disease associated with weight gain that include coadministration of an apelin receptor agonist and a satiety-inducing agent. Methods for increasing total weight loss in the subject relative to weight loss that would be caused by administration of a pre-determined amount of a satiety-inducing agent alone are also provided. In some embodiments, the method is for preserving, or maintaining muscle mass, muscle function, and/or muscle strength in a subject undergoing weight loss therapy.

Description

Attorney Docket No.: 32554-61637 (024WO) METHODS OF TREATING A DISEASE OR CONDITION ASSOCIATED WITH WEIGHT GAIN 1. BACKGROUND [0001] Obesity is a globally increasing health problem associated with various diseases, particularly cardiovascular disease (CVD), type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy. The rise in obesity drives an increase in diabetes, and approximately 90% of people with type 2 diabetes may be classified as obese. There are approximately 589 million people worldwide with diabetes, and by 2050 it is estimated that 853 million people will have diabetes. [0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are glucose-lowering drugs that induce clinically significant reductions in body weight. However, GLP-1 receptor agonists not only reduce fat mass, but have also been shown to reduce lean body mass and skeletal muscle. [0003] Cannabinoid -1 (CB1) receptor antagonists, such as rimonabant, selectively block CB1. When stimulated, the endocannabinoid system is linked to the regulation of gut motility, food intake, and energy metabolism. rimonabant has shown increased gut motility and decreases in food consumption and appetite in preclinical models. [0004] Methods are presently needed to reduce weight gain, inhibit weight gain, or prevent or reduce rebound weight gain, prevent muscle loss, and induce preservation of muscle function in patients having a condition or disease characterized by excess body weight, including patients who are undergoing weight loss treatments. 2. SUMMARY [0005] This disclosure provides methods for treating a condition or disorder associated with weight gain by co-administration of an apelin receptor agonist and a satiety-inducing agent. [0001] This disclosure also provides methods of inhibiting weight gain in a human subject having a condition caused or characterized by excess body weight by co- administration of an apelin receptor agonist and a satiety-inducing agent. This disclosure also provides methods of preventing or reducing rebound weight gain in a human subject e.g., who has previously lost weight, by co-administration of an apelin receptor agonist and a satiety inducing agent. [0002] Although weight loss therapies provide for treatment of weight-gain induced comorbidities, such as obesity-associated comorbidities, weight loss therapies can have an impact on body composition. Body composition includes free mass (FM), fat free mass (FFM), lean body mass (LBM), skeletal muscle mass, bone mineral content, and total body water (TBW). Free mass is a mass of all adipose tissue, FFM is a total body mass minus total fat mass, LBM includes organs, skin, bones, total body water, and muscle mass minus total fat mass, skeletal muscle mass includes lean body mass minus connective tissue, skin, and other organs, and TBW is the summation of intra- and extra-cellular water. [0003] The present inventors demonstrate synergistic effects of an apelin receptor agonist and a satiety-inducing agent that result in improved weight loss compared to a satiety- inducing agent alone. The present inventors discovered that co-administration of an apelin receptor agonist with a satiety-inducing agent can induce or increase total weight loss (e.g., including fat mass loss) but also preserve muscle function and muscle mass (e.g., including lean muscle). The present inventors discovered that the combination therapy can lead to increased total weight loss, reduction of fat mass percentage, increase in lean mass percentage, and/or improvement in body composition (higher lean mass / fat mass ratio) relative to that caused by administration of a pre-determined amount of a satiety-inducing agent alone. [0004] Agonists of the apelin receptor are tested in mouse models of obesity. The apelin receptor agonists tested included BGE-105. BGE-105 has the structure shown below: or a pharmaceutically acceptable salt thereof. [0005] Other apelin receptor agonists tested include, but are not limited to BAL-1480, BMS-986224, apelin-36, apelin-17, apelin-13, [Pyr1] apelin-13, E339-3D6, ML233, ANPA- 0073, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1-(cyclobutylamino)-1-oxo-5- (piperidin-1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3- carboxamide, and metabolically stable analogs thereof. [0006] The satiety-inducing agent tested in combinations with the apelin receptor agonist included rimonabant, which selectively blocks cannabinoid-1 receptors (CB1). [0007] Accordingly, one aspect of the present disclosure is a method for treating a disease or condition associated with weight gain, including co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof, and an effective dose of a satiety-inducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is obese. In some embodiments, the apelin receptor agonist is BGE-105, or a pharmaceutically acceptable salt thereof. [0008] Aspects of this disclosure include a method of increasing total weight loss caused by administration of a pre-determined amount of a satiety-inducing agent to a subject in need thereof. In some embodiments, the method includes co-administering to a subject in need thereof an effective dose of an apelin receptor agonist and an effective dose of a satiety- inducing agent, to increase total weight loss in the subject. The increase in total weight loss in the subject can be relative to weight loss that would be caused by administration of a pre- determined amount of a satiety-inducing agent alone. [0009] The present disclosure also provides a method for inducing weight loss with maintenance of muscle mass and/or muscle strength (e.g., lean muscle mass) in a subject in need thereof (e.g., a subject undergoing weight loss therapy). The method can include co- administering to the subject in need thereof an effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof, and an effective amount of a satiety-inducing agent, or a pharmaceutically acceptable salt thereof to maintain lean muscle mass while inducing fat and weight loss in the subject. [0010] The present disclosure also provides a method of inhibiting weight gain in a human subject having a condition caused or characterized by excess body weight a dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is obese. Various apelin receptor agonists that can be used in the methods of this disclosure are described herein. In some embodiments, the apelin receptor agonist is BGE- 105, or a pharmaceutically acceptable salt thereof. [0011] The present disclosure also provides a method for treating or preventing muscle mass decrease caused by administration of a satiety-inducing agent in a subject in need thereof. The method can include adding an effective dose of an apelin receptor agonist to the satiety-inducing agent treatment regimen of a subject in need thereof to treat or prevent lean muscle mass decrease in the subject after administration of the satiety-inducing agent. [0012] The inventors discovered that co-administering of the apelin receptor agonist in conjunction with a satiety-inducing agent according to the methods of this disclosure can stimulate muscle mass preservation or an increase in muscle mass in the subject. In some embodiments, the subject exhibits loss of fat mass after the co-administration of the apelin receptor agonist, while at the same time maintaining lean muscle mass and/or improving the ratio of lean muscle to fat mass, e.g., relative to baseline values prior to the co-administration. [0013] In some embodiments of the methods, the apelin receptor agonist is of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the apelin receptor agonist is BGE-105, or a pharmaceutically acceptable salt thereof. [0014] In some embodiments of the methods of this disclosure, the subject is an obese human and/or has, or is identified as having, or susceptible to or at risk of having, one or more of: diabetes mellitus, insulin insensitivity, cardiovascular disease, cardiorenal disease, neurologic disease, obesity, is obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, or nighttime hypoglycemia. In some embodiments, the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes. 3. BRIEF DESCRIPTION OF THE DRAWINGS [0015] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where: [0016] FIG. 1 shows a study design to measure the synergistic effect of BGE-105 and a CB1 receptor antagonist rimonabant on weight loss in diet-induced obese mice in Example 1. [0017] FIGs. 2A-2B show measurement of body weight (FIG. 2A) and body weight percent change (FIG. 2B) of DIO mice treatment groups in Example 1. 6.5-7 month old mice fed a high fat diet (HFD) and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) significantly reduced body weight compared to mice fed a HFD and treated with rimonabant at (10 mg/kilogram (mpk)) alone. [0018] FIGs. 3A-3B show daily food consumption (FIG. 3A) and absolute food consumption (FIG. 3B) for the duration of the study. 6.5-7-month old mice that were fed a HFD and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) (Group 5) showed reduced food consumption compared to mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with rimonabant at (10 mg/kilogram (mpk)) alone. [0019] FIG. 4 shows that 6.5-7 month old mice fed a HFD and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) (Group 5) reduced non-fasting blood glucose levels on day 6 and 9. [0020] FIGs. 5A-5B show measurements of fat body mass (FBM) and fat percentage for DIO mice treatment groups in Example 1. 6.5-7 month old mice fed a HFD and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) (Group 5) improved body composition as shown by reduced fat mass percentage (FIG. 5B) compared to mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with rimonabant at (10 mg/kilogram (mpk)) alone. [0021] FIGs. 6A-6B show measurements of lean body mass (LBM) as a percentage of total body weight (BW) of DIO mice of Example 1. 6.5-7 month old mice fed a HFD and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) (Group 5) improved body composition as shown by increased lean mass percentage (FIG. 6B) compared to mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with rimonabant at (10 mg/kilogram (mpk)) alone. [0022] FIG. 7 shows lean/fat ratio in DIO mice treatment groups of Example 1. 6.5-7 month old mice fed a HFD and treated with BGE-105 (1.1 g/L in drug water) in combination with rimonabant at (10 mg/kilogram (mpk)) (Group 5) showed improvement in body composition with better lean/fat ratio compared to mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with rimonabant at (10 mg/kilogram (mpk)) alone. [0023] FIGs. 8A-8B show that the addition of BGE-105 to the calorie restriction (CR) therapy increased the body weight loss significantly (Combo -14.6% vs. CR alone -10.4% on day 44) with overall p value < 0.0001. [0024] FIGs. 9A-9B show that food consumption was calculated as grams of food consumed per gram of body weight per day. Absolute food consumption was expressed as grams of food consumed per mouse per day. There was no significant difference in food consumption or absolute food consumption between calorie restriction alone and calorie restriction/BGE-105 combination treatment. [0025] FIGs. 10A-10B As shown in FIGs. 10A-10B, weight of inguinal fat (FIG. 10A) and gastrocnemius (FIG. 10B) expressed as a percentage of body weight, of DIO mice treated with vehicle, azelaprag (1.1 g/L in drinking water), rimonabant (10mpk, PO, QD), or Azelaprag + rimonabant were measured on day 14 after takedown (n=5/DIO group). Results are expressed as mean ± SEM and analyzed with 1-way ANOVA. The combination of azelaprag + rimonabant decreased % fat mass (FIG. 10A) and increased % muscle mass (FIG. 10B) vs. rimonabant alone. [0026] FIGs. 11A-11B show liver weight (FIG. 11A) and terminal liver enzyme ALT (FIG. 11B) on day 14 of treatment after takedown of DIO mice treated with vehicle, azelaprag (1.1 g/L in drinking water), rimonabant (10 mpk, PO, QD), or azelaprag + rimonabant (n=10/DIO group for blood glucose, n=5/DIO group for liver weight and enzyme). Results are expressed as mean ± SEM and analyzed with 1-way ANOVA. The results show that the combination of azelaprag and rimonabant decreased liver mass, and ALT levels of DIO mice. [0027] FIGs. 12A-12B show that treatment with a combination of BAL-1480 and tirzepatide at various doses reduced body weight and body weight percentage. [0028] FIGs. 13A-13B show food and water consumption of mice in treatment groups of Example 3 following treatment with vehicle, BAL-1480, tirzepatide, or combination with BAL-1480 and tirzepatide groups. [0029] FIG. 14 shows hydration ratio of mice in treatment groups of Example 3 following treatment vehicle, BAL-1480, tirzepatide, or combination with BAL-1480 and tirzepatide groups. [0030] FIGs. 15A-15B show lean mass (g) and lean mass percentage (LBM/BW) of mice in groups treated with vehicle, BAL-1480, tirzepatide, or combination with BAL-1480 and tirzepatide of Example 3. BAL-1480 and tirzepatide treatment combination restored lean mass percentage to lean control level. [0031] FIGs. 16A-16C show fat mass, fat mass percentage and lean/fat ratio in mice treated with vehicle, BAL-1480, tirzepatide, or combination with BAL-1480 and tirzepatide. BAL-1480 and tirzepatide combination treatment restored fat mass (FIG. 16A), fat mass percentage (FIG. 16B), and lean/fat ratio (FIG. 16C) to lean control level. [0032] FIG. 17 shows blood glucose level in mice treatment groups of Example 3. [0033] FIG. 18 shows rectal temperature of treated mice at Day 15 of Example 3. [0034] FIGs. 19A-19P show fatty liver weight and fat tissue weight measurements in tirzepatide treated mice of Example 3. Shown are results of fatty liver (FIG. 19A), fatty liver percentage (FIG. 19B), inguinal fat (FIG. 19C), inguinal fat percentage (FIG. 19D), perigonadal fat (FIG. 19E), perigonadal fat percentage (FIG. 19F), brown fat (FIG. 19G), brown fat percentage (FIG. 19H), tibialis anterior (TA) muscle (FIG. 19I), TA percentage (FIG. 19J), quadricep (quad) muscle (FIG. 19K), quadricep muscle percentage (FIG. 19L), gastrocnemius (gastric) muscle (FIG. 19M), gastrocnemius muscle percentage (FIG. 19N), total muscle (FIG. 19O), and total muscle percentage (FIG. 19P). [0035] FIG. 20 shows that AMG-8123 significantly increased DIO mice weight loss in combination with tirzepatide as assessed by body weight measurements of Example 4. [0036] FIG. 21 shows that AMG-8123 significantly increased DIO mice weight loss in combination with tirzepatide as assessed by percentage body weight changes of Example 4. [0037] FIG. 22 shows that AMG-8123 therapy did not significantly impact the normalized food consumption in mice treated with AMG-8123 of Example 4. 4. DETAILED DESCRIPTION OF THE INVENTION 4.1. Methods of Treating a Condition or Disorder Associated with Weight Gain [0038] The present disclosure provides a method of treating a subject for a condition associated with weight gain, using a combination of an apelin receptor agonist and a satiety- inducing agent. In some embodiments, the method is a method of weight loss in a subject in need thereof. In some embodiments, the method includes co-administering to a subject a therapeutically effective amount of an apelin receptor agonist (e.g., as described herein), and a therapeutically effective amount satiety-inducing agent (e.g., as described herein). [0039] A receptor agonist is a compound that binds to a receptor and elicits a response typical of the natural ligand. A full agonist may be defined as one that elicits a response of the same magnitude as the natural ligand. [0040] The “condition associated with weight gain” (referred to interchangeably herein as an “weight gain-related muscle condition” or “fat gain-related muscle condition”) refers to a disease or condition associated with weight gain in a mammalian subject, such as obesity- associated comorbidities. In some embodiments, weight gain includes fat gain. In some embodiments, weight gain consists of fat gain. [0041] Examples of conditions that can be targeted for treatment according to the methods of this disclosure include, but are not limited to, obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, cardiorenal disease, neurologic disease, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, nighttime hypoglycemia, or a combination of treatments including obesity and sarcopenia, diabetes mellitus and sarcopenia, insulin insensitivity and sarcopenia, cardiovascular disease and sarcopenia, cardiorenal disease and sarcopenia, neurologic disease and sarcopenia, obesity-linked gallbladder disease and sarcopenia, obesity-induced sleep apnea and sarcopenia, diabetes and sarcopenia, excessive appetite and sarcopenia, fatty liver disease and sarcopenia, non-alcoholic fatty liver disease (NASH) and sarcopenia, dyslipidemia and sarcopenia, metabolic syndrome and sarcopenia, insufficient satiety and sarcopenia, hyperinsulinemia and sarcopenia, nighttime hypoglycemia and sarcopenia, obesity and frailty, diabetes mellitus and frailty, insulin insensitivity and frailty, cardiovascular disease and frailty, cardiorenal disease and frailty, neurologic disease and frailty, obesity-linked gallbladder disease and frailty, obesity-induced sleep apnea and frailty, diabetes and frailty, excessive appetite and frailty, fatty liver disease and frailty, non- alcoholic fatty liver disease (NASH) and frailty, dyslipidemia and frailty, metabolic syndrome and frailty, insufficient satiety and frailty, hyperinsulinemia and frailty, or nighttime hypoglycemia and frailty. [0042] In some embodiments, the weight gain associated condition is obesity. In some embodiments, the weight gain associated condition is excessive weight gain. In some embodiments, the weight gain associated condition is diabetes mellitus. In some embodiments, the weight gain associated condition is insulin insensitivity. In some embodiments, the weight gain associated condition is cardiovascular disease. In some embodiments, the weight gain associated condition is neurologic disease. In some embodiments, the condition is obesity-linked gallbladder disease. In some embodiments, the weight gain associated condition is obesity-induced sleep apnea. In some embodiments, the condition is diabetes. In some embodiments, the weight gain associated condition is excessive appetite. In some embodiments, the weight gain associated condition is fatty liver disease. In some embodiments, the weight gain associated condition is non-alcoholic fatty liver disease (NASH). In some embodiments, the weight gain associated condition is dyslipidemia. In some embodiments, the condition is metabolic syndrome. In some embodiments, the condition is insufficient satiety. In some embodiments, the weight gain associated condition is hyperinsulinemia. In some embodiments, the weight gain associated condition is nighttime hypoglycemia. [0043] In another aspect, the present disclosure provides methods of inducing weight loss in a subject while preserving or maintaining muscle mass and/or muscle function, using a combination therapy of apelin receptor agonist and satiety-inducing agent. [0044] Aspects of the present disclosure include methods of using a combination of the apelin receptor agonist and satiety-inducing agent include use as an adjunct to a reduced- calorie diet and/or increased physical activity for chronic weight management in overweight or obese subjects, e.g., adults with an initial body mass index (BMI) of: 30 kg/m² or greater (obesity) or BMI of 27 kg/m² or greater (overweight). In some embodiments, the subject to be treated is overweight and in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease). [0045] Aspects of the present disclosure include methods of using of the apelin receptor agonist in combination with a satiety-inducing agent and/or another drug that reduces caloric intake, as an adjunct to a reduced-calorie diet and/or increased physical activity for chronic weight management in overweight or obese subjects (e.g., adults with an initial body mass index (BMI) of: 30 kg/m² or greater (obesity) or BMI of 27 kg/m² or greater (overweight). In some embodiments, the subject to be treated is overweight and in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease). [0046] A drug that reduces caloric intake is a drug that can regulate appetite to make a subject feel less hungry and/or feel full faster after eating less food, resulting in fewer calories and less food being consumed by the subject. In some embodiments, a drug that reduces caloric intake is an appetite suppressant (e.g., as described herein). In some embodiments, the drug that reduces caloric intake is a cannabinoid receptor 1 (CB1r or CANN6 or CNR1) antagonist (e.g., as described herein). 4.2. Methods of Increasing Weight Loss, or Inducing Weight Loss while Maintaining Muscle Mass or Muscle Strength [0047] The present inventors demonstrated that co-administration of the apelin receptor agonist with the satiety-inducing agent produced more weight loss, e.g., including more fat loss, than would have been expected from administration of satiety-inducing agent alone. Accordingly, aspects of this disclosure include a method of increasing total weight loss caused by administration of a pre-determined amount of a satiety-inducing agent to a subject in need thereof. In some embodiments, the method includes co-administering to a subject in need thereof an effective dose of an apelin receptor agonist and an effective dose of a satiety- inducing agent, to increase total weight loss and/or fat loss in the subject. The increase in total weight loss or fat loss in the subject can be relative to weight loss that would be caused by administration of a pre-determined amount of a satiety-inducing agent alone. [0048] In some embodiments, the method includes adding an effective dose of an apelin receptor agonist to the satiety-inducing agent treatment regimen of a subject in need thereof to increase total weight loss or fat loss caused by administration of a pre-determined amount of a satiety-inducing agent to the subject. [0049] In some embodiments, the increase in total weight loss is an increase of 5% or more over the weight loss that would be caused by, or expected for, administration of a pre- determined amount of a satiety-inducing agent alone to the subject, such as an increase of 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more in total weight loss. [0050] In some embodiments, the increase in fat loss is an increase of 5% or more over the fat loss that would be caused by, or expected for, administration of a pre-determined amount of a satiety-inducing agent alone to the subject, such as an increase of 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more in fat loss. [0051] Aspects of this disclosure include a method for inducing or increasing weight loss while maintaining and/or increasing muscle mass and/or muscle strength in a subject that has a condition or disease associated with weight gain. In some embodiments, the method is for maintenance of lean muscle mass. In some embodiments, the subject is undergoing weight loss therapy. [0052] In various embodiments, an apelin receptor agonist (e.g., as described herein) is administered to the subject to maintain or increase muscle mass (lean muscle) and/or muscle strength in skeletal muscle of the subject. [0053] The muscle mass and/or muscle strength of a subject can be monitored during treatment and compared to a baseline level assessed prior to dosing with the apelin receptor agonist and the satiety-inducing agent. In some embodiments, the muscle mass (e.g., lean muscle) or muscle strength of a subject is at least maintained at or near baseline levels during treatment, e.g., within 10% of baseline levels. In some embodiments, the subject is one who has suffered from declining muscle mass and/or muscle strength over time, and administration of the apelin receptor agonist according to methods of this disclosure reverses and/or ameliorates the decline. [0054] Fat mass levels and lean muscle mass levels in a subject can be assessed prior to administration of either of the compounds (e.g., in a subject naïve to treatment with a satiety- inducing agent). Baseline levels of fat mass and lean muscle mass in the subject can be assessed immediately prior to co-administration. In some embodiments, the subject exhibits loss of fat mass relative to baseline level but not a loss of lean muscle mass relative to baseline level after the co-administration. In some embodiments, the subject exhibits loss of fat mass relative to baseline level, an increase in lean to fat mass ratio, and/or increase in lean mass percentage, relative to baseline level in the subject (e.g., a baseline level in a subject naïve to treatment with a satiety-inducing agent) after the co-administration of the apelin receptor agonist and the satiety-inducing agent. [0055] In some embodiments, a decrease of fat mass (or fat % of body weight BW) relative to baseline level is a decrease of 10% or more, such as a decrease of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. In some embodiments, a decrease of fat % of body weight (BW) relative to baseline level is a decrease of 10% or more, such as a decrease of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. [0056] In some embodiments, the lean mass is maintained at a level that is within 10% of to baseline level, such as within 5% of baseline level. In some embodiments, the increase in lean muscle % of body weight is an increase of 5% or more relative to baseline level, such as an increase of 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. In some embodiments, the increase in lean to fat ratio is an increase of 5% or more relative to baseline level, such as an increase of 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. [0057] Aspects of this disclosure include methods of treating or preventing further muscle mass decrease caused by administration of a satiety-inducing agent to a subject in need thereof. Thus, the method can include adding an effective dose of an apelin receptor agonist to the satiety-inducing agent treatment regimen of a subject in need thereof. In some embodiments, the method treats or prevents lean muscle mass decrease in the subject after administration of the satiety-inducing agent. [0058] Fat mass levels and lean muscle mass levels in a subject undergoing satiety- inducing agent therapy can be assessed prior to administration of the satiety-inducing agent. A decrease in lean muscle mass caused by satiety-inducing agent monotherapy over time can be assessed. Baseline levels of fat mass and lean muscle mass in the subject can be assessed immediately prior to administration of the apelin receptor agonist. Further decreases from baseline in lean muscle mass after administration of the apelin receptor agonist can be at least ameliorated and/or prevented using the methods of this disclosure. In some embodiments, the subject exhibits loss or decrease of fat mass relative to baseline level but not a loss of lean muscle mass relative to baseline level after the co-administration of the apelin receptor agonist. In some embodiments, the subject exhibits more fat mass loss relative to baseline level. In some embodiments, the subject exhibits an increase in lean to fat mass ratio relative to baseline level. In some embodiments, the subject exhibits an increase in lean mass percentage, relative to baseline level in the subject after the co-administration of the apelin receptor agonist. [0059] In some embodiments, the subject exhibits an increased lean mass percentage, or increased lean/fat mass ratio after the co-administration, relative to a baseline level assessed before the co-administration. [0060] In some embodiments, the subject exhibits a normal fed glucose level after the co- administration, e.g., within 20 days or less, such as 12 days or less, or 6 days or less of the co- administration, where baseline fed glucose levels were elevated above normal. A normal blood glucose level can be readily determined by the skilled artisan and can vary depending on, e.g., whether the patient has diabetes. 4.3. Apelin receptor agonists [0061] Apelin is the endogenous peptide ligand for the apelin receptor (also referred to as APJ, or APLNR). The apelin receptor is a member of the rhodopsin-like G protein-coupled receptor (GPCR) family. The apelin/APJ system is distributed in diverse periphery organ tissues and can play various roles in the physiology and pathophysiology of many organs. The apelin/APJ system participates in various cell activities such as proliferation, migration, apoptosis or inflammation. An apelin receptor agonist is any compound capable of promoting or activating the apelin/APJ system directly or indirectly, competitively, or non- competitively. Agonistic activities of a compound toward apelin receptor may be determined by any suitable method in the art. For example, the agonist can be assessed using the natural agonist of apelin receptor (i.e. apelin) and its receptor for promotion of the function of the receptor. [0062] In some embodiments, the apelin receptor agonist is a polypeptide, such as an apelin polypeptide, e.g., one of several active isoforms ranging from 36 to 12 amino acids in length, or a fragment or analog thereof. In some embodiments, the apelin receptor agonist is a polypeptide, such as an apelin polypeptide, e.g., one of several active isoforms which is less than 12 amino acids in length, or a fragment or analog thereof. Exemplary polypeptides that can be apelin receptor agonists include, but are not limited to, apelin-36, apelin-17, apelin-13, [Pyr1] apelin-13, and metabolically stable apelin analogs described in International Publication No. WO2016102648. [0063] In some embodiments, the apelin receptor agonist is a small molecule. The term “small molecule” refers to an organic molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e.g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to 5000 Da, more preferably up to 2000 Da, and most preferably up to 1000 Da. [0064] Exemplary apelin receptor agonists of interest include, but are not limited to, E339-3D6 (see, e.g., Iturrioz et al. (FASEB Journal, Volume24, Issue5, May 2010, Pages 1506-1517), ML233, BMS-986224, ANPA-0073, AMG986, BAL-1480, AMG-8123, and the like. [0065] As further described below, in some embodiments of the methods of this disclosure, the apelin receptor agonist is a compound described in US Patent No. 9,573,936, US 9,868,721, International Publication No. WO2016196771, US 10,011,594, U.S. Patent No. RE49,594 E (a reissue of US 10,100,059) or Narayanan et al. (J. Med. Chem. 2021, 64, 3006−3025), the disclosures of which are herein incorporated by reference in their entirety. [0066] As known by those skilled in the art, certain compounds of this disclosure may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula. [0067] In some embodiments, the apelin receptor agonist is a compound of formula (I) or (II): (I) (II) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R¹ is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R^1a substituents; R^1a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, —O—(C1-C6 alkyl)-OH, —O— (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, — (C═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁- C₆ alkyl)₂, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R² is selected from —H, and C1-C4 alkyl or is absent in the compounds of Formula II; R³ is selected from an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R^1a substituents, a group of formula —(CR^3bR^3c)-Q, a group of formula —NH— (CR^3bR^3c)-Q, a group of formula —(CR^3bR^3c)—C(═O)-Q, a group of formula —(CR^3dR^3e)— (CR^3fR^3g)-Q, a group of formula —(CR^3b═CR^3c)-Q, and a group of formula –(heterocyclyl)- Q, wherein the heterocyclyl of the –(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R^3h substituents; R^1a in each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O— alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, —NH2, —NH(C1- C6 alkyl), and —N(C1-C6 alkyl)2; R^3b and R^3c are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂; R^3d and R^3e are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂; R^3f and R^3g are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R^3h in each instance is independently selected from —F, —Cl, —CN, —C1-C6 alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O— (C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, and oxo; Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C₆-C₁₀ aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 R^Q substituent; R^Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁- C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C₁-C₆ alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo R^Q substituent; R⁴ is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R^4a substituents; R^4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, — C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, — C(═O)NH(C1-C6 alkyl), and —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R⁴ group may be further substituted with 1 oxo substituent; and further wherein: if R⁴ is an unsubstituted or substituted phenyl ring and R³ is a group of formula — (CR^3b═CR^3c)-Q, then at least one of the following is true: a) R⁴ is substituted with at least one —O—(C₁-C₆ alkyl) group; b) Q is not an oxadiazole; c) R^3b is not —H; d) R^3c is not —H; e) R¹ is not a 2-pyridyl group; or f) R⁴ is substituted with two or more —O—(C1-C6 alkyl) groups. [0068] In some embodiments, the apelin receptor agonist is a compound of formula (I) or (II): (I) (II) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R¹ is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R^1a substituents; R^1a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O— (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, — C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S; R² is selected from —H, in the compounds of Formula II; R³ is a group of formula R^3d and R^3e are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O— haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^3f and R^3g are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; Q is a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C₃-C₈ cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 R^Q substituent; R^Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁- C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C1-C6 alkyl), phenyl, or a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo substituent; R⁴ is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R^4a substituents; and R^4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, — C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, — C(═O)NH(C1-C6 alkyl), or —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R⁴ group may be further substituted with 1 oxo substituent. [0069] As noted above, apelin receptor agonist compounds of this disclosure may exist in multiple tautomeric forms. This is particularly true in compounds of Formula I where R² is H. These forms are illustrated below as Tautomer A and Tautomer B: (Tautomer A) (Tautomer B). [0070] Apelin receptor agonist compounds of this disclosure are depicted structurally and generally named as compounds in the “Tautomer A” form. However, it is specifically contemplated and known that the compounds exist in “Tautomer B” form and thus compounds in “Tautomer B” form are expressly considered to be part of this disclosure. For this reason, the claims refer to compounds of Formula I and Formula II. Depending on the compound, some compounds may exist primarily in one form more than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as mixtures at room temperature whereas others may be isolated in one tautomeric form or the other. [0071] In some embodiments of formula (I) and (II), R¹ is an unsubstituted pyridyl or is a pyridyl substituted with 1 or 2 R^1a substituents. [0072] In some embodiments of formula (I) and (II), R^1a in each instance is independently selected from —CH₃, —CH₂CH₃, —F, —Cl, —Br, —CN, —CF₃, —CH═CH₂, — rest of the molecule. [0073] In some embodiments of formula (I) and (II), R¹ is selected from

wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. _{[0074] In some embodiments of formula (I) and (II), R1 is selected from} wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. _{[0075] In some embodiments of formula (I) and (II), R2 is —H.} _{[0076] In some embodiments of formula (I) and (II), R4 is a phenyl, pyridyl, pyrimidinyl,} isoxazolyl, indolyl, naphthyl, or pyridinyl any of which may be unsubstituted or substituted with 1, 2, or 3 R^4a substituents. In some embodiments of formula (I) and (II), R⁴ is a phenyl substituted with 1 or 2 R^4a substituents. In some embodiments of formula (I) and (II), the 1 or 2 R^4a substituents are —O—(C₁-C₂ alkyl) groups. _{[0077] In some embodiments of formula (I) and (II), R4a is in each instance independently} selected from —CH3, —F, —Cl, —Br, —CN, —CF3, —OCH3, —OCHF2, —OCH2CH3, — C(═O)OCH₃, —C(═O)CH₃, or —N(CH₃)₂. [0078] In some embodiments of formula (I) and (II), R⁴ is selected from:

wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. [0079] In some embodiments of formula (I) and (II), R³ is selected from a group of formula —(CR^3bR^3c)-Q, a group of formula —NH—(CR^3bR^3c)-Q, a group of formula — (CR^3bR^3c)—C(═O)-Q, a group of formula —(CR^3dR^3e)—(CR^3fR^3g)-Q, a group of formula — (CR^3b═CR^3c)-Q, or a group of formula –(heterocyclyl)-Q, wherein the heterocyclyl of the – (heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^3h substituents. [0080] In some embodiments of formula (I) and (II), Q is selected from pyrimidinyl, pyridyl, isoxazolyl, thiazolyl, imidazolyl, phenyl, tetrahydropyrimidinonyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, pyrrolidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolyl, or oxetanyl any of which may be unsubstituted or substituted with 1, 2, or 3, R^Q substituents. [0081] In some embodiments of formula (I) and (II), Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S and Q is unsubstituted or is substituted with 1 or 2 R^Q substituents. [0082] In some embodiments of formula (I) and (II), Q is selected from

wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. [0083] In some embodiments of formula (I) and (II), R³ is a group of formula – (heterocyclyl)-Q, wherein the heterocyclyl of the –(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^3h substituents. [0084] In some embodiments of formula (I) and (II), R³ is a group of formula —

[0085] In some embodiments of formula (I) and (II), R³ has one of the formula

wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. [0086] In some embodiments of formula (I) and (II), R³ has one of the formula wherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. [0087] In particular embodiments of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3- yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide; or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide. [0088] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0089] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0090] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0091] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0092] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0093] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0094] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0095] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof. [0096] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propane sulfonamide or the pharmaceutically acceptable salt thereof. [0097] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0098] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0099] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0100] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0101] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0102] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof. [0103] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0104] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0105] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0106] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0107] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0108] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof. [0109] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0110] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol- 3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0111] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0112] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. [0113] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0114] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0115] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0116] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0117] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0118] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0119] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0120] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof. [0121] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0122] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2, 6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0123] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0124] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2, 6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0125] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0126] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0127] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof. [0128] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0129] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0130] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0131] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0132] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0133] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof. [0134] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0135] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol- 3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0136] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0137] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0138] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-difluorophenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0139] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0140] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0141] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- isopropoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. [0142] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof. [0143] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide (BGE-105) or a pharmaceutically acceptable salt thereof. [0144] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (BGE-105) or a pharmaceutically acceptable salt thereof. [0145] U.S. Patents Nos. 9,573,936, 9,868,721, 9,745,286, 9,656,997, 9,751,864, 9,656,998, 9,845,310, 10,058,550, 10,221,162, and 10,344,016, the disclosures of which are incorporated herein by reference in their entirety, describe apelin receptor agonists of formula (I) or (II), and methods of synthesizing such triazole agonists of the apelin receptor, including BGE-105. See e.g., Example 263.0 of U.S. Patent No. 9,573,936. [0146] In some embodiments, the apelin receptor agonist is a compound of Formula (XI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: alk is C_1-6 alkyl substituted with 0-5 R^e; ring A is independently selected from the group consisting of:

ring B is independently selected from the group consisting of: and 6-membered heteroaryl; R¹ is independently selected from the group consisting of: H, halogen, NO₂, — (CH₂)_n—C_3-6 carbocyclyl substituted with 0-3 R^e, and —(CH₂)_n-heterocyclyl substituted with 0-3 R^e; R² is independently selected from the group consisting of: C1-5 alkyl substituted with 0-3 R^e, C1-5 alkenyl substituted with 0-3 R^e, and C1-6 cycloalkyl substituted with 0-3 R^e; provided when R² is C_1-5 alkyl, the carbon atom except the one attached directly to the pyridine ring may be replaced by O, N, and S; R³ is independently selected from the group consisting of: substituted with 0-5 R^e, (9) (CR⁴R⁴)_rC(═O)NR^a(CR⁴R⁴)_nR⁵; R⁴ is independently selected from the group consisting of: H, halogen, NR^aR^a, OC1- 4 alkyl, and C1-4 alkyl; or R⁴ and R⁴ together with the carbon atom to which they are both attached form C_3-6 cycloalkyl substituted with 0-5 R^e; R⁵ is independently selected from the group consisting of: —(CH2)n—C3-10 carbocycle and —(CH2)n-heterocycle, each substituted with 0-3 R⁶; R⁶ is independently selected from: H, halogen, ═O, —(CH₂)_nOR^b, (CH₂)_nS(O)_pR_c, — (CH₂)_nNR^aS(O)_pNR^aR^a, —(CH₂)_nNR^aS(O)_pR^c, C_1-5 alkyl substituted with 0-3 R^e, (CH₂)_n—C_3- 6 carbocyclyl substituted with 0-3 R^e, and —(CH2)n-heterocyclyl substituted with 0-3 R^e; R^a is independently selected from the group consisting of: H, C_1-6 alkyl substituted with 0-5 R^e, C_2-6 alkenyl substituted with 0-5 R^e, C_2-6 alkynyl substituted with 0-5 R^e, — (CH2)n—C3-10carbocyclyl substituted with 0-5 R^e, and —(CH2)n-heterocyclyl substituted with 0-5 R^e; or R^a and R^a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R^e; R^b is independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 R^e, C2-6 alkenyl substituted with 0-5 R^e, C2-6 alkynyl substituted with 0-5 R^e, — (CH₂)_n—C_3-10carbocyclyl substituted with 0-5 R^e, and —(CH₂)_n-heterocyclyl substituted with 0-5 R^e; R^c is independently selected from the group consisting of: C1-6 alkyl substituted with 0-5 R^e, C_2-6alkenyl substituted with 0-5 R^e, C_2-6alkynyl substituted with 0-5 R^e, C_3- 6carbocyclyl, and heterocyclyl; R^d is independently selected from the group consisting of: H and C1-4alkyl substituted with 0-5 R^e; R^e is independently selected from the group consisting of: C_1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, —(CH2)n—C3-6 cycloalkyl, —(CH2)n—C4-6 heterocyclyl, — (CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, CO2H, —(CH2)nORf, S(O)pR^f, R^f is independently selected from the group consisting of: H, F, Cl, Br, CN, OH, C_1- 5alkyl (optimally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl, or R^f and R^f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C_1-4alkyl; n is independently selected from zero, 1, 2, and 3; r is independently selected from zero, 1, 2, and 3; and p is independently selected from zero, 1, and 2. [0147] In some embodiments of the compound of Formula (XI), the compound is of Formula (XV): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R¹ is independently selected from the group consisting of: —CH2OH, —OCH3, — OCF3, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R² is independently selected from the group consisting of: C_1-4 alkyl substituted with 0-3 R^e, C2-4 alkenyl, C1-6 cycloalkyl, and CH2O(CH2)1-3CH3; R³ is independently selected from the group consisting of: (1) —CH₂C(═O)OC_1-4 alkyl substituted with 0-3 R^e, (2) —CH2NR^aR^a, (3) —CH2C(═O)NR^aR^a, (4) —CH₂NHC(═O)C_1-4alkyl substituted with 0-3 R^e, (5) —CH₂NR^aC(═O)(CH₂)_0-2OC_1-4alkyl substituted with 0-3 R^e, (6) —CH2—R⁵, (7) —CH2—OR⁵, (8) —CH₂NR^aC(═O)(CH₂)_0-2R⁵, and the group consisting of: aryl, C3-6 cycloalkyl, and heterocycle, each substituted with 0-3 R⁶; R⁶ is independently selected from the group consisting of: H, F, Cl, Br, —OR^b, ═O, S(O)2NH2, C1-4 alkyl substituted with 0-3 R^e, (CH2)n—C3-6 carbocyclyl substituted with 0-3 R^e, and —(CH₂)_n-heterocyclyl substituted with 0-3 R^e; R^a is independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 R^e, —(CH2)n—C3-10carbocyclyl substituted with 0-5 R^e, and —(CH2)n-heterocyclyl substituted with 0-5 R^e; or R^a and R^a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R^e; R^b is independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 R^e, C_2-6 alkenyl substituted with 0-5 R^e, C_2-6 alkynyl substituted with 0-5 R^e, — (CH₂)_n—C_3-10carbocyclyl substituted with 0-5 R^e, and —(CH₂)_n-heterocyclyl substituted with 0-5 R^e; R^e is independently selected from the group consisting of: C_1-6 alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_n—C_3-6 cycloalkyl, —(CH₂)_n—C_4- 6 heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, and CO2H; and n is independently selected from zero, 1, 2, and 3. _{[0148] In some embodiments, the apelin receptor agonist is a compound having the} structure: or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof [0149] In some embodiments, the apelin receptor agonist is a compound having the structure: or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. [0150] In some embodiments, the apelin receptor agonist is a pyrazole agonist as described in U.S. Patent No. RE49,594 E (a reissue of US 10,100,059) or by Narayanan et al. (J. Med. Chem. 2021, 64, 3006−3025). In some embodiments, the apelin receptor agonist is a compound of Formula (XXI): or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a salt of a prodrug thereof, wherein R₁ is represented by the formula: wherein is a monocyclic aryl or heteroaryl group; each A is independently fluoro substituted C1-C3 alkoxy or fluoro substituted C1- C3 alkyl; n is 1, 2, 3, 4, or 5; R₂ is C_3-8 alkyl, C_1-8 alkyl (C_3-8 cycloalkyl), C_3-8 cycloalkyl, heteroaryl, or substituted R4 is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or R7 and R8 together make a 5-8 nitrogen containing member ring with one or more each y is independently 1-8. [0151] In some embodiments of Formula (XXI), the apelin receptor agonist is a compound of the structure: or a pharmaceutically acceptable salt thereof, wherein R is selected from: ,

