Anti-obesity drug

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Editor-In-Chief: C. Michael Gibson, M.S., M.D.; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[1];Parth Vikram Singh, MBBS

Overview

Anti-obesity medications include pharmacologic treatments used as adjuncts to nutrition therapy, physical activity, behavioral intervention, and long-term obesity care to reduce body weight, maintain weight reduction, and improve obesity-related complications. Obesity is now treated as a chronic relapsing disease rather than a short-term cosmetic condition; therefore, medication discontinuation commonly leads to weight regain and reversal of cardiometabolic benefits.[1][2]

Modern obesity pharmacotherapy has changed substantially with the development of glucagon-like peptide-1 receptor agonists, dual GIP/GLP-1 receptor agonists, oral incretin therapies, and emerging multi-receptor hormone agonists. Older agents such as sibutramine, rimonabant, and lorcaserin are no longer current therapies because of safety concerns or market withdrawal.[3][4]

Evolution of Obesity Pharmacotherapy: Single to Multi-Receptor Targeting and Expected Weight Loss Magnitude [4]

Definition and Diagnostic Framework

The diagnosis and treatment of obesity should not rely on body mass index (BMI) alone. Newer frameworks distinguish excess adiposity from the clinical consequences of excess adiposity, and incorporate anthropometric measures such as waist circumference, waist-to-hip ratio, or waist-to-height ratio when available.[5][6]

The 2025 Lancet Commission proposed distinguishing clinical obesity from preclinical obesity. Clinical obesity refers to excess adiposity associated with organ dysfunction, reduced mobility, limitation of activities of daily living, or other clinically meaningful impairment. Preclinical obesity refers to excess adiposity without current organ dysfunction, but with increased future risk. This distinction is relevant to anti-obesity pharmacotherapy because medication intensity should reflect both anthropometric severity and obesity-related complications.[5]

The European Association for the Study of Obesity (EASO) framework incorporates BMI, waist-to-height ratio, and obesity-related complications. A waist-to-height ratio ≥0.5 may identify excess central adiposity in patients whose BMI alone underestimates obesity-related risk.[6][7]

The Edmonton Obesity Staging System (EOSS) classifies obesity severity from stage 0 to stage 4 based on metabolic, physical, and psychological complications rather than BMI alone. Staging systems may help guide treatment intensity and identify patients who require more potent pharmacotherapy, combination treatment, or metabolic/bariatric surgery referral.[8][9]

Patient Selection and Indications

Anti-obesity medications are generally indicated as adjuncts to lifestyle intervention in adults with BMI ≥30 kg/m2, or BMI ≥27 kg/m2 with at least one weight-related complication such as diabetes mellitus type 2, hypertension, dyslipidemia, obstructive sleep apnea, metabolic dysfunction-associated steatohepatitis, heart failure with preserved ejection fraction, or established cardiovascular disease.[1][10][9]

Lower BMI thresholds may be used in Asian and Southeast Asian populations because obesity-related metabolic risk occurs at lower BMI levels. Several medications are also approved for pediatric obesity, including liraglutide, semaglutide, tirzepatide, and phentermine-topiramate in adolescents ≥12 years, whereas setmelanotide is restricted to specific genetically confirmed monogenic or syndromic obesity disorders in patients as young as 2 years depending on the indication.[11][12]

Treatment Algorithm

Anti-obesity medications should be selected according to BMI, obesity-related complications, obesity stage, contraindications, patient preference, route of administration, cost, access, prior response, and long-term treatment goals.[9][1]

 
 
 
 
 
Adult or adolescent with obesity or overweight plus weight-related complication
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm excess adiposity and clinical risk: BMI, waist circumference or waist-to-height ratio, comorbidities, functional limitation, and obesity stage
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initiate or intensify lifestyle intervention: nutrition, physical activity, behavioral counseling, sleep optimization, and management of obesity-related complications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meets criteria for anti-obesity pharmacotherapy?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
No
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Select medication based on comorbidities, contraindications, expected efficacy, route, safety, and access
 
Continue lifestyle intervention and monitor weight trajectory, cardiometabolic risk, and complications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess response and tolerability at 12-16 weeks after reaching therapeutic or maintenance dose
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If effective and tolerated: continue long-term therapy. If ineffective, not tolerated, or contraindicated: adjust dose, switch medication, add complementary therapy, or consider metabolic/bariatric surgery when indicated
 
 
 
 
 

A common clinical rule is to reassess at 12 to 16 weeks after reaching the therapeutic or maintenance dose. If weight loss is insufficient, usually defined as less than approximately 5% weight loss when medication-specific labeling does not specify otherwise, clinicians should reassess adherence, dose, tolerability, secondary causes of weight gain, access barriers, and whether to discontinue, switch, or intensify treatment.[1][10]

The 2025 AACE framework emphasizes complication- and stage-based treatment intensity. Patients with earlier-stage adiposity-based chronic disease may be treated with lower-potency or first-generation pharmacotherapy when appropriate, whereas patients with more advanced complications generally warrant more effective second-generation agents such as semaglutide or tirzepatide, combination strategies, or referral for metabolic/bariatric surgery when indicated.[9]

Dosing and Response Assessment

Medication Typical adult dosing / titration Response or discontinuation principle
Semaglutide subcutaneous Start 0.25 mg once weekly and increase every 4 weeks through 0.5 mg, 1.0 mg, 1.7 mg, and maintenance 2.4 mg once weekly. Higher-dose semaglutide 7.2 mg weekly, marketed as Wegovy HD, is approved for selected adult patients according to product-specific labeling.[13][14] Assess weight response and tolerability after dose escalation; long-term continuation is generally needed to maintain effect.
Semaglutide oral Oral semaglutide for weight management requires strict administration under fasting conditions according to product-specific labeling.[15] Absorption is sensitive to administration technique; poor response should prompt review of fasting and dosing instructions.
Tirzepatide Start 2.5 mg once weekly for 4 weeks, then increase by 2.5 mg increments at intervals of at least 4 weeks; maintenance doses include 5 mg, 10 mg, or 15 mg once weekly.[16] Continue if effective and tolerated; discontinuation commonly leads to regain.
Orforglipron Once-daily oral non-peptide GLP-1 receptor agonist; use product-specific titration according to labeling.[17] Does not require the same fasting administration constraints as oral peptide semaglutide; monitor gastrointestinal tolerability.
Liraglutide Start 0.6 mg subcutaneously daily and increase weekly to 1.2 mg, 1.8 mg, 2.4 mg, and maintenance 3.0 mg daily according to labeling.[18] Discontinue if inadequate response after reaching maintenance dose according to labeling.
Phentermine-topiramate Start 3.75 mg/23 mg daily for 14 days, then 7.5 mg/46 mg daily; if inadequate response, escalate according to label to 11.25 mg/69 mg for 14 days and then 15 mg/92 mg daily.[19] Follow label-specific 12-week response rules; taper rather than abruptly stopping high dose because of seizure risk.
Naltrexone-bupropion Each tablet contains naltrexone 8 mg/bupropion 90 mg ER; titrate weekly to 2 tablets twice daily by week 4.[20] Discontinue if less than 5% weight loss after 12 weeks at maintenance dose; avoid high-fat meals.
Orlistat 120 mg orally three times daily with meals containing fat; lower-dose over-the-counter formulation is also available.[21] Omit dose if meal is missed or contains no fat; separate fat-soluble vitamin supplementation from dosing.
Setmelanotide Daily subcutaneous dosing is age- and indication-dependent and should follow product-specific labeling.[12] Use only for approved rare genetic or syndromic obesity indications; not for general obesity.
Short-term sympathomimetics Phentermine, diethylpropion, phendimetrazine, and benzphetamine are short-term agents with drug-specific dosing.[22] Use is limited by cardiovascular stimulation, abuse potential, and short-term approval status.

Mechanisms of Action

Anti-obesity medications operate through one or more of the following mechanisms:

Recent pharmacologic therapies for obesity target neuroendocrine regulation rather than isolated appetite suppression. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released from enteroendocrine cells in response to nutrient ingestion and act on receptors in the pancreas, gastrointestinal tract, and central nervous system to regulate appetite, insulin secretion, and energy metabolism.[1]

Available Anti-Obesity Medications

Medication Class Route General role Key safety issue
Semaglutide GLP-1 receptor agonist Subcutaneous weekly or oral daily formulation Chronic weight management; cardiovascular risk reduction in selected adults with established cardiovascular disease; noncirrhotic MASH with F2-F3 fibrosis according to labeling Gastrointestinal adverse effects, gallbladder disease, boxed warning for thyroid C-cell tumors
Tirzepatide Dual GIP / GLP-1 receptor agonist Subcutaneous weekly Chronic weight management; moderate-to-severe obstructive sleep apnea in adults with obesity Gastrointestinal adverse effects, boxed warning for thyroid C-cell tumors
Orforglipron Oral non-peptide GLP-1 receptor agonist Oral daily Chronic weight management in adults; no fasting requirement compared with oral peptide GLP-1 agents; potential oral maintenance strategy after injectable incretin treatment Gastrointestinal adverse effects, dehydration-related kidney injury, class boxed warning
Liraglutide GLP-1 receptor agonist Subcutaneous daily Chronic weight management in adults and adolescents Gastrointestinal adverse effects; daily injection burden
Phentermine-topiramate Sympathomimetic / antiepileptic combination Oral daily Chronic weight management in adults and adolescents ≥12 years Teratogenicity, heart rate increase, mood/cognitive effects, metabolic acidosis, nephrolithiasis
Naltrexone-bupropion Opioid antagonist / aminoketone antidepressant combination Oral twice daily after titration Chronic weight management; useful niche with depression, smoking cessation, or alcohol-use context Seizure risk, blood pressure elevation, opioid blockade
Orlistat Gastrointestinal lipase inhibitor Oral with meals Chronic weight management; non-systemic option Steatorrhea, fat-soluble vitamin malabsorption
Setmelanotide Melanocortin-4 receptor agonist Subcutaneous daily Rare genetic and syndromic obesity disorders Hyperpigmentation, sexual arousal effects, depression/suicidal ideation monitoring
Phentermine, diethylpropion, phendimetrazine, benzphetamine Short-term sympathomimetic anorectics Oral Short-term adjunctive therapy only Cardiovascular stimulation, insomnia, abuse potential