[0152] In some embodiments, the apelin receptor agonist is a compound of formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the apelin receptor agonist is (S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-5-(2,6- dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt of the compound. [0153] In some embodiments, the apelin receptor agonist is selected from: BAL-1480, BMS-986224, apelin-36, apelin-17, apelin-13, [Pyr1] apelin-13, E339-3D6, ML233, ANPA- 0073, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3- yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1-(cyclobutylamino)-1-oxo-5- (piperidin-1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3- carboxamide, and metabolically stable analogs thereof. 4.4. Satiety-inducing Agents [0154] The methods of the present disclosure include co-administering of an apelin receptor agonist and a satiety-inducing agent to the subject. [0155] In some embodiments, the method comprises co-administering one or more satiety inducing agents. In some embodiments, the method comprises co-administering a first satiety inducing agent. In some embodiments, the method comprises c-administering a second satiety inducing agent. In some embodiments, the method comprises co-administering one or more, two or more, or three or more satiety inducing agents. [0156] A “satiety-inducing agent” refers to an agent that regulates or induces satiety. As described in Benelam et al., (May 22, 2009, Nutrition Bulletin, Volume 23, issue 2, pages 126-173), satiation and satiety are controlled by a cascade of factors that begin when a food or drink is consumed and continues as it enters the gastrointestinal tract and is digested and absorbed. Signals about the ingestion of energy feed into specific areas of the brain that are involved in the regulation of energy intake, in response to the sensory and cognitive perceptions of the food or drink consumed, and distension of the stomach. These signals are integrated by the brain, and satiation is stimulated. When nutrients reach the intestine and are absorbed, a number of hormonal signals that are again integrated in the brain to induce satiety are released. In addition to these episodic signals, satiety is also affected by fluctuations in hormones, such as leptin and insulin, which indicate the level of fat storage in the body. [0157] In some embodiments, the satiety inducing agent reduces appetite and alters metabolic processes. In some embodiments, the satiety-inducing agent is a compound that regulates appetite, e.g., an appetite suppressant. In some embodiments, the satiety inducing agent is an agent that reduces or regulates caloric intake. In some embodiments, satiety- inducing agents help increase the feeling of fullness (satiety) and/or reduces the desire to overeat. In some embodiments, satiety-inducing agents provide appetite control. [0158] In certain embodiments, the satiety-inducing agent is a Taste receptor type 2 Member (TAS2R) agonist. In certain embodiments, the TAS2R is bittera (ARD-101). [0159] In certain embodiments, the satiety-inducing agent is a gut hormone. In some embodiments, the gut hormone is selected from: GLY-200, a peptide tyrosine tyrosine (PYY) (e.g., Y-242), Calcitonin Receptor (CALCR) Agonist; Islet Amyloid Polypeptide activator, Amylin activator, Diabetes Associated Peptide activator, Insulinoma Amyloid Peptide activator, IAPP activator, Amycretin (NNC-04870111), SCO-267, K-757, Ghrelin-O- acyltransferase inhibitor, AZD-6234, GUB-014295 (GUC-17), leptin receptor agonist (e.g., Mibavademab), eloralintide, NovOB, LY 3457263, REGN4461, LY-3541105, LY3841136, BI-1356225, NN 9838, AZ-12861903, C-2816, CV-08, DACRA-089, I2O-107, JY-54, NN- 9056, petrelintide, TBX-401, and Nisotirostide. [0160] In certain embodiments, the satiety-inducing agent is a neuropeptide Y receptor agonist. In certain embodiments, the neuropeptide Y receptor is selected from: a PYY3-36 receptor agonist and a neuropeptide Y receptor Y2 agonist. In certain embodiments, the neuropeptide Y receptor is selected from: GT-001, JNJ-9321, PYY-1119, CIN-110, and GUB-002496. [0161] In certain embodiments, the satiety-inducing agent is a cannabinoid receptor antagonist. In some embodiments, the satiety-inducing agent is a cannabinoid-1 (CB1) receptor inverse agonist. In some embodiments, the cannabinoid receptor antagonist or CB1 receptor inverse agonist is selected from: monlunabant (INV-202), INV-347, INV-300, INV- 101, NN-9441, NN-9440, nimacimab, DBPR-211, and rimonabant. In some embodiments, the cannabinoid receptor antagonist is a peripheral CB1 blocker. [0162] In some embodiments, the CB2 receptor inverse agonist is selected from AM-251, Taranabant, THCV, JD-5037, MRI-1867, BPR0912, TXX-522, ENP11, and TM-38837. In some embodiments, the satiety inducing agent is a CB1 neutral antagonist. In some embodiments, the CB1 neutral antagonist is selected from: AM-6545, NESS06SM, LH-21, AM-4113, SM-11, PIMSR, cannabidiol, Cannabinoids, DBPR-211, CRB-913, DBPR-211. [0163] In some embodiments, the satiety-inducing agent is selected from: APHD-012 (Distal jejunal-release dextrose beads), NGM-395, CORT118335, TNX-1900, CORT125329, DWP-306001, PF-07976016, XEN-101, 5-Hydroxytryptamine Receptor 1A (5 HT1A) agonist or G21 agonist, Serotonin Receptor 1A agonist, HTR1A Agonist, HTR1A agonist, CMND-100, 5-hydroxytryptamine receptor 2A agonist, 5-Hydroxytryptamine Receptor 2A agonist (e.g., 5 HT2A or Serotonin Receptor 2A or HTR2A), BMND06, Alpha 1,6 Mannosyl Glycoprotein 2 Beta N Acetylglucosaminyltransferase inhibitor (e.g., Beta 1,2 N Acetylglucosaminyltransferase II or Mannoside Acetylglucosaminyltransferase 2 or N Glycosyl Oligosaccharide Glycoprotein N Acetylglucosaminyltransferase II or GlcNAc-T II or MGAT2 or EC 2.4.1.143), S-309309, Alpha Amylase 2B (1,4-Alpha D-Glucan Glucanohydrolase 2B or Carcinoid Alpha Amylase or AMY2B or EC 3.2.1.1) Inhibitor; Gastric Triacylglycerol Lipase (Gastric Lipase or LIPF or EC 3.1.1.3) Inhibitor; Maltase Glucoamylase (Alpha-14-Glucosidase or MGAM or EC 3.2.1.20) Inhibitor; Pancreatic Alpha Amylase (1,4 Alpha D Glucan Glucanohydrolase or AMY2A or EC 3.2.1.1) Inhibitor; Pancreatic Triacylglycerol Lipase (Pancreatic Lipase or Triacylglycerol Acylhydrolase or PNLIP or EC 3.1.1.3) Inhibitor; Sucrase Isomaltase Intestinal (SI or EC 3.2.1.48 or EC 3.2.1.10) Inhibitor, Calcitonin Gene Related Peptide (CGRP) Inhibitor; Oxytocin Receptor (OTR or OXTR) Agonist, Glucocorticoid Receptor (GR or Nuclear Receptor Subfamily 3 Group C Member 1 or NR3C1) Antagonist, Miricorilant (CORT-118335), Zavacorilant, Growth/Differentiation Factor 15 (e.g., Macrophage Inhibitory Cytokine 1 or NSAID Regulated Gene 1 Protein or Placental Bone Morphogenetic Protein or Prostate Differentiation Factor or GDF15) Activator, JNJ-9090, NN-9215 (NNC0247-0829), Interleukin 22 Receptor (IL22R) Agonist, CK-0045, Melanocortin Receptor 4 (MC4R) Agonist, LB-54640, RM-718, NACHT LRR And PYD Domains Containing Protein 3 (e.g., Caterpiller Protein 1.1 or Cold Autoinflammatory Syndrome 1 Protein or Cryopyrin or Nucleotide Binding Oligomerization Domain Leucine Rich Repeat And Pyrin Domain) Inhibitor, VTX-3232, Tyrosine Protein Phosphatase Non Receptor Type 1 (e.g., Protein Tyrosine Phosphatase 1B or Protein Tyrosine Phosphatase Placental or PTP1B or PTPN1 or EC 3.1.3.48) Inhibitor, and ENT-03. [0164] In some embodiments, the satiety-inducing agent is a drug that reduces caloric intake selected from alpha amylase 2B (1,4-Alpha D-Glucan Glucanohydrolase 2B or Carcinoid Alpha Amylase or AMY2B or EC 3.2.1.1) inhibitor; gastric triacylglycerol lipase (Gastric Lipase or LIPF or EC 3.1.1.3) inhibitor; maltase glucoamylase (Alpha-14- Glucosidase or MGAM or EC 3.2.1.20) inhibitor; pancreatic alpha amylase (1,4 Alpha D Glucan Glucanohydrolase or AMY2A or EC 3.2.1.1) inhibitor; pancreatic triacylglycerol lipase (Pancreatic Lipase or Triacylglycerol Acylhydrolase or PNLIP or EC 3.1.1.3) inhibitor; and sucrase isomaltase intestinal (SI or EC 3.2.1.48 or EC 3.2.1.10) inhibitor. In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake selected from TAS2R receptor agonist; bitter taste receptor agonist; Nutrient receptor agonist; Cannabinoid Receptor 1 (CB1 or CANN6 or CNR1) Antagonist; Alpha 1,6 Mannosyl Glycoprotein 2 Beta N Acetylglucosaminyltransferase (Beta 1,2 N Acetylglucosaminyltransferase II or Mannoside Acetylglucosaminyltransferase 2 or N Glycosyl Oligosaccharide Glycoprotein N Acetylglucosaminyltransferase II or GlcNAc-T II or MGAT2 or EC 2.4.1.143) Inhibitor; Glabridin analog, Distal jejunal-release dextrose; and Mucin-complexing polymer. Drugs that reduce caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, EMP-16 ((acarbose + orlistat) MR), APH-012 (e.g., Distal jejunal-release dextrose beads), ARD-101 (Bittera), GLY-200, K-757 + K-833, INV-202, S-309309, BMND-06 (Mescaline), vutiglabridin, AMG-786, Amylin Agonist Long Acting, AZD-6234, CK-0045, ENT-03, ERX-1000, NO1820237, GUB- 014295, CIN-109, Dacra QW II, nimacimab, RAY-1225, XEN-101, ZP-8396, and LY- 3971297. In some embodiments, the additional therapeutic agent is a cannabinoid receptor 1 (CB1r or CANN6 or CNR1) antagonist, such as INV-202, or INV-300. [0165] Obesity related agents, such as satiety-inducing agents, that regulate energy metabolism or caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, CRB-913, DBPR-211, PB-722, (efpeglenatide + HM-15136), ACE- 167, AD-9308, AGEX-BAT1, AvR-2V10, AZ-12861903, AZ-13483342, AZD-3857, BEBT- 809, BF-114, Cannabinoids, CKR-334, CLS-1, CNIO-PI3Ki, CV-08, CYTX-100, Era-107, ETBD-03, FM-801, Fusion Proteins to Activate GDF15 for Obesity, FZ-010, GCG-06, GMA-107, HM-15275, HTD-1804, HUM-234, I2O-107, I2O-120, INHBE (Metabolic Disorders), CIN-110, KSB-10201, KY-19334, LR-19020, LR-19156, LY-3971297, M-43, MLX-0800, MLX-5000, MLX-7000, MNO-863, Monoclonal Antibody to Antagonize FSH Receptor for Obesity and Osteoporosis, MT-106, Myostatin antagonist, NM-136, NN-9056, NOVS-100, NPO-2237, OBE-2001, OLX-75016, orlistat, Peptide (PYY), Peptide to Antagonize MC3R for Obesity, Peptides for Non-Alcoholic Steatohepatitis and Obesity, Peptides to Agonize Oxytocin Receptor for Obesity, Peripheral CB1 Blockers, PF-06645849, PL-8905, PL-9610, psilocybin, PSYLO-3002, PYY-1119, RB-014, Recombinant Protein to Agonize Leptin Receptor for Obesity, Rejuva, REMD-524, REP-003, RES-010, RES-020, RMD-1202, RP-1208, RSVI-301, RSVI-303, RT-210, SAL-0125, Gastrointestinal Hormones, SJT-4a, SJT-7a, sobetirome, SPN-007, SRK-439, TB-592, Tespria, TF-0062, TF- 0103, ThermoStem, TLC-1235, VK-1430, XL-100, YH-34160, YN-103, YN-106, ZP-6590, ZYL-001, ADY-790011, ATC-601, AX-0601, BEBT-509, CBF-520, CYTA-002, DILOC-2, EB-012, ECN-0424, EMB-2, GM-60186, GPR75, GT-002, GUI-37, HLB-1007, HLB-1015, HMC-2073, and ICB-513. [0166] In some embodiments, the satiety-inducing agent is an incretin analog. [0167] Incretins represent a class of hormones that significantly contribute to the regulation of glucose metabolism and energy balance, demonstrating their utility as satiety- inducing agents. Among these, GLP-1 receptor agonists can enhance the feeling of fullness, reduce caloric intake, and facilitate weight management. [0168] In some embodiments, the satiety-inducing agent is a GLP-1 receptor agonist (GLP-1RA). In some embodiments, the satiety-inducing agent is a first satiety inducing agent. In some embodiments, the satiety-inducing agent is a second satiety inducing agent. [0169] In some embodiments, the GLP-1RA is selected from: dulaglutide, exenatide, semaglutide, liraglutide, insulin degludec + liraglutide, insulin glargine + lixisenatide, tirzepatide, cagrilintide [INN] + semaglutide, albenatide [INN],albiglutide, cotadutide, CT- 868, PF 06882961, efocipegtrutide, LY-3502970 (Orforglipron), NLY-001, pegapamodutide, pemvidutide, PF-07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD-01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA-105, HEC-88473, LY-3493269, NN-6177, NN-9847, NNC0519- 0130, PB-1023, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, SCO-094, semaglutide, VK-2735, YH- 25724, YN-012 (Supaglutide), NLY-02, ZP7570 (dapiglutide ), and YN-015. [0170] In some embodiments, the GLP-1RA is administered orally. [0171] In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a small molecule agonist of the GLP-1 receptor. In some embodiments, the GLP-1RA is PF- 07081532. PF-07081532 is an oral small molecule GLP-1 receptor agonist that is being developed for the treatment of Type 2 diabetes and obesity. [0172] In some embodiments, the GLP-1RA is GSBR-1290, and orally delivered small molecule. [0173] In some embodiments, the GLP-1RA is RGT-075. RGT-075 is an orally bioavailable, small-molecule GLP-1 RA. [0174] In some embodiments, the GLP-1RA is orforglipron (LY-3502970). [0175] In some embodiments, the GLP-1 receptor agonist is an orally active non-peptide agonist of glucagon-like peptide-1 (GLP-1) receptor. [0176] In some embodiments, the GLP-1RA is danuglipron (PF 06882961). [0177] In some embodiments, GLP-1RA agents can include, but are not limited to, dapagliflozin + semaglutide, 4P-004, AP-026, BGM-0504, CT-996, DD-01, DR-10624, DR- 10627, dulaglutide, ECC-5004, exenatide, exenatide biobetter, GL-0034, GLP-06, GMA-106, HB-1085, HDM-1002, HL-08, HZ-010, KN-056, liraglutide, MWN-101, NN-6177, NN- 9847, NN-9904, PF-06954522, SAL-0112, SCO-094, TERN-601, ecnoglutide (XW-004), XW003, XW-014, YH-25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), and ZT-002. [0178] In some embodiments, other GLP-1RA agents of interest, e.g., in clinical trials include, but are not limited to, (semaglutide + GIP analogue), AZD-9550, CT-388, CT-868, danuglipron tromethamine, dapiglutide, E-2HSA, efinopegdutide (HM12525A), efocipegtrutide, exenatide SR, froniglutide, GMA-105, GSBR-1290, GXG-6, GZR-18, HEC- 88473, HR-17031, HRS-7535, HRS-9531, HS-20004, HS-20094, JY-09, liraglutide biobetter, maridebart cafraglutide, MBX-1416, MDR-001, NLY-001, NN-9490, NNC0519- 0130, PB-718, pegapamodutide (OPK 88003 / TT401), pemvidutide (ALT-801), semaglutide injection, TTP-273, and VK-2735. [0179] Additional GLP-1RA agents of interest in clinical trials include, but are not limited to: (cagrilintide + semaglutide), retatrutide, (LAI-287 + semaglutide), albenatide, avexitide acetate, Diabegone, ecnoglutide, efpeglenatide LA, GMA-102, liraglutide, mazdutide, NN-6535 (semaglutide), NN-9932 (semaglutide), orforglipron calcium, PB-119, SAL-015, survodutide, Uni-E4, and vurolenatide. [0180] Further GLP-1RA agents of interest include, but are not limited to: (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM- 15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O- 105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND- 017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, and PT-3. [0181] Other GLP-1RA agents of interest include, but are not limited to: HMS-5678 BI- 3034701, DD-02S, DD-15, efpegerglucagon, I2O – 130, I2O-105S, MBX-4291, NA-931, RJVA-001, TERN-800, HZ-012, HS-10501, ZX-2010, ZX-2021, HYBR-014, PG-102, and VCT-220. [0182] In some embodiments, the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide. [0183] In some embodiments, the GLP-1 receptor agonist is semaglutide. [0184] In some embodiments, the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist. [0185] In some embodiments, the GLP-1 receptor agonist is tirzepatide. [0186] In some embodiments, the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist. [0187] In some embodiments, the GLP-1 receptor agonist is retatrutide. [0188] In some embodiments, the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI- 287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn/BMS-686117 adduct, CT-388, CT-868, CT-996, DD-01, DR- 10624, DR-10627, ECC-5004, E-2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA- 102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS- 20004, HS-20094, HB-1085, HDM-1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN- 9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF- 07081532, PF-06882961 (Danuglipron), PB-1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, ecnoglutide (XW-004), XW-003, XW-014, YH-25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), ZT-002, and pharmaceutically acceptable salts thereof. [0189] In some embodiments, the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM- 15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O- 105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND- 017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof. [0190] Other drugs that reduce caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, naltrexone-bupropion, phentermine-topiramate, benzphetamine, diethylpropion, phendimetrazine, phentermine, orlistat, and setmelanotide. 4.5. Additional Therapeutic Agents [0191] The methods of the present disclosure comprise co-administering an effective amount of an apelin receptor agonist and an effective amount of a satiety-inducing agent to the subject. In some embodiments, the methods of the present disclosure further comprise co- administering an effective amount of one or more additional therapeutic agents, i.e., pharmacologically active substances. [0192] In some embodiments, the methods of the present disclosure include administration of an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is amylin. In some embodiments, the additional therapeutic agent is cagrilintide. In some embodiments, the additional therapeutic agent is insulin degludec. In some embodiments, the additional therapeutic agent is insulin glargine. [0193] In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake that is not a GLP-1 receptor agonist. In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake that is a GLP-1 receptor agonist. In some embodiments, the additional therapeutic agent is a second satiety-inducing agent in addition to a first satiety inducing agent described herein. In some embodiments, the GLP-1 receptor agonist is co-administered with a first satiety inducing agent and/or an apelin receptor agonist or apelin peptide. In some embodiments, the GLP-1 receptor agonist is co- administered with a first satiety inducing agent. In some embodiments, the GLP-1 receptor agonist is co-administered with an apelin receptor agonist. In some embodiments, the GLP-1 receptor agonist is co-administered with an apelin receptor agonist and a first satiety inducing agent. [0194] It is understood that the following description, e.g., of isomers, salts, and other forms, etc., can apply to any classes of compounds and drugs within the scope of the specification. [0195] If any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of this disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. [0196] Certain compounds of this disclosure may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention. For example, when R⁴ is a phenyl group and is substituted with two groups bonded to the C atoms adjacent to the point of attachment to the N atom of the triazole, then rotation of the phenyl may be restricted. In some instances, the barrier of rotation is high enough that the different atropisomers may be separated and isolated. [0197] Unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. [0198] Various compounds of this disclosure contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. [0199] Compounds that are related to methods of the present disclosure include, but are not limited to, apelin receptor agonist compounds, satiety-inducing compounds, and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. The term “compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. In some embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C1-C4)alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers. [0200] The term “solvate” refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates. [0201] The compounds of this disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T). [0202] The term “pharmaceutically acceptable salt” refers to a salt that is acceptable for administration to a subject. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The term “salt(s)” as used herein encompass hydrate salt(s). [0203] Other examples of pharmaceutically salts include anions of the compounds of the present disclosure compounded with a suitable cation. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0204] Compounds included in the present compositions and methods that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts. [0205] Compounds included in the present compositions and methods that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. [0206] Furthermore, if the compounds of the present invention or salts thereof form hydrates or solvates, these are also included in the scope of the compounds of the present invention or salts thereof. [0207] Compounds included in the present compositions and methods that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. 4.6. Pharmaceutical Compositions [0208] The pharmaceutical compositions can include the compound(s) or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the compound or the pharmaceutically acceptable salt thereof, according to any one of the embodiments is present in an amount effective for the treatment of a condition or disease (e.g., as described herein). [0209] The apelin receptor agonist compounds and/or satiety-inducing compounds used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration. [0210] The satiety-inducing agents used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration. The pharmaceutical compositions can include the satiety-inducing agents or analogues thereof or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments described herein and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the satiety-inducing agents or analogues thereof or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments is present in an amount effective for the treatment of a condition or disease (e.g., as described herein), for activating the satiety-inducing agents. [0211] Suitable routes of administration for each of the apelin receptor agonists or satiety-inducing agents include, but are not limited to, oral, topical, subcutaneous injection, and intravenous routes of administration. Suitable routes also include pulmonary administration, including by oral inhalation. In some embodiments, the route of administration is subcutaneous injection. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. [0212] In some embodiments, the pharmaceutical composition is formulated for oral delivery whereas in other embodiments, the pharmaceutical composition is formulated for subcutaneous or intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once a day or QD, and in some such formulations is a tablet where the effective amount of the active ingredient ranges from 2 mg to 100 mg, 2 mg to 500 mg, 5 mg to 60 mg, from 6 mg to 58 mg, from 10 mg to 40 mg, from 15 mg to 30 mg, from 16 mg to 25 mg, or from 17 mg to 20 mg. In some such compositions, the amount of active ingredient is 17 mg. [0213] All methods include the step of bringing into association an apelin agonist, or a salt thereof, with the carrier which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [0214] All methods include the step of bringing into association an satiety-inducing agent, or a salt thereof, with the carrier which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [0215] In certain embodiments, the route of administration for use in the methods described herein can be different for the apelin receptor agonist and the satiety-inducing agents or the route of administration for the apelin receptor agonist and the satiety-inducing agents is the same. [0216] In some embodiments, the route of administration for the apelin receptor agonist is parenteral administration. In some embodiments, the route of administration for the apelin receptor agonist is intravenous administration (e.g., intravenous infusion). In some embodiments, the route of administration for the apelin receptor agonist is oral administration. In some embodiments, the route of administration for the apelin receptor agonist is constant intravenous infusion. In some embodiments, the route of administration for the apelin receptor agonist is subcutaneous injection. [0217] In some embodiments, the route of administration for the satiety-inducing agent is parenteral administration. In some embodiments, the route of administration for the satiety- inducing agent is intravenous administration (e.g., intravenous infusion). In some embodiments, the route of administration for the satiety-inducing agent is oral administration. In some embodiments, the route of administration for the satiety-inducing agents is constant intravenous infusion. In some embodiments, the route of administration for the satiety- inducing agent is subcutaneous injection. [0218] Formulations of the present methods suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [0219] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0220] The pharmaceutical composition may comprise one or more pharmaceutical excipients. The term “excipient” broadly refers to any component other than the active therapeutic ingredient(s). The excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance. [0221] Any suitable pharmaceutical excipient may be used, and one of ordinary skills in the art is capable of selecting suitable pharmaceutical excipients. The excipient may serve various purposes, e.g. as a carrier, vehicle, diluent, tablet aid, and/or to improve administration, and/or absorption of the active substance. Non-limiting examples of excipients are: Solvents, diluents, buffers, preservatives, tonicity regulating agents, chelating agents, and stabilizers. [0222] Examples of formulations include liquid formulations, i.e. aqueous formulations comprising water. A liquid formulation may be a solution, or a suspension. An aqueous formulation typically comprises at least 50% w/w water, or at least 60%, 70%, 80%, or even at least 90% w/w of water. [0223] Alternatively, a pharmaceutical composition may be a solid formulation, e.g. a freeze-dried or spray-dried composition, which may be used as is, or whereto the physician or the patient adds solvents, and/or diluents prior to use. [0224] A pharmaceutical composition may comprise a buffer. A pharmaceutical composition may comprise a preservative. A pharmaceutical composition may comprise a chelating agent. A pharmaceutical composition may comprise a stabilizer. A pharmaceutical composition may comprise one or more surfactants. A pharmaceutical composition may comprise one or more protease inhibitors, e.g., when the active compound is a polypeptide. [0225] A composition may be administered in several dosage forms, for example as a solution; a suspension; an emulsion; a microemulsion; multiple emulsions; an injection solution; an infusion solution. [0226] Systemic or parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe, or by means of an infusion pump. 4.7. Combination pharmaceutical products [0227] Aspects of this disclosure include a pharmaceutical composition including a combination of an apelin receptor agonist and a satiety-inducing agent in a single dosage form. In some embodiments, the pharmaceutical composition is formulated for oral administration, where the apelin receptor agonist and the satiety-inducing agent are both suitable for oral administration. In some embodiments, the apelin receptor agonist and the satiety-inducing agent are both small molecule drugs. [0228] In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. [0229] Aspects of this disclosure include kits that include an apelin receptor agonist and a satiety-inducing agent, e.g., each present in a unit dosage form. 4.8. Dosage form [0230] In some embodiments, an apelin receptor agonist or salt thereof is administered in a suspension. In other embodiments, an apelin receptor agonist or salt thereof is administered in a solution. In some embodiments, an apelin receptor agonist or salt thereof is administered in a solid dosage form. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a tablet. In specific embodiments, an apelin receptor agonist is in a crystalline or amorphous form. In some embodiments, an apelin receptor agonist is in amorphous form. In some embodiments, the apelin receptor agonist is an apelin receptor agonist. [0231] In one aspect of the methods, the apelin receptor agonist, or the pharmaceutical composition including same, is administered intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, by intra-articular administration, by intra-mammary administration, by topical administration or by absorption through epithelial or mucocutaneous linings. In certain embodiments, the apelin receptor agonist, or the pharmaceutical composition including same, is administered via intravenous infusion. [0232] In some embodiments, an satiety-inducing agent or salt thereof is administered in a suspension. In other embodiments, an satiety-inducing agent or salt thereof is administered in a solution. In some embodiments, an satiety-inducing agent or salt thereof is administered in a solid dosage form. In particular embodiments, the solid dosage form is a capsule. In particular embodiments, the solid dosage form is a tablet. In specific embodiments, a satiety- inducing agent is in a crystalline or amorphous form. In particular embodiments, a satiety- inducing agent is in amorphous form. [0233] In one aspect of the methods, the satiety-inducing agent, or the pharmaceutical composition including same, is administered intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, by intra-articular administration, by intra-mammary administration, by topical administration or by absorption through epithelial or mucocutaneous linings. In certain embodiments, the satiety-inducing agent, or the pharmaceutical composition including same, is administered via intravenous infusion. In certain embodiments, the satiety-inducing agent, or the pharmaceutical composition including same, is administered via subcutaneous injection. 4.9. Apelin receptor agonist dosing [0234] In various embodiments, the dose of the apelin receptor agonist is at least 0.01 mg/kg, such as at least 0.5 mg/kg, or at least 1 mg/kg. In certain embodiments, the dose is 25 mg/kg to 1,000 mg/kg per day. [0235] In some embodiments, the apelin receptor agonist is administered in a dose that is independent of patient weight or surface area (flat dose). [0236] In various embodiments, the dose is 1-5000 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 200 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 240 mg. In some embodiments, the dose is at least 250 mg. In some embodiments, the dose is at least 260 mg. In some embodiments, the dose is at least 270 mg. In some embodiments, the dose is at least 280 mg. In some embodiments, the dose is at least 290 mg. In some embodiments, the dose is at least 300 mg. In some embodiments, the dose is at least 310 mg. In some embodiments, the dose is at least 320 mg. In some embodiments, the dose is at least 330 mg. In some embodiments, the dose is at least 340 mg. In some embodiments, the dose is at least 350 mg. In some embodiments, the dose is at least 360 mg. In some embodiments, the dose is at least 370 mg. In some embodiments, the dose is at least 380 mg. In some embodiments, the dose is at least 390 mg. In some embodiments, the dose is at least 400 mg. In some embodiments, the dose is at least 500 mg. [0237] The apelin receptor agonist can be administered in a single dose or in multiple doses. [0238] In some embodiments, the dose is administered daily. [0239] In some embodiments, the dose is administered as a plurality of equally or unequally divided sub-doses. [0240] In certain embodiments, the dose is administered continuously (e.g., IV infusion) for a period of time. In certain embodiments, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours). In certain embodiments, following the dose, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a first dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours), followed by a second dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). [0241] In some embodiments, the apelin receptor agonist is administered orally, intravenously, intranasally, or intramuscularly. In some embodiments, the apelin receptor agonist is administered orally. In some embodiments, the apelin receptor agonist is administered via enteral route of administration. In some embodiments, the apelin receptor agonist is administered via PO. In some embodiments, the apelin receptor agonist is administered via PO BID. In some embodiments, the apelin receptor agonist is administered via PO with a dose ranging from 25-2000 mg. In some embodiments, the dose is at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg. [0242] In some embodiments, the apelin receptor agonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the apelin receptor agonist is administered continuously for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 100 hours, at least 110 hours, at least 115 hours, at least 120 hours, or at least 125 hours. 4.10. Satiety-inducing agent dosing [0243] In various embodiments, the dose of a satiety-inducing agent is adjusted according to the patient’s disease condition. [0244] In various embodiments, the dose of the satiety-inducing agent is at least 0.01 mg/kg, such as at least 0.5 mg/kg, or at least 1 mg/kg. In certain embodiments, the dose is 25 mg/kg to 1,000 mg/kg per day. [0245] In some embodiments, the satiety-inducing agent is administered in a dose that is independent of patient weight or surface area (flat dose). [0246] In various embodiments, the dose is 0.01-5000 mg. In various embodiments, the dose is 0.05 -5 mg. In various embodiments, the dose is at least 0.1 mg, at least 0.2 mg, at least 0.25 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.7 mg, at least 0.6 mg, at least 0.75 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, at least 1.2 mg, at least 1.25 mg, at least 1.3 mg, at least 1.4 mg, at least 1.5 mg, at least 1.6 mg, at least 1.75 mg, at least 1.8 mg, at least 1.9 mg, at least 2 mg, at least 2.1 mg, at least 2.2 mg, at least 2.25 mg, at least 2.3 mg, at least 2.4 mg, at least 2.5 mg, at least 2.6 mg, at least 2.75 mg, at least 2.8 mg, at least 2.9 mg, at least 3 mg, at least 3.1 mg, at least 3.2 mg, at least 3.25 mg, at least 3.3 mg, at least 3.4 mg, at least 3.5 mg, at least 3.6 mg, at least 3.75 mg, at least 3.8 mg, at least 3.9 mg, at least 4 mg, at least 4.1 mg, at least 4.2 mg, at least 4.25 mg, at least 4.3 mg, at least 4.4 mg, at least 4.5 mg, at least 4.6 mg, at least 4.75 mg, at least 4.8 mg, 4.9 mg, at least 5 mg, at least 5.25 mg, at least 5.5 mg, at least 5.75 mg, at least 6 mg, at least 6.25 mg, at least 6.5 mg, at least 6.75 mg, at least 7 mg, at least 7.25 mg, at least 7.5 mg, at least 7.75 mg, at least 8 mg, at least 8.25 mg, at least 8.5 mg, at least 8.75 mg, at least 9 mg, at least 9.25 mg, at least 9.5 mg, at least 9.75 mg, or at least 10 mg. In various doses, the dose is at least 10.5 mg, at least 11 mg, at least 11.5 mg, at least 12 mg, at least 12.5 mg, at least 13 mg, at least 13.5 mg, at least 14 mg, at least 14.5 mg, at least 15 mg, at least 15.5 mg, at least 16 mg, at least 16.5 mg, at least 17 mg, at least 17.5 mg, at least 18 mg, at least 18.5 mg, at least 19 mg, at least 19.5 mg, or at least 20 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 200 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 240 mg. In some embodiments, the dose is at least 250 mg. In some embodiments, the dose is at least 260 mg. In some embodiments, the dose is at least 270 mg. In some embodiments, the dose is at least 280 mg. In some embodiments, the dose is at least 290 mg. In some embodiments, the dose is at least 300 mg. In some embodiments, the dose is at least 310 mg. In some embodiments, the dose is at least 320 mg. In some embodiments, the dose is at least 330 mg. In some embodiments, the dose is at least 340 mg. In some embodiments, the dose is at least 350 mg. In some embodiments, the dose is at least 360 mg. In some embodiments, the dose is at least 370 mg. In some embodiments, the dose is at least 380 mg. In some embodiments, the dose is at least 390 mg. In some embodiments, the dose is at least 400 mg. In some embodiments, the dose is at least 500 mg. [0247] In some embodiments, the dose is at least 1 mg/kg, at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg, at least 8 mg/kg, at least 9 mg/kg, at least 10 mg/kg, at least 11 mg/kg, at least 12 mg/kg, at least 13 mg/kg, at least 14 mg/kg, at least 15 mg/kg, at least 16 mg/kg, at least 17 mg/kg, at least 18 mg/kg, at least 19 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 35 mg/kg, at least 40 mg/kg, at least 45 mg/kg, at least 50 mg/kg, at least 55 mg/kg, at least 60 mg/kg, at least 100 mg/kg, at least 120 mg/kg, at least 140 mg/kg, at least 160 mg/kg, at least 180 mg/kg, at least 200 mg/kg, at least 220 mg/kg, at least 240 mg/kg, at least 260 mg/kg, at least 280 mg/kg, at least 300 mg/kg, at least 320 mg/kg, at least 340 mg/kg, at least 360 mg/kg, at least 380 mg/kg, at least 400 mg/kg, at least 420 mg/kg, at least 440 mg/kg, at least 460 mg/kg, at least 480 mg/kg, or at least 500 mg/kg. [0248] In various embodiments, the dose is 0.01-5000 mcg. In various embodiments, the dose is 0.05 -5 mcg. In various embodiments, the dose is at least 0.1 mcg, at least 0.2 mcg, at least 0.25 mcg, at least 0.3 mcg, at least 0.4 mcg, at least 0.5 mcg, at least 0.7 mcg, at least 0.6 mcg, at least 0.75 mcg, at least 0.8 mcg, at least 0.9 mcg, at least 1 mcg, at least 1.2 mcg, at least 1.25 mcg, at least 1.3 mcg, at least 1.4 mcg, at least 1.5 mcg, at least 1.6 mcg, at least 1.75 mcg, at least 1.8 mcg, at least 1.9 mcg, at least 2 mcg, at least 2.1 mcg, at least 2.2 mcg, at least 2.25 mcg, at least 2.3 mcg, at least 2.4 mcg, at least 2.5 mcg, at least 2.6 mcg, at least 2.75 mcg, at least 2.8 mcg, at least 2.9 mcg, at least 3 mcg, at least 3.1 mcg, at least 3.2 mcg, at least 3.25 mcg, at least 3.3 mcg, at least 3.4 mcg, at least 3.5 mcg, at least 3.6 mcg, at least 3.75 mcg, at least 3.8 mcg, at least 3.9 mcg, at least 4 mcg, at least 4.1 mcg, at least 4.2 mcg, at least 4.25 mcg, at least 4.3 mcg, at least 4.4 mcg, at least 4.5 mcg, at least 4.6 mcg, at least 4.75 mcg, at least 4.8 mcg, 4.9 mcg, at least 5 mcg, at least 5.25 mcg, at least 5.5 mcg, at least 5.75 mcg, at least 6 mcg, at least 6.25 mcg, at least 6.5 mcg, at least 6.75 mcg, at least 7 mcg, at least 7.25 mcg, at least 7.5 mcg, at least 7.75 mcg, at least 8 mcg, at least 8.25 mcg, at least 8.5 mcg, at least 8.75 mcg, at least 9 mcg, at least 9.25 mcg, at least 9.5 mcg, at least 9.75 mcg, or at least 10 mcg. In various doses, the dose is at least 10.5 mcg, at least 11 mcg, at least 11.5 mcg, at least 12 mcg, at least 12.5 mcg, at least 13 mcg, at least 13.5 mcg, at least 14 mcg, at least 14.5 mcg, at least 15 mcg, at least 15.5 mcg, at least 16 mcg, at least 16.5 mcg, at least 17 mcg, at least 17.5 mcg, at least 18 mcg, at least 18.5 mcg, at least 19 mcg, at least 19.5 mcg, or at least 20 mcg. In various embodiments, the dose is 25-2000 mcg. In some embodiments, the dose is at least 25 mcg, at least 30 mcg, at least 35 mcg, at least 40 mcg, at least 45 mcg, at least 50 mcg, at least 55 mcg, at least 60 mcg, or at least 100 mcg. [0249] The satiety-inducing agent can be administered in a single dose or in multiple doses. [0250] In some embodiments, the dose is administered daily. In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered twice daily. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered monthly. In some embodiments, the dose is administered every 30 days. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered bimonthly. In some embodiments, the dose is administered once daily. [0251] In some embodiments, the dose is administered as a plurality of equally or unequally divided sub-doses. [0252] In some embodiments, the dose is administered as a single dose in the form of a pen. In some embodiments, the dose is administered at a single dose ranging from 0.5 – 50 mg once weekly. In some embodiments, the dose is administered at a single dose ranging from 0.5 – 500 mg once weekly. In some embodiments, the dose is administered at a single dose ranging from 0.5 – 1000 mg once weekly. In some embodiments, the dose is administered at a single dose ranging from 0.75 – 4.5 mg once weekly. In some embodiments, the dose is administered at a single dose ranging from 0.75 – 20 mg once weekly. [0253] In certain embodiments, the dose is administered continuously (e.g., IV infusion) for a period of time. In certain embodiments, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours). In certain embodiments, following the dose, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a first dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours), followed by a second dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). [0254] In some embodiments, the satiety-inducing agent is administered orally, intravenously, intranasally, or intramuscularly. In some embodiments, the G satiety-inducing agent is administered orally. [0255] In some embodiments, the satiety-inducing agent is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the satiety- inducing agent is administered continuously for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 100 hours, at least 110 hours, at least 115 hours, at least 120 hours, or at least 125 hours. [0256] In some embodiments, the satiety-inducing agent is administered once weekly. In some embodiments, the satiety-inducing agent is administered subcutaneously, once weekly. In some embodiments, the recommended starting dosage of the satiety-inducing agent is 2.5 mg injected subcutaneously once weekly. In some embodiments, after an initial period (e.g., 4 weeks), dosage of the satiety-inducing agent is increased (e.g., in 2.5 mg increments to e.g., 5 mg) injected subcutaneously once weekly. In some embodiments, maintenance dosages of the satiety-inducing agent of 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly can be utilized. Treatment response and tolerability are considered when selecting a maintenance dosage. In some embodiments, the satiety-inducing agent is rimonabant or a pharmaceutically acceptable salt thereof. 