Semaglutide

Semaglutide is a long-acting GLP-1 receptor agonist approved for chronic weight management. It is available as once-weekly subcutaneous semaglutide and oral semaglutide formulations for selected indications. In the STEP program, semaglutide 2.4 mg produced mean weight loss of approximately 15% to 17% in adults without diabetes, and weight loss was maintained over 2 years in STEP 5.[24][25]

In STEP 8, once-weekly semaglutide produced greater weight loss than once-daily liraglutide in adults with overweight or obesity without diabetes. Mean body weight reduction from baseline was 15.8% with semaglutide 2.4 mg versus 6.4% with liraglutide 3.0 mg at 68 weeks.[26]

Higher-dose semaglutide has been evaluated in the STEP UP program. In STEP UP, a randomized phase 3b trial of adults with obesity without diabetes, once-weekly semaglutide 7.2 mg produced 20.7% mean weight loss at 72 weeks compared with 17.5% with semaglutide 2.4 mg and 2.4% with placebo; 33.2% of participants receiving 7.2 mg achieved at least 25% weight loss compared with 16.7% receiving 2.4 mg and 0% receiving placebo.[27] In STEP UP T2D, semaglutide 7.2 mg produced greater weight loss than semaglutide 2.4 mg in adults with obesity and type 2 diabetes, with mean weight loss of 13.2% versus 10.4%, respectively.[28]

Dysesthesia-associated adverse events, including abnormal skin sensations such as tingling or burning, were more frequent with higher-dose semaglutide than with semaglutide 2.4 mg. These events usually improved or resolved, but they led to treatment discontinuation in a small number of participants.[27][28]

In SELECT, semaglutide reduced the risk of major adverse cardiovascular events in adults with established cardiovascular disease and overweight or obesity without diabetes. The primary composite endpoint occurred less frequently with semaglutide than placebo, with a hazard ratio of 0.80 (95% CI, 0.72-0.90).[29] Prespecified analyses suggest that cardiovascular benefit was not explained solely by baseline adiposity or achieved weight loss, supporting effects beyond simple weight reduction.[30]

Semaglutide has also received FDA approval for treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced liver fibrosis consistent with stages F2-F3, under accelerated approval based on histologic endpoints.[13][31]

Common adverse effects include nausea, vomiting, diarrhea, constipation, and abdominal discomfort, particularly during dose escalation. Clinicians should monitor for gallbladder disease, pancreatitis symptoms, dehydration-related acute kidney injury, heart rate increase, diabetic retinopathy worsening in patients with diabetes and rapid glycemic improvement, and dysesthesia-associated adverse events at higher doses.[13][1][27]

Tirzepatide

Tirzepatide is a dual GIP/GLP-1 receptor agonist approved for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity. It is also approved for moderate-to-severe obstructive sleep apnea in adults with obesity.[32]

In SURMOUNT-1, tirzepatide produced mean weight loss of 15.0%, 19.5%, and 20.9% at doses of 5 mg, 10 mg, and 15 mg, respectively, compared with 3.1% with placebo at 72 weeks.[33] In SURMOUNT-2, tirzepatide produced clinically meaningful weight loss in patients with type 2 diabetes and obesity or overweight.[34]

In a head-to-head randomized trial, tirzepatide produced greater weight loss than semaglutide 2.4 mg in adults with obesity without diabetes.[35]

Orforglipron

Orforglipron is an oral non-peptide small-molecule GLP-1 receptor agonist approved for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity, in combination with reduced-calorie diet and increased physical activity.[17] Unlike oral peptide semaglutide, it is not subject to the same digestive enzyme degradation constraints and can be taken without fasting requirements, which may improve adherence in patients who prefer oral therapy or decline injectable medications.[36][17]

Phase 2 data showed dose-dependent weight loss in adults with obesity or overweight without diabetes, and phase 3 ATTAIN studies support clinically meaningful weight reduction in adults with and without type 2 diabetes.[36][37][38]

ATTAIN-MAINTAIN evaluated oral orforglipron as maintenance therapy after prior injectable incretin-based weight reduction. At 52 weeks, patients previously treated with tirzepatide maintained 74.7% of prior weight loss with orforglipron versus 49.2% with placebo, while those previously treated with semaglutide maintained 79.3% of prior weight loss with orforglipron versus 37.6% with placebo.[39] These findings support a potential clinical role for oral orforglipron as a step-down or maintenance strategy after injectable GLP-1 or dual GIP/GLP-1 receptor agonist therapy, although long-term implementation depends on labeling, access, tolerability, and comparative durability.

Liraglutide

Liraglutide is a daily injectable GLP-1 receptor agonist approved for chronic weight management. In the SCALE trial, liraglutide 3.0 mg produced greater weight loss than placebo in adults with obesity or overweight with weight-related comorbidities.[40]

Liraglutide generally produces less weight loss than semaglutide or tirzepatide, but it remains clinically relevant, especially when weekly injectable agents are unavailable, contraindicated, or not tolerated. In STEP 8, mean body weight reduction was 6.4% with liraglutide 3.0 mg versus 15.8% with semaglutide 2.4 mg at 68 weeks.[26][1]

Phentermine-Topiramate

Phentermine-topiramate extended-release combines a sympathomimetic anorectic with topiramate. In CONQUER, low-dose controlled-release phentermine plus topiramate produced clinically meaningful weight loss and improvements in cardiometabolic risk factors.[41]