4.11. Patients [0257] In some embodiments of the methods of this disclosure, the subject is overweight or obese. In some embodiments, the subject has, is suspected of having, or is at risk of developing a metabolic disease. In some embodiments, the metabolic disease is weight gain or obesity. In some embodiments, the subject has, is suspected of having, or is at risk of developing weight gain. In some embodiments, the subject to be treated is overweight or obese and in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease). [0258] In some embodiments, the subject is obese. In some embodiments, the subject is overweight. In some embodiments, the subject has, is suspected of having, or is at risk of developing a disease or condition associated with obesity. In some embodiments, the subject has a BMI of 25 to <30 kg/m². In some embodiments, the subject has a BMI of 27 to <30 kg/m². In some embodiments, the subject has a BMI of 27 kg/m² or greater, which is overweight. In some embodiments, the subject has a BMI of 30 kg/m² or higher, which is obese. In some embodiments, the subject is Class 1 obese (BMI of 30 to < 35), Class 2 obese (BMI of 35 to < 40), or Class 3 three obese (BMI of 40 or higher). Body Mass Index (BMI) is calculated by: BMI = weight (kg)/ [height (m)]². [0259] In some embodiments, the subject can have, is suspected of having, is at risk of developing, or is diagnosed with diabetes type I, diabetes type II, diabetes type Illa, or a metabolic syndrome. [0260] In some embodiments, the condition caused or characterized by excess body weight is obesity. In some embodiments, the condition caused or characterized by excess body weight is excessive weight gain. In some embodiments, the condition caused or characterized by excess body weight is diabetes mellitus. In some embodiments, the condition caused or characterized by excess body weight is insulin insensitivity. In some embodiments, the condition caused or characterized by excess body weight is cardiovascular disease. In some embodiments, the condition caused or characterized by excess body weight is neurologic disease. In some embodiments, the condition is obesity-linked gallbladder disease. In some embodiments, the condition caused or characterized by excess body weight is obesity-induced sleep apnea. In some embodiments, the condition is diabetes. In some embodiments, the condition caused or characterized by excess body weight is excessive appetite. In some embodiments, the condition caused or characterized by excess body weight is fatty liver disease. In some embodiments, the condition caused or characterized by excess body weight is non-alcoholic fatty liver disease (NASH). In some embodiments, the condition caused or characterized by excess body weight is dyslipidemia. In some embodiments, the condition is metabolic syndrome. In some embodiments, the condition is insufficient satiety. In some embodiments, the condition caused or characterized by excess body weight is hyperinsulinemia. In some embodiments, the condition caused or characterized by excess body weight is nighttime hypoglycemia. [0261] In some embodiments, the patient had previously been treated for a condition caused or characterized by excess body weight. In some embodiments, a pre-determined dose of GLP-1 receptor agonist had previously been and/or is concurrently being administered to the patient. In some embodiments, the patient has previously been and/or is concurrently being treated with a GLP-1 receptor agonist for a condition caused or characterized by excess body weight prior to treatment with the apelin receptor agonist. In some embodiments, the patient has previously been and/or is concurrently being treated with a GLP-1 receptor agonist and an apelin receptor agonist for a condition caused or characterized by excess body weight prior to treatment with the apelin receptor agonist. In some embodiments, the patient is currently being treated with a GLP-1 receptor agonist for a condition caused or characterized by excess body weight prior to treatment with the apelin receptor agonist. [0262] A “GLP-1 receptor agonist” (GLP-1RA) is a compound which is capable of binding to the GLP-1 receptor (GLP-1R) and capable of activating it. In one embodiment the GLP-1 receptor is the human GLP-1 receptor. In some embodiments, the GLP-1RA is also capable of agonizing one or more additional receptors or functions. In some embodiments, the GLP-1RA is also an agonist of GIP receptor. In some embodiments, the GLP-1RA is also an agonist of glucagon receptor. In some embodiments, the GLP-1RA is also an agonist of GIP receptor and glucagon receptor. [0263] In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a polypeptide or polypeptide analog. A GLP-1RA can be an incretin mimetic, or GLP-1 analog. In some embodiments, the GLP-1RA is a fusion protein, or fusion of a protein and peptide. In some embodiments, the GLP-1RA is a recombinant polypeptide. In some embodiments, the GLP- 1RA is a synthetic polypeptide. [0264] In some embodiments, the GLP-1RA is a fusion protein to agonize GLP1R for Type 2 diabetes. [0265] In some embodiments, the GLP-1RA has additional agonist activity at one or more receptors or relevant biological targets. In some embodiments, the GLP-1RA is a dual agonist (also referred to as a twincretin). In some embodiments, the dual agonist is an agonist of GLP-1R and glucose-dependent insulinotropic peptide (GIP) receptor. Tirzepatide is an exemplary dual agonist. [0266] In some embodiments, the GLP-1RA is an agonist of GLP-1R, and GIP receptor and/or glucagon receptor. In some embodiments, the GLP-1RA is an agonist of GLP-1R and glucagon receptor (GL R or GCGR). In some embodiments, the GLP-1RA is an agonist of GLP-1R and GIP receptor. [0267] In some embodiments, the GLP-1RA is a peptide drug for diabetes and/or obesity that agonizes GLP-1 and GCGR. [0268] In some embodiments, the GLP-1RA is a triple agonist (also referred to as a triple G agonist), e.g., an agonist of GLP-1R, GIP receptor and glucagon receptor. Retatrutide (LY3437943) is an exemplary triple G agonist. Other triple G agonists of interest include those described by Knerr et al. (Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice, Mol. Metab. 2022 Sep; 63: 101533). [0269] In some embodiments, the GLP-1RA is selected from: dulaglutide, exenatide, semaglutide, liraglutide, insulin degludec + liraglutide, insulin glargine + lixisenatide, tirzepatide, cagrilintide [INN] + semaglutide, albenatide [INN], cotadutide, CT-868, PF 06882961, efocipegtrutide, LY-3502970 (Orforglipron), NLY-001, pegapamodutide, pemvidutide, PF-07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD-01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA-105, HEC-88473, LY-3493269, NN-6177, NN-9847, NNC0519- 0130, PB-1023, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, SCO-094, semaglutide, VK-2735, YH- 25724, YN-012 (Supaglutide), NLY-02, ZP7570 (dapiglutide ), and YN-015. [0270] In some embodiments, the GLP-1RA is dulaglutide. Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying. [0271] In some embodiments, the GLP-1RA is exenatide. In some embodiments, the GLP-1RA is Byetta. Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1). [0272] In some embodiments, the GLP-1RA is semaglutide. Semaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP- 1) which is typically used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR) and used for the treatment of type 2 diabetes. semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by peptide linkages. It has a role as a hypoglycemic agent, a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a neuroprotective agent and an appetite depressant. It is a polypeptide and a lipopeptide. [0273] In some embodiments, the GLP-1RA is liraglutide. Liraglutide is a lipopeptide that is an analogue of human GLP-1 in which the lysine residue at position 27 is replaced by arginine and a hexadecanoyl group attached to the remaining lysine via a glutamic acid spacer. Liraglutide is typically used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has a role as a glucagon-like peptide-1 receptor agonist and a neuroprotective agent. It is a lipopeptide and a polypeptide. [0274] In some embodiments, the GLP-1RA is liraglutide. In certain embodiments, the method further comprises administering an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is insuline degludec. Insulin degludec is typically used with a proper diet and exercise program to control high blood sugar in people with diabetes. The combination therapy of insulin degludec and liraglutide gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss. [0275] In some embodiments, the GLP-1RA is lixisenatide. In some embodiments, the method further comprises administering GLP-1RA in combination with insulin glargine. In some embodiments, the insulin glargine in combination with lixisenatide is Soliqua 100/33. Insulin glargine and lixisenatide is a combination medicine that is typically used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes. Insulin glargine is a long-acting insulin that starts to work several hours after injection and keeps working evenly for 24 hours. Lixisenatide is a drug that helps the pancreas produce insulin more efficiently. [0276] In some embodiments, the GLP-1RA is tirzepatide. tirzepatide is a dual glucose- dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA). Tirzepatide works by activating both the GLP-1 and GIP receptors in the body. This triggers the release of insulin from the pancreas that blocks glucagon, a hormone that increases blood sugar levels. [0277] In some embodiments, the GLP-1RA is semaglutide. [0278] In some embodiments, the GLP-1RA is albenatide. [0279] In some embodiments, the GLP-1RA is albiglutide. [0280] In some embodiments, the GLP-1RA is cotadutide. Cotadutide (MEDI0382), a dual GLP-1 and glucagon receptor agonist, is currently under development for type 2 diabetes and NASH. [0281] In some embodiments, the GLP-1RA is CT-868. CT-868 is a dual GLP-1 and GIP receptor modulator that is optimized for improved tolerability at the GLP-1 receptor. The combined action of GLP-1 and GIP result in greater body weight loss and glucose control. [0282] In some embodiments, the GLP-1RA is efocipegtrutide. Efocipegtrutide is a glucagon, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors agonist. Efocipegtrutide shares sequence homology with glucagon, glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide, incretin hormone), where the gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) triple full agonist is chemically conjugated with constant region of human immunoglobulin via non-peptidyl flexible linker. [0283] In some embodiments, the GLP-1RA is NLY-001. NLY-001 is a microglia- targeted GLP-1RA. NLY-001 is a pegylated exendin-4 analogue of Glucagon Like Peptide-1 Receptor (GLP-1R) agonist. [0284] In some embodiments, the GLP-1RA is pegapamodutide. [0285] In some embodiments, the GLP-1RA is pemvidutide. Pemvidutide is a peptide- based GLP-1/glucagon dual receptor agonist developed for the treatment of obesity and non- alcoholic steatohepatitis (NASH). Pemvidutide has been shown to substantially decrease the amount of fat within the liver which could have beneficial effects on insulin resistance and cardiorenal risk, common problems in people with obesity. In clinical trials, pemvidutide demonstrated striking reductions in body weight, liver fat, serum lipids and markers of liver inflammation. [0286] In some embodiments, the GLP-1RA is retatrutide. Retatrutide stimulates GIPR, GLP-1, and GLP-1 receptors. [0287] In some embodiments, the GLP-1RA is TTP-273. [0288] In some embodiments, the GLP-1RA is vurolenatide. Vurolenatide is a GLP-1 receptor agonist that is administered via injection. [0289] In some embodiments, the GLP-1RA is GZR-18. GZR-18 is an analog of glucagon-like peptide-1 (GLP-1). In vitro pharmacology and activity of GZR18 were previously characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose- stimulated insulin secretion (GSIS) in primary mice islets. [0290] In some embodiments, the GLP-1RA is mazdutide. Mazdutide (IBI362) is a glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Mazdutide is a long- acting synthetic peptide related to mammalian oxyntomodulin (OXM), which uses a fatty acid side chain to prolong the duration of action and allow once-weekly administration. Mazdutide is thought to exert its biological effects by activating GLP-1 receptor and glucagon receptor in human beings, which is estimated to improve glucose tolerance and induce weight loss, mimicking the effects of endogenous oxyntomodulin. [0291] In some embodiments, the GLP-1RA is PB-119. PB-119 is a pegylated human glucagon-like peptide-1 (GLP-1) receptor agonist. [0292] In some embodiments, the GLP-1RA is AMG-133. AMG 133 is a bispecific glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist and glucagon-like peptide-1 (GLP-1) receptor agonist molecule. AMG 133 mimics the agonist effects of GLP-1 and antagonizes the effects of glucose-dependent insulinotropic polypeptide (GIP). [0293] In some embodiments, the GLP-1RA is dapiglutide. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. It has been shown that dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. [0294] In some embodiments, the GLP-1RA is DD-01. DD-01 is a pegylated, long- acting, peptide based dual agonist of glucagon-like peptide 1 (GLP-1) receptor and glucagon receptor (GCGR). [0295] In some embodiments, the GLP-1RA is DR-10627. [0296] In some embodiments, the GLP-1RA is orally administered. [0297] In some embodiments, the GLP-1RA is ECC-5004. ECC-5004 is an orally administered small-molecule GLP-1 RA. [0298] In some embodiments, the GLP-1RA is exenatide biobetter. [0299] In some embodiments, the GLP-1RA is GL-0034. GL0034 is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been shown to have glucose-lowering effects with increased insulin and C-peptide levels, reduced plasma glucagon levels, long-term reduction in HbA1C, and reduced body weight when tested in type 2 diabetic mice. [0300] In some embodiments, the GLP-1RA is GMA-105. GMA-105 is a humanized anti-GLP-1R monoclonal antibody carrying a GLP-1 fragment. [0301] In some embodiments, the GLP-1RA is HEC-88473. HEC88473 is a GLP- 1/FGF21 dual agonist. [0302] In some embodiments, the GLP-1RA is LY-3493269. LY-3493269 is a GIP/GLP coagonist peptide. [0303] In some embodiments, the GLP-1RA is NN-6177. NN-6177 acts by targeting glucagon receptor (GCGR) and glucagon like peptide 1 receptor (GLP1R). [0304] In some embodiments, the GLP-1RA is NN-9847. [0305] In some embodiments, the GLP-1RA is NNC0519-0130. [0306] In some embodiments, the GLP-1RA is PB-1023. PB-1023 is a recombinant GLP- 1 analogue used to treat sarcopenia-related diseases. [0307] In some embodiments, the GLP-1RA is SCO-094. SCO-094 is a dual agonist for GLP-1R and GIPR. Preclinical studies have shown that SCO-094 is more effective in improving diabetes and obesity than the GLP-1R mono-agonist. [0308] In some embodiments, the GLP-1RA is semaglutide. semaglutide is a GLP-1 agonist and works by increasing insulin release, lowering the amount of glucagon released, delaying gastric emptying and reducing appetite. [0309] In some embodiments, the GLP-1RA is VK-2735. VK-2735 is a dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders such as diabetes, obesity and NASH. [0310] In some embodiments, the GLP-1RA is YH-25724. YH-25724 is a long-acting GLP-1/FGF21 dual agonist that lowers both non-alcoholic fatty liver disease activity score and fibrosis stage in a diet-induced obese mouse model of biopsy-confirmed non-alcoholic steatohepatitis. [0311] In some embodiments, the GLP-1RA is YN-012 (Supaglutide). [0312] In some embodiments, the GLP-1RA is and YN-015. [0313] In some embodiments, the GLP-1RA is ZP7570 (dapiglutide). [0314] In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a small molecule agonist of the GLP-1 receptor. In some embodiments, the GLP-1RA is PF- 07081532. PF-07081532 is an oral small molecule GLP-1 receptor agonist that is being developed for the treatment of Type 2 diabetes and obesity. [0315] In some embodiments, the GLP-1RA is GSBR-1290, and orally delivered small molecule. [0316] In some embodiments, the GLP-1RA is RGT-075. RGT-075 is an orally bioavailable, small-molecule GLP-1 RA. [0317] In some embodiments, the GLP-1RA is orforglipron (LY-3502970). LY-3502970 is an orally active non-peptide agonist of glucagon-like peptide-1 (GLP-1) receptor. See Kawai et al., PNAS November 11, 2020, 117 (47) 29959-29967. In some embodiments, the GLP-1RA is Danuglipron (PF-06882961). [0318] In some embodiments, the GLP-1RA is danuglipron (PF 06882961). Danuglipron activates the canonical G protein signaling activity only in the Glucagon-like peptide-1 (GLP- 1) receptor with Trp33^ECD. Danuglipron has been shown to potentiate glucose-stimulated insulin release and reduces food intake in monkeys. [0319] GLP-1RA agents can include, but are not limited to, dapagliflozin + semaglutide, 4P-004, AP-026, BGM-0504, CT-996, DD-01, DR-10624, DR-10627, dulaglutide, ECC- 5004, exenatide, exenatide biobetter, GL-0034, GLP-06, GMA-106, HB-1085, HDM-1002, HL-08, HZ-010, KN-056, liraglutide, MWN-101, NN-6177, NN-9847, NN-9904, PF- 06954522, SAL-0112, SCO-094, TERN-601, ecnoglutide (XW-004), XW003, XW-014, YH- 25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), and ZT-002. [0320] Other GLP-1RA agents of interest, e.g., in clinical trials include, but are not limited to, (semaglutide + GIP analogue), AZD-9550, CT-388, CT-868, danuglipron tromethamine, dapiglutide, E-2HSA, efinopegdutide (HM12525A), efocipegtrutide, exenatide SR, froniglutide, GMA-105, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR- 17031, HRS-7535, HRS-9531, HS-20004, HS-20094, JY-09, liraglutide biobetter, maridebart cafraglutide, MBX-1416, MDR-001, NLY-001, NN-9490, NNC0519-0130, PB-718, pegapamodutide (OPK 88003 / TT401), pemvidutide (ALT-801), semaglutide injection, TTP-273, and VK-2735. [0321] Additional GLP-1RA agents of interest in clinical trials include, but are not limited to: (cagrilintide + semaglutide), retatrutide, (LAI-287 + semaglutide), albenatide, avexitide acetate, Diabegone, ecnoglutide, efpeglenatide LA, GMA-102, liraglutide, mazdutide, NN-6535 (semaglutide), NN-9932 (semaglutide), orforglipron calcium, PB-119, SAL-015, survodutide, Uni-E4, and vurolenatide. [0322] Further GLP-1RA agents of interest include, but are not limited to: (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM- 15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O- 105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND- 017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, and PT-3. [0323] Other GLP-1RA agents of interest include, but are not limited to: HMS-5678 BI- 3034701, DD-02S, DD-15, efpegerglucagon, I2O – 130, I2O-105S, MBX-4291, NA-931, RJVA-001, TERN-800, HZ-012, HS-10501, ZX-2010, ZX-2021, HYBR-014, PG-102, and VCT-220. [0324] In some embodiments, the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide. [0325] In some embodiments, the GLP-1 receptor agonist is semaglutide. [0326] In some embodiments, the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist. [0327] In some embodiments, the GLP-1 receptor agonist is tirzepatide. [0328] In some embodiments, the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist. [0329] In some embodiments, the GLP-1 receptor agonist is retatrutide. [0330] In some embodiments, the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI- 287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn/BMS-686117 adduct, CT-388, CT-868, CT-996, DD-01, DR- 10624, DR-10627, ECC-5004, E-2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA- 102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS- 20004, HS-20094, HB-1085, HDM-1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN- 9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF- 07081532, PF-06882961 (Danuglipron), PB-1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, ecnoglutide (XW-004), XW-003, XW-014, YH-25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), ZT-002, and pharmaceutically acceptable salts thereof. [0331] In some embodiments, the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM- 15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O- 105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND- 017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof. 4.11.1. Patient Age [0332] In some embodiments of the method of treating a subject for a condition, the subject has, or is suspected of having, a condition associated with weight gain. In some embodiments of the method of inducing weight loss and preserving muscle function, the subject has, or is suspected of having, a condition associated with weight gain. [0333] In some embodiments, the subject is human. The subject can be a human patient suffering from, or a risk of, an age-related muscle condition. In some embodiments, the patient is at least 30-years-old. In some embodiments, the patient is at least 40-years-old. In some embodiments, the patient is at least 50-years-old. In some embodiments, the patient is at least 60-years-old. In some embodiments, the patient is at least 65-years-old. In some embodiments, the patient is at least 70-years-old. In some embodiments, the patient is at least 75-years-old. In some embodiments, the patient is at least 80-years-old. In some embodiments, the patient is at least 85-years-old. In some embodiments, the patient is at least 90-years-old. In certain embodiments, the patient is 40-50 years old, 50-60 years old, 60-70 years old, 70-80 years old, or 80-90 years old. 4.11.2. Assessment of patients [0334] A subject can be being susceptible of having a condition or disease, at risk of having a condition or disease, or having a condition or disease and identified as in need of treatment according to the methods of this disclosure, using a variety of different assessment methods. [0335] In some embodiments, the patient has a BMI of at least 25. In some embodiments, the patient has a BMI of at least 30. In some embodiments, the patient has a BMI of at least 35, at least 40, at least 45, at least 50, at least 55, or at least 60. In some embodiments, the patient has a BMI of at 25 or more. In some embodiments, the patient has a BMI of 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 55 or more, or 60 or more. In some embodiments, a patient with a BMI of 25 or more is considered overweight. In certain embodiments, a patient with a BMI 25 or more is considered obese. In certain embodiments, a patient with a BMI 30 or more is considered obese. [0336] Low muscle mass can be assessed using appendicular lean body mass (ALBM). In some embodiments, low muscle mass is indicated by an ALBM adjusted for body mass index (BMI) of < 0.789 kg for men or < 0.512 kg for women, where ALBM can be measured by dual energy X-ray absorptiometry (DXA) or echoMRI. Additional muscle mass measurements include DEXA, total body potassium (TBK), MRI, total body electrical conductivity (TOBEC), and CT. [0337] Low muscle mass can be assessed by the appendicular skeletal muscle index (ASMI). In some low muscle mass is indicated by an appendicular skeletal muscle index (ASMI) of less than 7.26 kg/m² for men, or less than 5.5 kg/m² for women, said ASMI being defined as appendicular skeletal muscle mass divided by the square of height, said ASMI being measured by dual