The major limitation is teratogenicity from topiramate, especially risk of oral clefts with fetal exposure. Pregnancy testing, contraception counseling, heart rate monitoring, mood and cognitive adverse-effect monitoring, and dose-specific discontinuation rules are required.[19]

Because topiramate is a carbonic anhydrase inhibitor, clinically important adverse effects may include metabolic acidosis, hypokalemia, nephrolithiasis, cognitive slowing, paresthesias, mood symptoms, and ocular adverse effects. Serum bicarbonate, renal function, electrolytes, heart rate, mood, and cognitive symptoms should be monitored according to clinical context and labeling.[19]

Naltrexone-Bupropion

Naltrexone-bupropion extended-release combines an opioid antagonist with an aminoketone antidepressant. Bupropion stimulates proopiomelanocortin neurons, while naltrexone blocks beta-endorphin-mediated feedback inhibition, producing appetite and reward-pathway effects.[10][1]

Across COR trials, naltrexone-bupropion produced modest but clinically meaningful weight loss compared with placebo, with placebo-adjusted weight reduction generally in the range of approximately 2.5% to 5.2%.[1][20] Treatment should be discontinued if patients have not lost at least 5% of baseline body weight after 12 weeks at the maintenance dose.[20]

The medication may be useful in selected patients with coexisting depression, smoking cessation goals, or alcohol-use concerns, but it is contraindicated in uncontrolled hypertension, seizure disorder, eating disorders such as anorexia nervosa or bulimia nervosa, chronic opioid use, abrupt discontinuation of alcohol or sedatives, use of other bupropion-containing products, and monoamine oxidase inhibitor use within 14 days.[20]

Because naltrexone blocks opioid receptors, naltrexone-bupropion should be stopped before procedures or acute clinical situations in which opioid analgesia is expected. Patients who require intermittent opioids for surgery, endoscopy sedation, acute trauma, or cancer pain need specific perioperative planning to avoid ineffective analgesia or precipitated opioid withdrawal.[20]

Bupropion inhibits CYP2D6 and may increase exposure to selected antidepressants, antipsychotics, beta-blockers, and class 1C antiarrhythmics. Dose adjustment is required in moderate-to-severe renal impairment and in moderate hepatic impairment, and the medication is not recommended in severe hepatic impairment or end-stage renal disease. Cardiovascular safety has not been definitively established because the LIGHT cardiovascular outcomes trial was terminated early.[20]

Orlistat

Orlistat is a gastrointestinal lipase inhibitor that reduces intestinal fat absorption. It is available by prescription and over the counter in lower-dose form. Its adverse effects include oily stools, fecal urgency, flatulence, and fat-soluble vitamin malabsorption.[1][21]

Patients taking orlistat should receive counseling regarding fat-soluble vitamins vitamin A, vitamin D, vitamin E, and vitamin K, with supplementation separated from orlistat dosing. Clinicians should also consider potential interactions with cyclosporine, levothyroxine, warfarin, and antiepileptic drugs.[21]

Setmelanotide

Setmelanotide is a melanocortin-4 receptor agonist approved for chronic weight management in specific rare genetic or syndromic obesity disorders, including obesity due to POMC deficiency, PCSK1 deficiency, LEPR deficiency, Bardet-Biedl syndrome, and acquired hypothalamic obesity according to approved labeling. It is not indicated for general polygenic obesity.[12][23]

In pivotal studies, setmelanotide produced clinically meaningful weight loss in selected patients with melanocortin pathway disorders. Reported responses include approximately 25.6% mean weight loss in POMC deficiency, approximately 12.5% in LEPR deficiency, and a substantial proportion of patients with Bardet-Biedl syndrome achieving at least 10% weight loss.[12][23] Dosing is age- and indication-specific and should follow product labeling, with careful attention to pediatric age thresholds and dose escalation schedules.[12]

Distinctive adverse effects include skin hyperpigmentation, injection-site reactions, nausea, vomiting, diarrhea, spontaneous penile erections, female sexual arousal effects, depression, and suicidal ideation monitoring.[12]

Short-Term Sympathomimetic Agents

Phentermine, diethylpropion, phendimetrazine, and benzphetamine are sympathomimetic anorectics approved only for short-term use. They are generally avoided in patients with coronary artery disease, uncontrolled hypertension, arrhythmia, glaucoma, hyperthyroidism, or substance use disorder.[22][42]

Metformin

Metformin may produce modest weight reduction or weight neutrality in patients with diabetes mellitus type 2, but it is not approved as an anti-obesity medication. It may be clinically useful when obesity coexists with insulin resistance, prediabetes, polycystic ovary syndrome, or type 2 diabetes, but it should not be presented as a primary obesity pharmacotherapy.[1]

Gelesis100 / Plenity

Gelesis100, marketed as Plenity, is an oral superabsorbent hydrogel device rather than a drug. It is composed of cellulose and citric acid particles that hydrate in the stomach and small intestine to promote satiety. In a randomized trial, Gelesis100 produced modest placebo-adjusted weight loss.[43] The American Gastroenterological Association recommended against routine use outside clinical trials because of low-certainty evidence.[10]

Nutritional and Lifestyle Counseling During Pharmacotherapy

Anti-obesity medications should be combined with structured nutrition, physical activity, and behavioral intervention. Potent incretin-based therapies reduce appetite and energy intake, but inadequate dietary quality during rapid weight loss may increase risk of lean mass loss, micronutrient inadequacy, constipation, gallstone symptoms, and treatment discontinuation.[44]

Key counseling priorities include:

  • Adequate protein intake, often approximately 1.0-1.2 g/kg/day depending on age, kidney function, activity level, and clinical context.
  • Resistance exercise to preserve skeletal muscle and physical function.
  • Regular physical activity and reduction of sedentary time.
  • Adequate hydration and fiber intake, especially in patients with constipation or reduced oral intake.
  • Screening for disordered eating, sarcopenia risk, frailty, and micronutrient deficiency in selected patients.
  • Ongoing nutrition counseling when dose escalation produces nausea, early satiety, or marked reduction in food intake.[44]

Comparative Efficacy

Therapy Approximate mean weight reduction in major trials Key clinical context
Semaglutide 7.2 mg 20.7% in STEP UP; 13.2% in STEP UP T2D Higher-dose semaglutide option for selected adults according to product labeling
Tirzepatide Approximately 15%-21% in SURMOUNT-1, with higher-dose groups achieving the largest reduction Among most effective approved agents; OSA indication in adults with obesity
Semaglutide 2.4 mg Approximately 15%-17% in STEP trials Proven cardiovascular outcome benefit in SELECT for adults with established CVD and overweight/obesity without diabetes
Orforglipron Approximately 7%-15% depending on dose, population, and trial; maintenance of 74.7%-79.3% of prior injectable-associated weight loss in ATTAIN-MAINTAIN Oral non-peptide GLP-1 receptor agonist; no fasting requirement; potential step-down maintenance strategy
Liraglutide 3.0 mg Approximately 5%-8%; 6.4% in STEP 8 Daily injectable GLP-1 receptor agonist
Phentermine-topiramate Approximately 8%-10% depending on dose and adherence High oral efficacy but teratogenicity and sympathomimetic safety issues
Naltrexone-bupropion Approximately 3%-6% placebo-adjusted Oral non-incretin option; useful niche with depression, smoking cessation, or alcohol-use context
Orlistat Approximately 3% placebo-adjusted Non-systemic; limited by gastrointestinal tolerability and vitamin malabsorption

Comorbidity-Specific Drug Selection

Clinical phenotype / comorbidity Preferred or useful medication options Rationale
Established atherosclerotic cardiovascular disease Semaglutide SELECT demonstrated reduced major adverse cardiovascular events in adults with established CVD and overweight/obesity without diabetes.[29]
Diabetes mellitus type 2 Tirzepatide, semaglutide, liraglutide Strong weight loss and glycemic efficacy.
Moderate-to-severe obstructive sleep apnea with obesity Tirzepatide FDA-approved for moderate-to-severe OSA in adults with obesity.[32]
Metabolic dysfunction-associated steatohepatitis Semaglutide; investigational role for tirzepatide, survodutide, pemvidutide, and retatrutide Semaglutide is FDA-approved for selected adults with noncirrhotic MASH and F2-F3 fibrosis; emerging agents are being studied for steatohepatitis.[31]
Chronic kidney disease with type 2 diabetes Semaglutide may be useful when otherwise appropriate FLOW demonstrated kidney outcome benefit in patients with type 2 diabetes and chronic kidney disease.[45]
Migraine history Phentermine-topiramate may be considered when otherwise appropriate Topiramate has migraine-prevention relevance, but teratogenicity and neuropsychiatric effects must be considered.
Depression, smoking cessation, or alcohol-use context Naltrexone-bupropion may be considered when not contraindicated Bupropion and naltrexone have non-obesity indications relevant to these phenotypes.
Rare monogenic or syndromic obesity Setmelanotide Specific role in MC4R-pathway disorders and Bardet-Biedl syndrome.

Cardiovascular and Renal Outcomes

Semaglutide reduced major adverse cardiovascular events in SELECT among adults with established cardiovascular disease and overweight or obesity without diabetes, with a hazard ratio of 0.80 for the primary 3-point MACE outcome.[29] This result supports semaglutide selection in patients with established atherosclerotic cardiovascular disease when not contraindicated.

Kidney outcome data are increasingly relevant to obesity pharmacotherapy. In FLOW, semaglutide reduced the risk of clinically important kidney outcomes in patients with type 2 diabetes and chronic kidney disease.[45] A SELECT kidney analysis also suggested kidney benefit in patients with overweight or obesity and established cardiovascular disease without diabetes.[46] Across GLP-1 receptor agonist trials, meta-analytic evidence suggests reduced risk of worsening kidney function and albuminuria progression.[47]

Safety and Adverse Effects

Common adverse effects of incretin-based therapies include nausea, vomiting, diarrhea, constipation, and abdominal discomfort, particularly during dose escalation. These effects are usually dose-dependent and may improve over time.[1][48]

GLP-1 receptor agonists and related incretin therapies carry warnings for thyroid C-cell tumors based on rodent data and are contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. They are also generally avoided in pregnancy and should be discontinued before planned conception according to labeling.[13][16]

Gallbladder disease risk is increased with GLP-1 receptor agonists, particularly at weight-loss doses and longer treatment durations. Pancreatitis is rare, but therapy should be discontinued if pancreatitis is suspected.[49]

Weight loss from potent incretin therapy may include loss of lean mass. Resistance exercise, adequate protein intake, and monitoring for sarcopenia risk are important, especially in older adults or patients with frailty.[50]