energy X-ray absorptiometry (DXA). [0338] Low muscle strength can include low grip strength, and be determined using a handgrip strength test. In some embodiments, low grip strength is assessed by measuring the amount of static force that the hand can squeeze around a handgrip dynamometer, e.g., as indicated by a value of less than 30 kg, such as less than 26 kg for men, or less than 20 kg for women, such as less than 16 kg, in the handgrip strength test. [0339] In some embodiments, the human subject has, or is identified as having, low muscle strength. In some embodiments, the human subject has, or is identified as having, low muscle force. In some embodiments of the methods of this disclosure, the subject is human and has, or is identified as having or is at risk of having, one or more of low muscle strength, low muscle force, low muscle mass, low muscle volume. In some embodiments, the muscle is skeletal muscle. In some embodiments, the muscle is the diaphragm, tibialis anterior, tibialis posterior, gastrocnemius, sartorius, quadriceps femoris (rectus femoris, vastus intermedius, vastus lateralis, and vastus medialis), soleus, or extensor digitorum longus. [0340] In some embodiments, the human subject has, is susceptible of having, is at risk of having, low lower limb muscle mass. In some embodiments, the human subject has, or is identified as having, low upper limb muscle mass. In some embodiments, the human subject has, or is identified as having, after undergoing weight loss therapy, low lower limb muscle mass. In some embodiments, the human subject has, or is identified as having, after undergoing weight loss therapy, low upper limb muscle mass. [0341] In some embodiments, the human subject has, is susceptible or having, or is at risk of having, low muscle volume. In some embodiments, the muscle volume is skeletal muscle volume. In some embodiments, the muscle is a skeletal muscle. In some embodiments, the skeletal muscle is a diaphragm. In some embodiments, the muscle is diaphragm, tibialis anterior, tibialis posterior, gastrocnemius, sartorius, vastus intermedius, vastus lateralis, vastus medialis, soleus, or extensor digitorum longus. In some embodiments, the muscle is diaphragm, tibialis anterior, tibialis posterior, sartorius, soleus, or extensor digitorum longus. In some embodiments, the muscle is diaphragm muscle. [0342] In some embodiments, the muscle volume is the muscle volume of one or more upper limb muscles selected from the group consisting of: shoulder abductors, shoulder adductors, elbow flexors, elbow extensors, wrist flexors, and wrist extensors. [0343] In some embodiments, muscle mass is assessed after the dosing. In some embodiments, muscle mass is assessed at least one day after dosing. In some embodiments, the muscle mass is assessed at least one week after dosing. In some embodiments, the muscle mass is assessed at least one month after dosing. [0344] In some embodiments of the methods of this disclosure, the subject is human and has, is identified as having, or is at risk of having, one or more of diabetes mellitus, insulin insensitivity, and cardiovascular disease. [0345] In some embodiments, the patient is diagnosed as obese. In some embodiments, the patient is diagnosed with diabetes mellitus. In some embodiments, the patient is diagnosed with insulin insensitivity. In some embodiments, the patient is diagnosed with cardiovascular disease. In some embodiments, the patient is diagnosed with obesity-linked gallbladder disease. In some embodiments, the patient is diagnosed with is obesity-induced sleep apnea. In some embodiments, the patient is diagnosed with diabetes. In some embodiments, the patient is diagnosed with excessive appetite. In some embodiments, the patient is diagnosed with fatty liver disease. In some embodiments, the patient is diagnosed with non-alcoholic fatty liver disease (NASH). In some embodiments, the patient is diagnosed with dyslipidemia. In some embodiments, the patient is diagnosed with insufficient satiety. In some embodiments, the patient is diagnosed with hyperinsulinemia. In some embodiments, the patient is diagnosed with nighttime hypoglycemia. 4.12. Definitions [0346] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. [0347] The terms “individual,” “host,” and “subject” are used interchangeably, and refer to an animal to be treated, including but not limited to humans and non-human primates; rodents, including rats and mice; bovines; equines; ovines; felines; and canines. “Mammal” means a member or members of any mammalian species. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorpha, etc. may be used for experimental investigations. The term “patient” refers to a human subject. [0348] The term “modulator” refers to a compound or composition that modulates the level of a target, or the activity or function of a target, which may be, but is not limited to, apelin receptor. In some embodiments, the modulator compound can agonize or activate the target, such as apelin receptor. An agonist or activator of a target can increase the level of activity or signaling associated with the target. [0349] The terms “treating,” “treatment,” and grammatical variations thereof are used in the broadest sense understood in the clinical arts. Accordingly, the terms do not require cure or complete remission of disease, and the terms encompass obtaining any clinically desired pharmacologic and/or physiologic effect, including improvement in physiologic measures associated with “normal”, non-pathologic, aging. Unless otherwise specified, “treating” and “treatment” do not encompass prophylaxis. [0350] The phrase “therapeutically effective amount” refers to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to effect treatment of the disease, condition, or disorder. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. [0351] Ranges: throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6, should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. as well as individual number within that range, for example, 1, 2, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. [0352] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive. [0353] Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural. That is, the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [0354] Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within range of normal tolerance in the art, for example within 2 standard deviations of the mean, and is meant to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the stated value. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context. [0355] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0356] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” are used interchangeably and refer to an excipient, diluent, carrier, or adjuvant that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that is acceptable for veterinary use as well as human pharmaceutical use. The phrase “pharmaceutically acceptable excipient” includes both one and more than one such excipient, diluent, carrier, and/or adjuvant. [0357] “Alkyl” refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2- methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises 1 to 20 carbon atoms. In some embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a (C1-C6)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (C1-C4)alkyl. This nomenclature may also be used for alkyl groups with differing numbers of carbon atoms. The term “alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom. For example, a group —O—(C₁-C₆ alkyl)-OH will be recognized as a group where an —O atom is bonded to a C₁-C₆ alkyl group and one of the H atoms bonded to a C atom of the C1-C6 alkyl group is replaced with a bond to the O atom of an —OH group. As another example, a group —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl) will be recognized as a group where an —O atom is bonded to a first C₁-C₆ alkyl group and one of the H atoms bonded to a C atom of the first C1-C6 alkyl group is replaced with a bond to a second O atom that is bonded to a second C1-C6 alkyl group. [0358] “Alkenyl” refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E-form (cis or trans) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2- en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1- yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C2-C6)alkenyl group. [0359] “Alkynyl” refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a —(C2-C6)alkynyl group. [0360] “Alkoxy” refers to a radical —OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as —O—(C1-C6) alkyl or as —O—(C1-C6 alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as —O—(C₁-C₄) alkyl or as —O—(C₁-C₄ alkyl) groups group. [0361] “Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene. Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene. Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C₆-C₁₀ aryl groups. Aryl, however, does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein. [0362] “Carbonyl” refers to the radical —C(O) or —C(═O) group. [0363] “Carboxy” refers to the radical —C(O)OH. [0364] “Cyano” refers to the radical —CN. [0365] “Cycloalkyl” refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, 87astric87idi, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example a cycloalkyl group having 3 to 7 ring members may be referred to as a (C₃-C₇)cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C4-C7)cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C₃-C₁₀)cycloalkyl, a (C₃-C₈)cycloalkyl, a (C₃- C₇)cycloalkyl, a (C₃-C₆)cycloalkyl, or a (C₄-C₇)cycloalkyl group and these may be referred to as C3-C10 cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4- C7 cycloalkyl groups using alternative language. [0366] “Heterocyclyl” refers to a cyclic group that includes at least one saturated or unsaturated, but non-aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include O, S and N and are independently chosen. Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems. Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms. The point of attachment of a bicyclic heterocyclyl group may be at the non- aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6-membered ring. [0367] In some embodiments, a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatoms are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6- tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Substituted heterocyclyl also _{includes ring systems substituted with one or more oxo (═O) or oxide (—O ) substituents,} such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-onyl, 3,4-dihydroisoquinolin-1(2H)-onyl, indolin- onyl, 1H-imidazo[4,5-c]pyridin-2(3H)-onyl, 7H-purin-8(9H)-onyl, imidazolidin-2-onyl, 1H- imidazol-2(3H)-onyl, 1,1-dioxo-1-thiomorpholinyl, and the like. [0368] “Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group. [0369] “Haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). Representative “haloalkyl” groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trichloroethyl, and the like. The term “perhaloalkyl” means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom. For example, the term “perhaloalkyl”, includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1- trifluoro-2-bromo-2-chloroethyl, and the like. [0370] “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2 In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1 Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine. [0371] As described herein, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology. 5. EXAMPLES [0372] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for. [0373] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. 5.1. Example 1: Efficacy Study assessing the synergistic effect of BGE-105 and CB1 inhibitor rimonabant in adult Diet-Induced Obese (DIO) mice Study Objectives: [0374] The objective of this study was to measure the synergistic effect of BGE-105 and a CB1 antagonist, rimonabant, on weight loss in Diet-Induced Obese Mice. Methods: [0375] The study outline is provided in FIG. 1. 6.5-7-month-old male C57BL/6 mice (Jackson Laboratory) were acclimated to a single house cage for two weeks before randomization and treatment. DIO mice were randomized into four groups and subjected to the following regimens for 14 days (n=10 per group): vehicle; azelaprag 1.1 g/L in drinking water; rimonabant at 10 mpk (PO, QD); and rimonabant and azelaprag in combination at the above doses and routes. Mice were 6.5–7 months old at the start of the study, and had received a high-fat diet starting at the age of 6 weeks. Age-matched lean mice were used as controls. Body weight and food intake were measured daily, and body composition was measured three times during the study. [0376] Body weight, non-fasting blood glucose, and body composition were measured for randomization one day before treatment (Day -1). 6.5-7-month-old mice were randomized on the basis of body weight, non-fasting blood glucose, and body composition, into the following study Groups (n=10 per group) as shown in FIG. 1: Group 1: Age-matched lean Control mice + Vehicle (VEH) (5 mM of sucrose, without pH adjustment) Group 2: DIO mice + Vehicle (VEH) (5 mM sucralose, pH 8.5 + 0.1% Tween-80, PO, QD) Group 3: DIO mice + BGE-105 (1.1 g/L in 5 mM sucralose, pH 8.5 + 0.1% tween-80, PO, QD) Group 4: DIO mice + rimonabant (10 milligrams per kilogram (mpk) in 0.1% Tween-80, PO, QD) + 5 mM sucralose, pH 8.5 Group 5: DIO mice + rimonabant (10 milligrams per kilogram in 0.1% Tween-80, PO, QD) + BGE-105 (1.1 g/L in 5 mM sucralose, pH 8.5) [0377] After randomization, 6.5-7 month old mice were given treatment with either vehicle, BGE-105, rimonabant , or BGE-105 + rimonabant . All groups were paired with relative dosing PO vehicle (Groups 2-5) or pH 8.5 drinking water with addition of 5 mM Sucralose (Groups 1-5) to insure water consumption despite possible taste alterations from drug). [0378] Diets: [0379] 6.5-7 month old mice were fed with a lean control diet D12450B (10 kcal% fat) (Group 1) or a diet-induced obesity (DIO) high fat diet (HFD) D12492 (60 kcal% fat) (Groups 2-5) (Research Diets, Inc.) for the duration of the study (mice were sacrificed after day 14 of study). [0380] Treatment: [0381] Mice in Groups 1-5 received VEH or drug water daily starting at Day 0 (D0) for the duration of the study (14 days). [0382] Body weight (FIGs. 2A-2B), food consumption (FIGs. 3A-3B), blood glucose (FIG. 4), and body composition (fat mass (FIGs. 5A-5B), lean mass (FIGs.6A-6B)) were measured during the duration of the study. Results were expressed as mean ± SEM and analyzed using 1 or 2-way ANOVA with with Tukey’s multiple comparisons test. [0383] Harvest: [0384] After treatment and measurement, lean and DIO mice were sacrificed to harvest tissues for further downstream analysis. On the day of necropsy, blood plasma and organ/tissue samples were collected. Tissue samples were weighed and processed for further tests. Terminal cardiac blood samples (Heparin plasma) are obtained. [0385] Tissue: Half of the tissue samples are frozen down for molecular biology analysis and the other half are fixed in 10% neutral buffered formalin (or embedding in OTC) for histological analysis. [0386] Fat: Inguinal fat; perigonadal fat, brown fat; Muscle: quadricep, tibialis anterior, and gastrocnemius were isolated for further testing and analysis. Results: [0387] Body weight: As shown in FIG. 2A, 6.5-7-month-old mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) resulted in reduced body weight (FIG. 2A) similar to the body weight in the lean control group (Group 1). As shown in Table 1 below, on day 14, no statistical significance was shown between the lean control group and the group treated with BGE-105 + rimonabant (Group 5). Table 1: Statistical analysis of Body Weight (g) [0388] Body-weight (BW) % change: As shown in FIG. 2B and Table 2 below, 6.5-7 month old mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) showed a significant difference in body weight % change on day 14 than that of mice fed a HFD and treated with vehicle (Group 2). 6.5-7-month old mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) showed an increased body weight % change compared to mice fed a HFD and treated with rimonabant alone (Group 4). [0389] Thus, the addition of BGE-105 in combination with rimonabant improved weight loss (Group 5) compared to rimonabant alone (Group 4). Table 2: Statistical analysis of body-weight % change [0390] Food Consumption: As shown in FIGs. 3A-3B, food consumption was expressed as gram food per gram body weight per day (FIG. 3A) or absolute food consumption expressed as grams per mouse per day (FIG. 3B). DIO mice fed a HFD and treated with rimonabant (Group 4) or rimonabant + BGE-105 (Group 5) showed a decrease in food consumption and absolute food consumption compared to food consumption and absolute food consumption in mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with BGE-105 alone (Group 3) up until day 11. DIO mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) showed a significant reduction of food consumption as compared to mice treated with rimonabant alone (Group 4). [0391] Therefore, the addition of BGE-105 + rimonabant (Group 5) reduced food consumption compared to rimonabant alone (Group 4). [0392] Table 3: Statistical analysis of Food consumption [0393] Table 4: Statistical analysis of absolute food consumption [0394] Blood Glucose. As shown in FIG. 4, mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) reduced non-fasting blood glucose levels on day 6 and 9. [0395] Fat Mass and fat mass % [0396] As shown in FIGs. 5A-5B, mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) showed a significant decrease in fat mass on Day 13 compared to mice fed a HFD and treated with rimonabant alone (Group 4). Therefore, the synergistic effects of treatment with BGE-105 and rimonabant improved body composition (reduced fat mass % as shown in FIG. 5B) compared to treatment with rimonabant alone (Group 4). Table 5: Statistical analysis of fat mass % [0397] Lean Mass & Lean mass percentage [0398] As shown in FIG. 6A-6B, mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) showed an improvement in body composition on day 13 as a result of increased lean mass percentage compared to mice fed a HFD and treated with vehicle (Group 2) and mice fed a HFD and treated with BGE-105 alone (Group 3). As shown in FIG. 8B, the mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) improved body composition (increased lean mass%) compared to rimonabant alone (Group 4). This was unexpected. Table 6: Statistical analysis of lean mass percentage [0399] Lean/Fat Ratio. As shown in FIG. 7, mice fed a HFD and treated with BGE-105 + rimonabant (Group 5) improved body composition (increased lean/fat ratio) compared to mice fed a HFD and treated with rimonabant alone (Group 4). This was unexpected. Table 7: Statistical analysis of lean/fat Ratio: [0400] In DIO mice, addition of azelaprag to rimonabant significantly increased weight loss relative to rimonabant monotherapy (26.6% vs 16.8% after 14 days, p<0.0001), bringing body weight within the range of lean controls. The combination of azelaprag and rimonabant increased lean mass percentage (70.4% vs. 63.5% in combination vs. monotherapy, p < 0.0001) and decreased fat mass percentage (24.3% vs. 31.6%, p< 0.0001), bringing body composition within the range of lean controls (70.7% lean mass, 25.1% fat mass). [0401] As shown in FIGs. 10A-10B, weight of inguinal fat (FIG. 10A) and gastrocnemius (FIG. 10B) expressed as a percentage of body weight, of DIO mice treated with vehicle, azelaprag (1.1 g/L in drinking water), rimonabant (10mpk, PO, QD), or Azelaprag + rimonabant were measured on day 14 after takedown (n=5/DIO group). Results are expressed as mean ± SEM and analyzed with 1-way ANOVA. The combination of azelaprag + rimonabant decreased % fat mass (FIG. 10A) and increased % muscle mass (FIG. 10B) vs. rimonabant alone. [0402] As shown in FIGs. 11A-11B, liver weight (FIG. 11A) and terminal liver enzyme ALT (FIG. 11B) were measured on day 14 of treatment after takedown of DIO mice treated with vehicle, azelaprag (1.1 g/L in drinking water), rimonabant (10 mpk, PO, QD), or azelaprag + rimonabant (n=10/DIO group for blood glucose, n=5/DIO group for liver weight and enzyme). Results are expressed as mean ± SEM and analyzed with 1-way ANOVA. The results show that the combination of azelaprag and rimonabant decreased liver mass, and ALT levels of DIO mice. [0403] Conclusion: Mice fed a HFD and treated with BGE-105 and rimonabant show synergistic effects of BGE-105 and rimonabant and body composition with increased lean mass to body weight percentage. Addition of azelaprag to rimonabant significantly increased weight loss and improved body composition relative to monotherapy with the CB1 antagonist. The combination of CB1 inhibition and apelin pathway activation results in a synergistic change in metabolic processes. 