Drug Interactions

Medication / class Important interactions
Orlistat May reduce absorption of fat-soluble vitamins, cyclosporine, levothyroxine, warfarin, and some antiepileptic drugs; separate vitamin supplementation from dosing.
Naltrexone-bupropion Contraindicated with chronic opioids, other bupropion products, and MAOIs; bupropion inhibits CYP2D6 and may increase levels of selected antidepressants, antipsychotics, beta-blockers, and antiarrhythmics. Stop before procedures requiring opioid analgesia when clinically appropriate.
Phentermine-topiramate Avoid with MAOIs; topiramate may reduce oral contraceptive efficacy and increase CNS adverse effects when combined with alcohol or sedatives; monitor for metabolic acidosis and nephrolithiasis risk.
GLP-1 receptor agonists and dual incretin agents Delayed gastric emptying may affect absorption of oral medications, especially drugs with narrow therapeutic index; oral semaglutide has strict fasting administration requirements.
Short-term sympathomimetics Avoid with MAOIs and other sympathomimetic agents; use caution in cardiovascular disease.

Special Populations

Anti-obesity medications are contraindicated during pregnancy. GLP-1 receptor agonists are generally discontinued before planned conception according to labeling, and phentermine-topiramate has specific fetal toxicity risk because of topiramate-associated oral clefts.[13][19][51]

In chronic kidney disease, dose limits or avoidance may be required for naltrexone-bupropion and phentermine-topiramate, while dehydration-related kidney injury should be considered during incretin dose escalation. In hepatic impairment, medication selection should account for severity of liver disease and label-specific dose limits or contraindications.[20][19]

In older or sarcopenic patients, preservation of lean mass is a major clinical goal. Resistance exercise and adequate protein intake should accompany pharmacotherapy.[50][44]

Weight Regain After Discontinuation

Weight regain after stopping anti-obesity medication is common. In the STEP 1 extension, participants who discontinued semaglutide regained a substantial proportion of lost weight within one year, with parallel worsening of cardiometabolic improvements.[52]

In SURMOUNT-4, patients who continued tirzepatide maintained or further reduced body weight, whereas those switched to placebo regained weight.[53] A 2026 systematic review and meta-analysis found progressive weight regain after medication cessation, with regain averaging approximately 0.4 kg/month and cardiometabolic markers projected to return toward baseline within approximately 1.4 years after discontinuation.[2] These findings support long-term therapy for most patients when treatment is effective, tolerated, accessible, and not contraindicated.

Comparison With Bariatric Surgery and Endoscopic Therapies

Anti-obesity medications, endoscopic therapies, and bariatric surgery differ in invasiveness, reversibility, cost, durability, risk profile, and expected magnitude of weight loss. Modern incretin-based pharmacotherapy can approach surgery-like short-term weight reduction in some patients, but metabolic/bariatric surgery remains among the most durable interventions for severe obesity and obesity-related complications.[54][55]

Bariatric surgery commonly achieves approximately 25%-30% total body weight loss at 12 months, with durable results in many patients at 5 years or longer. Endoscopic therapies, including intragastric balloon therapy and endoscopic sleeve gastroplasty, generally produce more modest weight loss, often approximately 10%-13% at 6 months depending on procedure, patient selection, and follow-up intensity.[54][55]

A 2026 GRADE-based network meta-analysis found that surgery remains superior for long-term weight loss, whereas semaglutide and tirzepatide showed non-inferior short-term results at approximately 26 to 52 weeks in selected comparisons.[55] Medication-based treatment may be preferred when patients decline surgery, have lower surgical risk thresholds, require reversible treatment, or need cardiometabolic risk reduction without anatomic intervention. Bariatric surgery should be considered in patients with severe obesity, advanced obesity complications, inadequate response to medication, or when durable remission of obesity-related disease is a major treatment goal.[54]

Cost, Access, and Adherence

Access to anti-obesity medications is limited by cost, insurance coverage, prior authorization requirements, medication shortages, and long-term adherence. In the United States, injectable GLP-1 receptor agonists and dual incretin agents often have annual list prices in the approximate range of $12,000 to $16,000, though actual patient cost varies substantially by insurance coverage, rebates, patient assistance programs, and pharmacy benefit design.[56][57]

Coverage for obesity-only indications remains variable across private insurance plans and public payers, and Medicare coverage has historically been restricted for drugs used solely for weight loss. Real-world adherence is substantially lower than clinical-trial completion rates, with persistence estimates ranging from approximately one-third to one-half at 1 year and substantially lower by 2 years in many analyses.[56][57]

Economic evaluations of GLP-1 receptor agonists for non-diabetic obesity have reported incremental cost-effectiveness ratios well above common willingness-to-pay thresholds, including estimates in the approximate range of $237,000-$483,000 per quality-adjusted life-year in some U.S.-based models.[56] Proposed or announced price reductions, including Medicare-related pricing initiatives, may improve affordability but do not eliminate the need to address long-term cost, access, and persistence before initiating therapy.[57]

Cost and access should be addressed before prescribing because abrupt discontinuation due to loss of coverage or unaffordability may lead to weight regain. When access to high-potency incretin therapy is limited, alternative medications, combination strategies, intensive lifestyle intervention, endoscopic therapy, or metabolic/bariatric surgery referral may be appropriate depending on clinical context.[56][1]