5.2. Example 2: BGE-105/Calorie Restriction Efficacy in Diet-Induced Obese (DIO) Mice [0404] This study was to evaluate the efficacy of BGE-105 and calorie restriction (CR) therapy in weight loss to mimic whether there would be a synergistic weight loss effect between a satiety-inducing agent and BGE-105 when co-administered. [0405] Male C57BL/6 DIO mice on an average of 7.6 months old were acclimated to a single house cage for two weeks before the experiment. Age-matched lean mice were used as a control. Body weight, morning non-fasted blood glucose, and body composition were measured for randomization. After randomization, mice were given treatment as the following groups: [0406] A. Lean control n=8; [0407] B. DIO+VEH, n=9; [0408] C. DIO+BGE-105 (1.1 g/L), n=8; [0409] D. DIO+Calorie Restriction (CR, 0.038g/gBW/day), n=8 [0410] E. DIO+ Calorie Restriction (CR, 0.038g/gBW/day) + BGE-105 (1.1 g/L), n=8. [0411] All groups were paired with relative dosing pH 8.5 drinking water with addition of 5 mM Sucralose to insure water consumption despite possible taste alterations from the drug. The body weight and food consumption were measured during the entire study. [0412] Body weight: [0413] As shown in FIGs. 8A-8B, the addition of BGE-105 to the calorie restriction therapy increased the body weight loss significantly (Combination -14.6% vs. CR alone - 10.4% on day 44) with overall p value < 0.0001. [0414] Food Consumption: [0415] FIGs. 9A-9B show that food consumption was calculated as grams of food consumed per gram of body weight per day. Absolute food consumption was expressed as grams of food consumed per mouse per day. There was no significant difference in food consumption or absolute food consumption between calorie restriction alone and calorie restriction/BGE-105 combination treatment. [0416] Results: [0417] A continuation of the calorie restriction in combination with BGE-105 showed synergistic weight loss. 5.3. Example 3: Effects of combination of BAL-1480 and tirzepatide in obese mice Study objective [0418] This study aimed to measure the effect of another APJ agonist, BAL-1480, compound 13 as described by Narayanan et al. in J. Med. Chem. 2021, 64, 3006−3025, on weight loss or body composition in Diet-Induced Obese Mice by GLP-1 receptor agonist tirzepatide. Methods [0419] Measurement used and justifications included: body weight, food intake, water intake, non-fasted blood glucose, and body composition by Echo-MRI. [0420] C57BL/6 obese male mice from Jax and housed to 9-months old were fed with a lean control diet D12450B (10 kcal% fat) and a diet-induced obesity (DIO) diet D12492 (60 kcal% fat) (Research Diets, Inc.). [0421] Male DIO mice were acclimated to a single house cage for two weeks. Body weight, morning non-fasted blood glucose, and body composition were measured for randomization. Target DIO weight range at randomization was 51.4-67.5 grams. After randomization, mice were divided into different study groups groups. All groups were paired with relative dosing s.c. vehicle (20 mM citrate buffer at pH 7.0, 4 mL/kg) or drinking water with addition of 5 mM Sucralose (5 mM Sucralose, pH 3) to insure water consumption despite possible taste alterations from drug. [0422] Study groups 0. Lean ctrl, n=7 1. DIO+VEH (vehicle), n=7 2. DIO + BAL-1480 (0.25 g/L in drug water), n=7 3. DIO + BAL-1480 (1 g/L in drug water), n=7 4. DIO + tirzepatide (10 nmol/kg), n=7 5. DIO + tirzepatide (10 nmol/kg) + BAL-1480 (0.25 g/L in drug water), n=7 6. DIO + tirzepatide (10 nmol/kg) + BAL-1480 (1 g/L in drug water), n=7 [0423] Group (0) Lean control included age matched lean mice control (5mM sucralose water + vehicle, s.c., every 3 days); [0424] Group (1) DIO+VEH: diet-induced obese mice were treated with vehicle control (5mM sucralose water, pH 3 + vehicle, s.c., every 3 days); [0425] Group (2) DIO+BAL-1480 (0.25 g/L in drug water) included diet-induced obese mice treated with BAL-1480 at 0.25 g/L; (3) DIO+BAL-1480 (1 g/L in drug water): diet- induced obese mice treated with BAL-1480 at 1 g/L; [0426] Group (4) DIO + tirzepatide (10 nmol/kg) included diet-induced obese mice treated with tirzepatide at 10 nmol/kg, s.c., every 3 days + 5mM sucralose water, pH 3; [0427] Group (5) DIO + tirzepatide (10 nmol/kg) + BAL-1480 (0.25 g/L in drug water) included diet-induced obese mice treated with tirzepatide at 10 nmol/kg in combination with BAL-1480 at 0.25 g/L; [0428] Group (6) DIO+ tirzepatide (10 nmol/kg) + BAL-1480 (1 g/L in drug water) included diet-induced obese mice treated with tirzepatide at 10 nmol/kg in combination with BAL-1480 at 1 g/L. [0429] Tirzepatide (hydrochloride) was purchased from MCE (Cat No. HY-P1731B/CS- 0107005). Mw = 4849.91 Da, 10 nmol/kg = 0.0485 mg/kg, 4 mL/kg, drug concentration: 0.012 mg/mL in s.c. vehicle, every 3 days. [0430] BAL-14800.25 g/L or 1 g/L was prepared in drinking water with 5 mM Sucralose, pH 3. [0431] Body weight, food intake, water intake, body composition and morning non-fasted blood glucose were measured during the entire study. After 20 days of treatment and measurement, mice were sacrificed to harvest tissues for further downstream analysis. On the day of necropsy, blood plasma and organ/tissue samples were collected. Tissue samples were weighed and processed for further tests. Terminal cardiac blood samples (Heparin plasma) were obtained. [0432] Tissue: Half of the tissue samples are frozen down for molecular biology analysis and the other half are fixed in 10% neutral buffered formalin (or embedding in OTC) for histological analysis. [0433] For fat: Inguinal fat, perigonadal fat, and brown fat were harvested and weighed. For muscle: quadricep, tibialis anterior, and gastrocnemius were harvested and weighed. Liver were harvested and weighed. [0434] Data were expressed as mean ± SEM and statistically analyzed by 1-way or 2-way ANOVA Results [0435] Body Weight: BAL-1480, an APJ agonist, showed a dose-dependent effect on weight loss in obese mice. The combination of BAL-1480 and tirzepatide significantly decreased body weight in obese mice compared to tirzepatide alone, and restored body weight to a similar level as lean control mice after two weeks of combination treatment. The effect of the BAL-1480 and tirzepatide combination was independent of BAL-1480 dosage. The results are shown in FIGs. 12A-12B and Tables 8-9. FIGs. 12A-12B show absolute body weight and body weight percentage change in mice treatment groups at Day 18. [0436] Daily Food Consumption: The food consumptions (g/gBW/day) of BAL-1480 and tirzepatide combination groups (DIO+TZP (10 nmol/kg)+BAL-1480 (0.25 g/L); DIO+TZP (10 nmol/kg)+BAL-1480 (1 g/L)) showed significantly less food intake than the tirzepatide monotherapy group by comparing the entire curve up to Day 18. Combination treatment with tirzepatide and BAL-1480 significantly reduced food intake in a dose dependent fashion (p <0.005). The results are shown in FIG. 13A and Table 10. FIG. 13A shows daily food consumptions in mice treatment groups. [0437] Water Consumption: The water consumption in the BAL-1480 groups was significantly lower than the tirzepatide group by comparing the entire curve up to 18 days. The effect of tirzepatide combination with BAL-1480 (DIO+TZP (10 nmol/kg)+BAL-1480 (0.25 g/L); DIO+TZP (10 nmol/kg)+BAL-1480 (1 g/L)) on reducing water consumption is dose independent. The results are shown in FIG. 13B and Table 11. FIG. 13B shows daily water consumption in mice treatment groups. [0438] Hydration Ratio (%): For normal animals, the hydration ratio (Total Water - Free Water) / Lean is typically within a few percent of 80%. All study groups had hydration ratios within the normal range. FIG. 14 shows hydration ratio in treatment groups. [0439] Absolute Lean Mass and Fat Mass: BAL-1480 monotherapy at 1 g/L and both combination groups (DIO+TZP (10 nmol/kg)+BAL-1480 (0.25 g/L); DIO+TZP (10 nmol/kg)+BAL-1480 (1 g/L)) showed significant reduction of absolute fat mass in comparison with monotherapy of tirzepatide, which was more dramatic than the change of absolute lean mass. The effects of tirzepatide and BAL-1480 on lean mass and lean mass percentage are dose independent. FIGs. 15A-15B and Table 12 show absolute lean mass and lean mass percentage. [0440] Lean Mass Percentage: BAL-1480 monotherapy at 1 g/L and both combination groups (i.e., BAL-1480 at 0.25 g/L and Tirzepatide; BAL-1480 at 1 g/L and tirzepatide) showed a significant increase in lean mass percentage compared to Tirzepatide alone. The combination groups were able to restore the lean mass percentage to the similar level of lean control mice. It is noted that the effect of BAL-1480 is dosage independent in the combination groups. The results are shown FIG. 15B and Table 13. [0441] FIG. 16A and Table 14 provide statistical significance values for BAL-1480 monotherapy at 1 g/L and both combination groups, resulting in significant reduction of absolute fat mass in comparison with tirzepatide alone. The effect of BAL-1480 and tirzepatide combinations on reducing absolute fat mass is dose independent of BAL-1480. [0442] Fat Mass Percentage: BAL-1480 monotherapy at 1 g/L and both combination groups showed significant decrease of fat mass percentage in comparison with monotherapy of tirzepatide. The combination groups were able to restore the fat mass percentage to the similar level of lean control mice. The effect of BAL-1480 and tirzepatide combinations on reducing fat mass percentage is dose independent of BAL-1480. The results are shown in FIG. 16B and the Table 15 below. [0443] Lean/Fat Ratio: BAL-1480 monotherapy at 1 g/L and both combination groups showed significant increase of lean/fat ratio in comparison with monotherapy of tirzepatide. The combination groups were able to restore the lean/fat ratio to the similar level of lean control mice. The effect of BAL-1480 and tirzepatide combinations on lean/fat ratio is dose independent of BAL-1480. The results are shown in FIG. 16C and Table 16 below. [0444] Morning non-fasted blood glucose: blood glucose in the BAL-1480 and tirzepatide combination groups were significantly lower than that in the Tirzepatide monotherapy group. The results are shown in FIG. 17 and Table 17. [0445] Rectal Temperature: The rectal temperature was measured in the afternoon on day 15. Monotherapy of BAL-1480 showed a dose-dependent increase of body temperature than the VEH group. The results are shown in FIG. 18. *=p<0.05; **=p<0.01. [0446] Terminal liver, fat and muscle harvest: Half of the mice (n=3/DIO groups) were sacrificed two days after the last dose of tirzepatide to harvest the liver, fat and muscle for further test. BAL-1480 at 1g/L and combination groups reduced the fatty liver weight and fat tissue weights in comparison to tirzepatide monotherapy and dramatically increased the muscle to body weight percentages to the similar level as lean control mice. The results are shown in FIGs. 19A-19P. Quad: quadricep; TA: tibialis anterior; Gastroc: gastrocnemius. Total muscle is the sum of TA, Quad and Gastroc. *=p<0.05; **=p<0.01; ***=p<0.001; [0447] In summary, combination of BAL-1480 and tirzepatide was effective in decreasing body weight, restoring body weight to lean control level, and treating obesity. 5.4. Example 4: Effect of AMG-8123 and tirzepatide in Diet-Induced Obese (DIO) mice treated with BGE-105 [0448] This study evaluated the efficacy of another apelin receptor agonist, AMG-8123, as monotherapy or in combination with tirzepatide, in weight loss on diet-induced obese (DIO) mice as measured by body weight and food consumption. [0449] Study Design: Mice: DIO mice fed with 60 kcal% fat diet, age matched lean control mice fed with 10 kcal% fat diet. Study groups (n=6-7/group): 10.7 months old at treatment start. 0. Lean/VEH 1. DIO/VEH 2. DIO/AMG-8123 (1.1 g/L) 3. DIO/Tirzepatide (10 nmol/kg, s.c., q3d) 4. DIO/AMG-8123/Tirzepatide Drug preparation: s.c. vehicle: 20 mM citrate buffer at pH 7.0, 4 mL/kg. Drug water vehicle: 5 mM Sucralose, pH 8.5 Drug information: Tirzepatide (hydrochloride) was purchased from MCE (Cat No. HY-P1731B/CS- 0107005). Mw = 4849.91, 10 nmol/kg = 0.0485 mg/kg, 4 mL/kg, drug concentration: 0.012 mg/mL in s.c. vehicle, every 3 days AMG-8123: 1.1 g/L in drinking water with 5 mM Sucralose, pH 8.5. [0450] All groups were paired with relative dosing s.c. vehicle or drinking water with addition of 5 mM Sucralose to insure water consumption despite possible taste alterations from drug. [0451] Measurement: body weight, food consumption [0452] Results: [0453] AMG-8123 significantly increased DIO mice weight loss in combination with tirzepatide as measured by body weight (FIG. 20) and % body weight (BW) change (FIG. 21). See tables below: [0454] Table 18. Body Weight: [0455] Table 19. BW % Change: [0456] AMG-8123 did not impact the normalized food consumption. See table below and FIG. 22. Overall, AMG-8123 and tirzepatide combination treatment had a stronger effect in weight loss than tirzepatide alone in DIO mice. Table 20. Food Consumption: [0457] AMG-8123 in combination with tirzepatide significantly increased DIO mice weight loss. Mice treated with AMG-8123 did not impact the normalized food consumption. AMG- 8123 and tirzepatide combination treatment had a stronger effect in weight loss compared to tirzepatide alone in DIO mice. 5.5. Example 5: Study of the effect of BGE-105 in aged Diet-Induced Obese (DIO) mice treated with BGE-105 Study Objectives: [0458] The objective of this study was to measure the effect of BGE-105 monotherapy on weight loss or weight gain prevention in Diet-Induced Obese Mice. Methods: [0459] 4-week old male C57BL/6 mice (Jackson Laboratory) were acclimated to a single house cage for one week. [0460] Baseline blood samples (100 ul) were collected via tail nick. Body weight, rectal temperature, and body composition were measured for randomization from Day 0 (D0) to D1. 5-week old Mice were randomized on the basis of body weight, rectal body temperature, and body composition, into the following study Groups (n=15-16 per group): Group 1: Lean Control mice + Vehicle (VEH) Group 2: DIO mice + vehicle (DIO + VEH) Group 3: DIO mice + BGE-105 (0.55 g/L) Group 4: DIO mice + BGE-105 (1.1 g/L) Group 5: DIO mice + BGE-105 (3.3 g/L) [0461] After randomization, 5-week old mice were given treatment with either vehicle or BGE-105 in drinking water. All groups were paired with relative dosing s.c. vehicle (Groups 1 and 2) or pH 8.5 (Groups 3 and 4) or pH 8.7 (Group 5) drinking water with addition of 5 mM Sucralose to insure water consumption despite possible taste alterations from drug). [0462] Diets: [0463] 5-week old mice were fed with a lean control diet D12450B (10 kcal% fat) (Group 1) or a diet-induced obesity (DIO) high fat diet (HFD) D12492 (60 kcal% fat) (Groups 2-5) (Research Diets, Inc.) starting on Day 8 (D8) for the duration of the study (mice were sacrificed at 30 weeks). [0464] Treatment: [0465] Mice in Groups 1-5 received VEH or drug water daily starting at Day 2 (D2) for the duration of the study. [0466] Body weight, body weight gain, food intake, water intake, and body composition were measured every 2-3 weeks until the mice were 29-weeks old. The rectal temperature (1-2 hours before lights off) was measured every 2-3 weeks until the mice were 18 weeks old. Results were expressed as mean ± SEM and analyzed using 1 or 2-way ANOVA with uncorrected Fisher's LSD test. [0467] Harvest: [0468] After treatment and measurement, 30-month old mice were sacrificed to harvest tissues for further downstream analysis. On the day of necropsy, blood plasma and organ/tissue samples were collected. Tissue samples were weighed and processed for further tests. Terminal cardiac blood samples (Heparin plasma) are obtained. [0469] Tissue: Half of the tissue samples are frozen down for molecular biology analysis and the other half are fixed in 10% neutral buffered formalin (or embedding in OTC) for histological analysis. [0470] Fat: Inguinal fat; Muscle: quadricep, tibialis anterior, and gastrocnemius were isolated and analyzed. Results: [0471] Body weight: 29-week old mice that were fed a HFD and treated with BGE-105 at 3.3 g/L in drug water (Group 5) significantly slowed down body weight gain in the BGE-105 treated mice compared to vehicle control (Group 2). At 29-weeks old, mice that were fed a HFD and treated with BGE-105 at 3.3 g/L (Group 5) had body weight of 52.7 g and mice that were fed a HFD and treated with VEH (Group 2) had body weight of 55.6 g. The body weight difference was 2.9 g. See Table 21 below: [0472] Body weight gain: 29-week old mice that were fed a HFD and treated with 3.3 g/L BGE-105 (Group 5) showed significantly lower body weight gain than that of the mice that were fed a HFD and treated with vehicle (Group 2) (31.7 g vs. 34.75 g, respectively; 3.05 g less in Group 5, P<0.0001). See Table 22 below: [0473] Body weight (BW) % change: 29-week old mice that were fed a HFD and treated with 3.3 g/L of BGE-105 in drug water (Group 5) slowed down body weight gain (17.5% less BW change %) compared to mice treated with vehicle and fed a HFD (Group 2) (BW change% of Group 5 was 154%; BW change% of Group 2 was 171.5%). See Table 23 below: [0474] Food intake: The food intake was expressed as gram food per gram body weight per day or kcal per day per mouse. DIO mice fed a HFD (Groups 2-5) had no significant difference in food intake during the entire study. DIO mice fed a HFD and treated with BGE- 105 at 3.3 g/L had no significant effect on food intake. See Table 24 below: [0475] Rectal temperature: Mice that were fed a HFD and treated with BGE-105 at 3.3 g/L in drug water (Group 5) had overall higher rectal temperature than other HFD groups (Groups 2-4). Temperature measurement was not pursued later due to operator changes. At 13 weeks, the rectal temperature of mice that were fed a HFD and treated with BGE-105 at 3.3 g/L (Group 5) was 0.5°C higher than mice that were fed a HFD and treated with VEH water (Group 2) (38.1°C vs. 37.6 °C, p = 0.0003). See Table 25 below: [0476] Lean mass to body weight percentage: Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose-dependent improvement in body composition as a result of increased lean mass percentage. At 29-weeks old, lean mass percentage of mice that were fed a HFD and treated with BGE-105 at 3.3 g/L (Group 5) was 3.8% higher than mice that were fed a HFD and treated with VEH (Group 2) (58.5% vs. 54.7%, respectively; p<0.0001). See Table 26 below: [0477] Mice that were treated with BGE-105 at 3.3 g/L (Group 5) showed a significant increase in lean mass (% of body weight) compared to mice on a high fat diet (HFD) (p<0.0001). BGE-105 monotherapy thus improved body composition on a HFD. [0478] Fat mass to body weight percentage: Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose-dependent improvement in body composition as shown by decreased fat mass percentage compared to mice that were fed with a HFD and treated with VEH (Group 2). At 29-weeks old, mice that were fed a HFD and treated with BGE-105 at 3.3 g/L (Group 5) had 4.3% less fat mass percentage than mice that were fed a HFD and treated with VEH (Group 2) (37.8% vs. 42.1%, respectively; p<0.0001). Mice that were treated with BGE-105 at 3.3 g/L (Group 5) showed a significant decrease in fat mass (% of body weight) compared to mice on a HFD (p<0.05). See Table 27 below: [0479] Lean/Fat ratio: Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed dose-dependent improvement in body composition at 29-weeks as shown by an increased lean/fat ratio (lean/fat ratio of HFD+BGE-105 (3.3 g/L) (Group 5) is 1.55; lean/fat ratio of HFD+VEH (Group 2) is 1.3). See Table 28 below: [0480] Tissue to body weight percentage: Muscle samples (quadricep, tibialis anterior, gastrocnemius) and inguinal fat tissue were weighed and normalized to body weight. Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose-dependent effect on increasing muscle percentage and reducing inguinal fat percentage as compared to mice that were fed a HFD and treated with VEH (Group 2). [0481] Liver Enzyme and Free fatty acid levels [0482] Treatment of BGE-105 on HFD mice reduced liver enzyme and free fatty acid levels as shown by the reduction of ALT, ALP, AST, and FFA levels compared to mice fed a HFD without BGE-105 treatment. [0483] Conclusion: [0484] Mice that were fed a HFD and treated with BGE-105 at 3.3 g/L in drug water (Group 5) slowed down the body weight gain of C57BL/6 mice as compared with mice that were fed a HFD and treated with vehicle (Group 2). [0485] Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose- dependent improvement in body composition as shown by increased lean mass percentage and decreased fat mass percentage as compared with mice that were fed a HFD and treated with vehicle (Group 2). [0486] Mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose- dependent effect on increasing muscle percentage and reducing inguinal fat percentage as compared with mice that were fed a HFD and treated with vehicle (Group 2). [0487] In HFD-fed mice, Azelaprag 3.3 g/L significantly slowed body weight gain relative to vehicle (+31.7 g vs +34.75 g after 29 weeks; P<0.05). Azelaprag dose-dependently improved body composition, increasing lean mass percentage (58.5% vs. 54.7% in 3.3 g/L vs. vehicle, P<0.05) and decreasing fat mass percentage (37.8% vs. 42.1%, P<0.05). HFD + azelaprag 3.3 g/L mice had higher rectal temperatures than other HFD groups (38.1°C vs. 37.6°C at 13 weeks, P<0.05). Food intake did not differ significantly among HFD groups. [0488] BGE-105 (Azelaprag) monotherapy effectively delayed weight gain, improved body composition, and increased body temperature in DIO mice without affecting food intake. The data herein suggests that apelin pathway activation delays weight gain by regulating homeostatic energy balance and stimulating energy expenditure. The data herein further suggests that administering an apelin receptor agonist such as BGE-105 can be effective in preventing or reducing rebound weight gain. 6. EQUIVALENTS AND INCORPORATION BY REFERENCE [0489] While the various embodiments of the present disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made herein without departing from the spirit and scope of the disclosure. [0490] All references to issued patents and patent applications (see, e.g., U.S. Patent Application Nos. 63/654,827, 63/657,076, 63/667,108, 63/706,557, 63/742,410, 63/744,164, 63/654,771, 63/667,052, 63/705,017, 63/709,404, 63/742,411, 63/744,163, 63/654,854, 63/667,116, 63/712,346, and PCT Application No. PCT/US/2025/023529) as well as non- patent documents cited within the body of the instant specification are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS: 1. A method of inducing weight loss in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: a dose of an apelin receptor agonist; and a dose of a satiety-inducing agent, that is effective to induce fat and weight loss in the subject.

2. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: a dose of an apelin receptor agonist; and a dose of a satiety-inducing agent, that is effective to maintain lean muscle mass while inducing fat and weight loss in the subject.

3. A method of increasing total weight loss caused by administration of a pre-determined amount of a satiety-inducing agent to a subject in need thereof, the method comprising: co-administering to a subject in need thereof: a dose of an apelin receptor agonist; and a dose of satiety-inducing agent, that is effective to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of satiety-inducing agent alone.

4. A method of increasing total weight loss caused by administration of a pre-determined amount of a satiety-inducing agent to a subject in need thereof, the method comprising: co-administering to a subject in need thereof: a dose of an apelin receptor agonist; and a dose of satiety-inducing agent, that is effective to increase total weight loss in the subject caused by synergistic effects of co- administering the pre-determined amount of satiety-inducing agent and the apelin receptor agonist relative to weight loss caused by administration of the pre-determined amount of satiety-inducing agent alone.

5. A method of inhibiting weight gain in a subject having a condition caused or characterized by excess body weight, the method comprising: co-administering to a subject in need thereof: a dose of an apelin receptor agonist, and a dose of a satiety-inducing agent, that is effective to inhibit weight gain in the subject.

6. A method of preventing or reducing rebound weight gain in a subject who has previously lost weight, the method comprising: co-administering to a subject in need thereof a dose of: a dose of an apelin receptor agonist, and a dose of a satiety-inducing agent, that is effective to prevent or reduce rebound weight gain in the subject.

7. A method of treating or preventing muscle mass decrease caused by administration of a satiety-inducing agent or a calorie-restricted diet, to a subject in need thereof, the method comprising: adding a dose of an apelin receptor agonist to the satiety-inducing agent treatment regimen of a subject in need thereof, that is effective to treat or prevent further lean muscle mass decrease in the subject.

8. The method of any one of claims 1-7, wherein the subject had previously been, and/or is concurrently being, treated for a condition caused or characterized by excess body weight.

9. The method of claim 8, wherein a pre-determined dose of a GLP-1 receptor agonist had previously been, and/or or is concurrently being, administered to the subject.

10. The method of claim 8, wherein the subject has previously been treated with a GLP-1 receptor agonist for a condition caused or characterized by excess body weight prior to treatment with the apelin receptor agonist.

11. The method of any one of claims 1 to 10, wherein the subject regulates or reduces food intake during the administering.

12. The method of any one of claims 1 to 11, wherein the co-administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level.

13. The method of any one of claims 1 to 12, wherein the co-administering regulates gut motility and energy metabolism in the subject relative to a baseline level.

14. The method of any one of claims 1 to 13, wherein the subject exhibits, after the administration: reduction in weight loss; loss of fat but not lean muscle; decreased fat mass percentage; increased lean mass percentage; increased muscle percentage; reduced lipid accumulation; increased fat oxidation; increased insulin sensitivity; decrease in waist circumference; increase in percent appendicular lean mass; increase glucose utilization, relative to a baseline level immediately before administration; increased lean/fat mass ratio; and/or reduced or normal fed (e.g., non-fasting) glucose level, relative to a baseline level immediately before co-administration.

15. The method of any one of claims 1 to 14, wherein the subject exhibits, after the co- administration, decreased inguinal fat percentage in the subject relative to a baseline level immediately before administration.

16. The method of any one of claims 1 to 15, wherein the co-administering prevents rebound weight gain in the subject.

17. The method of claim 16, wherein the subject had previously lost weight from a baseline level (e.g., overweight or obese level) caused by administration of a GLP-1 receptor agonist therapy and the co-administering prevents weight gain to the baseline level in the subject.

18. The method of any one of claims 1 to 17, wherein the subject is overweight.

19. The method of any one of claims 1 to 18, wherein the subject is obese.

20. The method of any one of claims 1 to 19, wherein the subject has a disease or condition associated with weight gain.

21. The method of any one of claim 20, wherein the disease or condition associated with weight gain is selected from obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, nighttime hypoglycemia, and heart failure with preserved ejection fraction (HFpEF).

22. The method of any one of claims 1 to 21, wherein the subject has, or is at risk of developing a metabolic disorder or dysmetabolic disorder.

23. The method of claim 22, wherein the subject has, or is at risk of developing diabetic obesity.

24. The method of claim 22 or 23, wherein the subject has, or is at risk of developing type 1 diabetes, type 2 diabetes, or gestational diabetes.

25. The method of any one of claims 1 to 24, wherein the subject has, or is at risk of developing one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease.

26. The method of any one of claims 1 to 25, wherein the apelin receptor agonist is selected from BAL-1480, BMS-986224, apelin-36, apelin-17, apelin-13, [Pyr1] apelin-13, E339-3D6, ML233, ANPA-0073, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3- pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1- (cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1- cyclopentyl-1H-pyrazole-3-carboxamide, and metabolically stable analogs thereof.

27. The method of any one of claims 1 to 26, wherein the apelin receptor agonist is a compound of the structure: or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 1 to 27, wherein the apelin receptor agonist is of formula (I) or (II): or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R¹ is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R^1a substituents; R^1a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁- C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O— (C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, — (C═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R² is selected from —H, and C1-C4 alkyl or is absent in the compounds of Formula II; R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^1a substituents, a group of formula —(CR^3bR^3c)-Q, a group of formula —NH— (CR^3bR^3c)-Q, a group of formula —(CR^3bR^3c)—C(═O)-Q, a group of formula —(CR^3dR^3e)— (CR^3fR^3g)-Q, a group of formula —(CR^3b═CR^3c)-Q, and a group of formula -(heterocyclyl)- Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R^3h substituents; R^1a in each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, —NH2, —NH(C1- C6 alkyl), and —N(C1-C6 alkyl)2; R^3b and R^3c are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂; R^3d and R^3e are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)₂; R^3f and R^3g are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R^3h in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O— (C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, and oxo; Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C₆-C₁₀ aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 R^Q substituent; R^Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁- C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1- C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C₁-C₆ alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo R^Q substituent; R⁴ is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R^4a substituents; R^4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, — C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, — C(═O)NH(C1-C6 alkyl), and —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R⁴ group may be further substituted with 1 oxo substituent; and further wherein: if R⁴ is an unsubstituted or substituted phenyl ring and R³ is a group of formula — (CR^3b═CR^3c)-Q, then at least one of the following is true: a) R⁴ is substituted with at least one —O—(C₁-C₆ alkyl) group; b) Q is not an oxadiazole; c) R^3b is not —H; d) R^3c is not —H; e) R¹ is not a 2-pyridyl group; or f) R⁴ is substituted with two or more —O—(C1-C6 alkyl) groups.

29. The method of any one of claims 1 to 28, wherein the apelin receptor agonist is of Formula (XXI): or a pharmaceutically acceptable salt thereof, wherein R1 is represented by the formula: wherein is a monocyclic aryl or heteroaryl group; CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)x SO2NR7R8; or R₄ and R₅ together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R4 and R5 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; wherein the group R₄ is substituted with one or more fluorine atoms; R6 is H; R7 and R8 each are independently H, C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1- ₈ alkyl amino, C_1-8 alkyl amido, C_1-8 alkyl(aryl), C_1-8 alkyl (C_3-8 cycloalkyl), C_1-8 alkyl tetrazol- 5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C1- 8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl; or R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or R₇ and R₈ together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and each y is independently 1-8.

30. The method of any one of claims 1 to 29, wherein the apelin receptor agonist is a compound of the structure (BAL-1480) or a pharmaceutically acceptable salt thereof.

31. The method of any one of claims 1 to 30, wherein the apelin receptor agonist is a compound of Formula (XV): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R¹ is independently selected from the group consisting of: —CH2OH, —OCH3, — OCF3, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R² is independently selected from the group consisting of: C_1-4 alkyl substituted with 0-3 R^e, C_2-4 alkenyl, C_1-6 cycloalkyl, and CH₂O(CH₂)_1-3CH₃; R³ is independently selected from the group consisting of: (1) —CH₂C(═O)OC_1-4 alkyl substituted with 0-3 R^e, (2) —CH₂NR^aR^a, (3) —CH2C(═O)NR^aR^a, (4) —CH₂NHC(═O)C_1-4alkyl substituted with 0-3 R^e, substituted with 0-3 R^e, R⁵ is independently selected from the group consisting of: aryl, C3-6 cycloalkyl, and heterocycle, each substituted with 0-3 R⁶; R⁶ is independently selected from the group consisting of: H, F, Cl, Br, —OR^b, ═O, —S(O)₂NH₂, C_1-4 alkyl substituted with 0-3 R^e, (CH₂)_n—C_3-6 carbocyclyl substituted with 0-3 R^e, and —(CH₂)_n-heterocyclyl substituted with 0-3 R^e; R^a is independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 R^e, —(CH₂)_n—C_3-10carbocyclyl substituted with 0-5 R^e, and —(CH₂)_n- heterocyclyl substituted with 0-5 R^e; or R^a and R^a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R^e; R^b is independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 R^e, C_2-6 alkenyl substituted with 0-5 R^e, C_2-6 alkynyl substituted with 0-5 R^e, —(CH2)n—C3-10carbocyclyl substituted with 0-5 R^e, and —(CH2)n-heterocyclyl substituted with 0-5 R^e; R^e is independently selected from the group consisting of: C_1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, —(CH2)n—C3-6 cycloalkyl, —(CH2)n— C4-6 heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, and CO₂H; and n is independently selected from zero, 1, 2, and 3. _{32. The method of any one of claims 1 to 31, wherein the apelin receptor agonist is a} compound having one of the following structures:

or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 1 to 32, wherein the apelin receptor agonist is a _{compound of formula:} or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the apelin receptor agonist is (1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide, or a pharmaceutically acceptable salt thereof, such as a hydrocholoride salt of the compound.

35. The method of any one of claims 1 to 34, wherein the apelin receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly.

36. The method of any one of claims 1 to 35, wherein the apelin receptor agonist is administered daily.

37. The method of any one of claims 1-36, wherein the satiety-inducing agent is a cannabinoid receptor antagonist.

38. The method of claim 37, wherein the cannabinoid receptor antagonist is a CB1 receptor antagonist.

39. The method of claim 38, wherein the CB1 receptor antagonist is rimonabant, monlunabant (INV-202), INV-347, INV-300, INV-101, NN-9441, NN-9440, nimacimab, DBPR-211, rimonabant, or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 1-36, wherein the satiety-inducing agent is a cannabinoid-1 (CB1) receptor inverse agonist.

41. The method of claim 40, wherein the CB1 receptor inverse agonist is monlunabant (INV-202), AM-251, Taranabant, THCV, JD-5037, MRI-1867, BPR0912, TXX-522, ENP11, TM-38837, or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 1-36, wherein the satiety-inducing agent is a gut hormone, or an incretin analog.

43. The method of claim 42, wherein the gut hormone is selected from: GLY-200, a peptide tyrosine tyrosine (PYY) (e.g., Y-242), calcitonin receptor (CALCR) agonist; islet amyloid polypeptide activator, Amycretin (NNC-04870111), amylin activator, diabetes associated peptide activator, insulinoma amyloid peptide activator, IAPP activator, SCO-267, K-757, ghrelin-O-acyltransferase inhibitor, AZD-6234, GUB-014295 (GUC-17), leptin receptor agonist (e.g., mibavademab), eloralintide, eloralintide, NovOB, LY 3457263, REGN4461, LY-3541105, LY3841136, BI-1356225, NN 9838, AZ-12861903, C-2816, CV- 08, DACRA-089, I2O-107, JY-54, NN-9056, petrelintide, TBX-401, and nisotirostide.

44. The method of any one of claims 1-36, wherein the satiety-inducing agent is a neuropeptide Y receptor agonist.

45. The method of claim 44, wherein the neuropeptide Y receptor agonist is selected from: GT-001, GT-01, JNJ-9321, GUB-002496, PYY-1119, CIN-110, and GUB-002496.

46. The method of any one of claims 1-36, wherein the satiety-inducing agent is selected from: CRB-913, DBPR-211, PB-722, (efpeglenatide + HM-15136), ACE-167, AD-9308, AGEX-BAT1, AvR-2V10, AZ-12861903, AZ-13483342, AZD-3857, BEBT-809, BF-114, Cannabinoids, CKR-334, CLS-1, CNIO-PI3Ki, CV-08, CYTX-100, Era-107, ETBD-03, FM- 801, Fusion Proteins to Activate GDF15 for Obesity, FZ-010, GCG-06, GMA-107, HM- 15275, HTD-1804, HUM-234, I2O-107, I2O-120, INHBE (Metabolic Disorders), CIN-110, KSB-10201, KY-19334, LR-19020, LR-19156, LY-3971297, M-43, MLX-0800, MLX-5000, MLX-7000, MNO-863, Monoclonal Antibody to Antagonize FSH Receptor for Obesity and Osteoporosis, MT-106, Myostatin antagonist, NM-136, NN-9056, NOVS-100, NPO-2237, OBE-2001, OLX-75016, orlistat, Peptide (PYY), Peptide to Antagonize MC3R for Obesity, Peptides for Non-Alcoholic Steatohepatitis and Obesity, Peptides to Agonize Oxytocin Receptor for Obesity, Peripheral CB1 Blockers, PF-06645849, PL-8905, PL-9610, psilocybin, PSYLO-3002, PYY-1119, RB-014, Recombinant Protein to Agonize Leptin Receptor for Obesity, Rejuva, REMD-524, REP-003, RES-010, RES-020, RMD-1202, RP- 1208, RSVI-301, RSVI-303, RT-210, SAL-0125, Gastrointestinal Hormones, SJT-4a, SJT- 7a, sobetirome, SPN-007, SRK-439, TB-592, Tespria, TF-0062, TF-0103, ThermoStem, TLC-1235, VK-1430, XL-100, YH-34160, YN-103, YN-106, ZP-6590, ZYL-001, ADY- 790011, ATC-601, AX-0601, BEBT-509, CBF-520, CYTA-002, DILOC-2, EB-012, ECN- 0424, EMB-2, GM-60186, GPR75, GT-002, GUI-37, HLB-1007, HLB-1015, HMC-2073, and ICB-513.

47. The method of any one of claims 1-36, wherein the satiety-inducing agent is selected from: APHD-012 (Distal jejunal-release dextrose beads), PF-07976016, XEN-101, 5- Hydroxytryptamine Receptor 1A (5 HT1A) agonist or G21 agonist, Serotonin Receptor 1A agonist, HTR1A Agonist, HTR1A agonist, CMND-100, 5-hydroxytryptamine receptor 2A agonist, 5-Hydroxytryptamine Receptor 2A agonist (e.g., 5 HT2A or Serotonin Receptor 2A or HTR2A), BMND06, Alpha 1,6 Mannosyl Glycoprotein 2 Beta N Acetylglucosaminyltransferase inhibitor (e.g., Beta 1,2 N Acetylglucosaminyltransferase II or Mannoside Acetylglucosaminyltransferase 2 or N Glycosyl Oligosaccharide Glycoprotein N Acetylglucosaminyltransferase II or GlcNAc-T II or MGAT2 or EC 2.4.1.143), S-309309, Alpha Amylase 2B (1,4-Alpha D-Glucan Glucanohydrolase 2B or Carcinoid Alpha Amylase or AMY2B or EC 3.2.1.1) Inhibitor; Gastric Triacylglycerol Lipase (Gastric Lipase or LIPF or EC 3.1.1.3) Inhibitor; Maltase Glucoamylase (Alpha-14-Glucosidase or MGAM or EC 3.2.1.20) Inhibitor; Pancreatic Alpha Amylase (1,4 Alpha D Glucan Glucanohydrolase or AMY2A or EC 3.2.1.1) Inhibitor; Pancreatic Triacylglycerol Lipase (Pancreatic Lipase or Triacylglycerol Acylhydrolase or PNLIP or EC 3.1.1.3) Inhibitor; Sucrase Isomaltase Intestinal (SI or EC 3.2.1.48 or EC 3.2.1.10) Inhibitor, Calcitonin Gene Related Peptide (CGRP) Inhibitor; Oxytocin Receptor (OTR or OXTR) Agonist, Glucocorticoid Receptor (GR or Nuclear Receptor Subfamily 3 Group C Member 1 or NR3C1) Antagonist, Miricorilant (CORT-118335), Zavacorilant, Growth/Differentiation Factor 15 (e.g., Macrophage Inhibitory Cytokine 1 or NSAID Regulated Gene 1 Protein or Placental Bone Morphogenetic Protein or Prostate Differentiation Factor or GDF15) Activator, JNJ-9090, NN-9215 (NNC0247-0829), Interleukin 22 Receptor (IL22R) Agonist, CK-0045, Melanocortin Receptor 4 (MC4R) Agonist, LB-54640, RM-718, NACHT LRR And PYD Domains Containing Protein 3 (e.g., Caterpiller Protein 1.1 or Cold Autoinflammatory Syndrome 1 Protein or Cryopyrin or Nucleotide Binding Oligomerization Domain Leucine Rich Repeat And Pyrin Domain) Inhibitor, VTX-3232, Tyrosine Protein Phosphatase Non Receptor Type 1 (e.g., Protein Tyrosine Phosphatase 1B or Protein Tyrosine Phosphatase Placental or PTP1B or PTPN1 or EC 3.1.3.48) Inhibitor, and ENT-03.

48. The method of any one of claims 1-26, wherein the satiety inducing agent is a GLP-1 receptor agonist.

49. The method of claim 48, wherein the method further comprises administering a second satiety inducing agent.

50. The method of claim 49, wherein the second satiety inducing agent is a GLP-1 receptor agonist.

51. The method of any one of claims 9, 10, 17, and 49-50, wherein the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide.

52. The method of claim 51, wherein the GLP-1 receptor agonist is semaglutide.

53. The method of claim 51, wherein the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist.

54. The method of claim 51, wherein the GLP-1 receptor agonist is tirzepatide.

55. The method of any one of claims 9, 10, and 17, wherein the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist.

56. The method of claim 55, wherein the GLP-1 receptor agonist is retatrutide.

57. The method of any one of claims 9, 10, and 17, wherein the GLP-1 receptor agonist is orally administered.

58. The method of any one of claims 1-36, wherein the effective dose of the apelin receptor agonist is administered twice daily (bid).

59. The method of any one of claims 1-36, wherein the effective dose of the apelin receptor agonist is in the range from 150 mg to 400 mg.

60. The method of any one of claims 9, 10, and 17, wherein the GLP-1 receptor agonist is an orally active non-peptide agonist of glucagon-like peptide-1 (GLP-1) receptor.

61. The method of claims 57 or 60, wherein the GLP-1 receptor agonist is orforglipron (LY-3502970).

62. The method of any one of claims 1 to 61, wherein the apelin receptor agonist is ANPA-0073.

63. The method of claim 22, wherein the metabolic disorder is a glucose metabolic disorder.

64. The method of claim 22, wherein the dysmetabolic disorder is dysmetabolic syndrome X.

65. The method of claim 22, wherein the metabolic disorder is insulin resistance syndrome or syndrome X.

66. The method of claim 22, wherein the metabolic disorder is selected from the group consisting of diabetes, metabolic syndrome, obesity, hyperlipidemia, hyperinsulinemia, high cholesterol, arteriosclerosis, hypertension, non-alcoholic steatohepatitis, non-alcoholic fatty liver, NASH, MASH, hepatic steatosis, and any combination thereof.

67. The method of any one of claims 1 to 25, wherein the subject has, or is at risk of developing pancreatic beta-cell dysfunction.

68. The method of any one of claims 1 to 25, wherein the subject has, or is at risk of developing a condition in which there is a lack of or diminished insulin production.