Compounded GLP-1 and Dual GIP/GLP-1 Products

Professional societies recommend against routine use of compounded semaglutide or tirzepatide when approved products are available. Concerns include lack of standardized quality oversight, salt forms that are not chemically identical to approved products, dosing errors from variable concentrations, counterfeit products, and increased adverse-event reporting signals.[58][59]

The FDA has expressed concerns about unapproved GLP-1 products sold for weight loss, including unapproved semaglutide, tirzepatide, and retatrutide products, compounded products made with inappropriate ingredients, and dosing errors caused by variable concentrations or patient measurement errors.[60]

Withdrawn and Historical Agents

Drug Historical role Current status
Sibutramine Serotonin-norepinephrine reuptake inhibitor appetite suppressant formerly marketed as Meridia / Reductil Withdrawn from the U.S. market in 2010 because of increased cardiovascular events in high-risk patients.
Rimonabant Cannabinoid CB1 receptor antagonist formerly approved in Europe Withdrawn because of psychiatric adverse effects, including depression and suicidality; never approved in the United States.
Lorcaserin Selective 5-HT2C receptor agonist formerly approved for chronic weight management Voluntarily withdrawn from the U.S. market in 2020 because of cancer safety signal.
Fenfluramine / dexfenfluramine Components of historical “fen-phen” therapy Withdrawn because of association with valvular heart disease and pulmonary hypertension.
Phenylpropanolamine Sympathomimetic formerly used in weight-loss and cold products Removed because of hemorrhagic stroke risk.

Investigational and Emerging Therapies

Cagrilintide-Semaglutide

Cagrilintide-semaglutide, also known as CagriSema, combines an amylin analogue with semaglutide. In REDEFINE trials, co-administered cagrilintide and semaglutide produced greater weight loss than semaglutide or cagrilintide alone, with gastrointestinal adverse events as the most common tolerability issue.[61][62]

Retatrutide

Retatrutide is a triple GIP/GLP-1/glucagon receptor agonist. In phase 2 trials, high-dose retatrutide produced very large weight reductions in adults with obesity, and phase 3 trials are ongoing.[63]

Survodutide, Mazdutide, Pemvidutide, MariTide, Ecnoglutide, and Bimagrumab

Other emerging therapies include dual GLP-1/glucagon receptor agonists such as survodutide, mazdutide, and pemvidutide, long-acting antibody-based or peptide-conjugate approaches such as maridebart cafraglutide (MariTide), biased GLP-1 receptor agonists such as ecnoglutide, and body-composition-targeted therapies such as bimagrumab, which targets activin type II receptors to reduce fat mass while preserving or increasing lean mass.[4][64]

Pemvidutide is a dual GLP-1/glucagon receptor agonist under investigation for obesity and metabolic liver disease. Clinical studies have shown reductions in body weight and liver fat, supporting continued evaluation in obesity and MASH-related indications.[65]

Danuglipron is an oral non-peptide GLP-1 receptor agonist formerly under investigation for chronic weight management. Development was limited by gastrointestinal tolerability and later discontinued after safety concerns in clinical development, illustrating the challenge of balancing oral incretin efficacy, tolerability, and safety.[66][67]

Monlunabant is a small-molecule cannabinoid receptor 1 (CB1) inverse agonist evaluated for obesity and metabolic syndrome. This mechanism is distinct from incretin-based therapy but is clinically relevant because prior centrally active CB1 antagonist therapy, such as rimonabant, was limited by psychiatric adverse effects.[68]

VK2735 is a dual GIP/GLP-1 receptor agonist under investigation for weight management. Subcutaneous VK2735 has shown clinically meaningful weight loss in phase 2 study, and oral formulations are also under clinical development.[69]

Investigational pathway Representative agents Clinical rationale
Amylin + GLP-1 combination Cagrilintide-semaglutide Complementary satiety and gastric-emptying effects
Triple incretin / glucagon agonism Retatrutide Appetite suppression, insulin-sensitizing effects, and glucagon-mediated energy expenditure
GLP-1 / glucagon dual agonism Survodutide, mazdutide, pemvidutide Weight loss plus potential metabolic liver disease benefit
Oral small-molecule incretin therapy Orforglipron, danuglipron, and related agents Easier administration and potential access/adherence advantage; development has been limited for some agents by gastrointestinal tolerability and safety challenges
Dual GIP / GLP-1 receptor agonism VK2735 and related agents Potential high-efficacy incretin-based weight loss with injectable and oral development programs
Peripheral or modified cannabinoid receptor 1 signaling Monlunabant and related agents Non-incretin appetite and metabolic pathway; psychiatric safety remains an important consideration because of historical experience with rimonabant
Body-composition therapy Bimagrumab and related myostatin-activin pathway inhibitors Preferential fat loss and lean mass preservation

Limitations of Current Knowledge

Although newer pharmacotherapies produce substantially greater and more sustained weight loss than earlier agents, several limitations remain. These include medication cost, access, insurance coverage, long-term adherence, adverse-effect burden, management of weight regain after discontinuation, long-term effects on lean mass and bone density, and optimization of combination strategies.[1][2]

The older concept that anti-obesity drugs are only short-term tools is no longer accurate for most modern chronic weight-management agents. However, short-term sympathomimetics remain approved only for limited-duration use, and several historical anti-obesity medications have been withdrawn because of adverse effects.[22][3]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Gudzune KA, Kushner RF (2024). "Medications for Obesity: A Review". JAMA. 332 (7): 571–584. doi:10.1001/jama.2024.10816. PMID 39885012 Check |pmid= value (help).
  2. ↑ 2.0 2.1 2.2 West S, Scragg J, Aveyard P; et al. (2026). "Weight Regain After Cessation of Medication for Weight Management: Systematic Review and Meta-Analysis". BMJ. 392: e085304. doi:10.1136/bmj-2025-085304.
  3. ↑ 3.0 3.1 Onakpoya IJ, Heneghan CJ, Aronson JK (2016). "Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review". BMC Med. 14 (1): 191. doi:10.1186/s12916-016-0735-y. PMID 27894343.
  4. ↑ 4.0 4.1 4.2 Kushner RF, Jastreboff AM, Ryan DH (2025). "Current and Future Medications for Obesity Treatment". JAMA. 334 (17): 1551–1552. doi:10.1001/jama.2025.13665. PMID 40932726 Check |pmid= value (help).
  5. ↑ 5.0 5.1 Rubino F, Cummings DE, Eckel RH; et al. (2025). "Definition and diagnostic criteria of clinical obesity". Lancet Diabetes Endocrinol. 13 (3): 221–262. doi:10.1016/S2213-8587(24)00316-4.
  6. ↑ 6.0 6.1 Busetto L, Dicker D, Frühbeck G; et al. (2024). "A new framework for the diagnosis, staging and management of obesity in adults". Nat Med. 30 (9): 2395–2399. doi:10.1038/s41591-024-03095-3.
  7. ↑ Liu XY, Ge SY, Liu CA; et al. (2025). "Validation of the 2024 European Association for the Study of Obesity diagnostic criteria: A comprehensive assessment of obesity-related mortality risks". Diabetes Obes Metab. 27 (5): 2405–2417. doi:10.1111/dom.16236.
  8. ↑ Sharma AM, Kushner RF (2009). "A proposed clinical staging system for obesity". Int J Obes (Lond). 33 (3): 289–295. doi:10.1038/ijo.2009.2. PMID 19430523.
  9. ↑ 9.0 9.1 9.2 9.3 Nadolsky K, Garvey WT, Agarwal M; et al. (2025). "American Association of Clinical Endocrinology Consensus Statement: Algorithm for the Evaluation and Treatment of Adults With Obesity/Adiposity-Based Chronic Disease - 2025 Update". Endocr Pract. 31 (11): 1351–1394. doi:10.1016/j.eprac.2025.07.017.
  10. ↑ 10.0 10.1 10.2 10.3 Grunvald E, Shah R, Hernaez R, Chandar AK, Pickett-Blakely O, Teigen LM; et al. (2022). "AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity". Gastroenterology. 163 (5): 1198–1225. doi:10.1053/j.gastro.2022.08.045. PMID 36273831 Check |pmid= value (help).
  11. ↑ American Diabetes Association Professional Practice Committee (2026). "8. Obesity and Weight Management for the Prevention and Treatment of Diabetes: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Supplement_1): S166–S182. doi:10.2337/dc26-S008.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 "IMCIVREE prescribing information" (PDF). U.S. Food and Drug Administration. 2026. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "WEGOVY prescribing information" (PDF). U.S. Food and Drug Administration. 2026. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  14. ↑ "FDA Approves Fourth Product Under National Priority Voucher Program: Higher-Dose Semaglutide". U.S. Food and Drug Administration. March 19 2026. Retrieved May 27 2026. Check date values in: |accessdate=, |date= (help)
  15. ↑ Wharton S, Lingvay I, Bogdanski P; et al. (2025). "Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity". N Engl J Med. 393 (11): 1077–1087. doi:10.1056/NEJMoa2500969.
  16. ↑ 16.0 16.1 "ZEPBOUND prescribing information" (PDF). U.S. Food and Drug Administration. 2025. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  17. ↑ 17.0 17.1 17.2 "FOUNDAYO prescribing information" (PDF). U.S. Food and Drug Administration. 2026. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  18. ↑ "SAXENDA prescribing information" (PDF). U.S. Food and Drug Administration. 2024. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  19. ↑ 19.0 19.1 19.2 19.3 19.4 "QSYMIA prescribing information" (PDF). U.S. Food and Drug Administration. 2024. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 "CONTRAVE prescribing information" (PDF). U.S. Food and Drug Administration. 2025. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  21. ↑ 21.0 21.1 21.2 "XENICAL prescribing information" (PDF). U.S. Food and Drug Administration. 2015. Retrieved May 27 2026. Check date values in: |accessdate= (help)
  22. ↑ 22.0 22.1 22.2 Yanovski SZ, Yanovski JA (2014). "Long-term drug treatment for obesity: a systematic and clinical review". JAMA. 311 (1): 74–86. doi:10.1001/jama.2013.281361. PMID 24438740.
  23. ↑ 23.0 23.1 23.2 Chakhtoura M, Haber R, Ghezzawi M, Rhayem C, Tcheroyan R, Mantzoros CS (2023). "Pharmacotherapy of obesity: an update on the available medications and drugs under investigation". EClinicalMedicine. 58: 101882. doi:10.1016/j.eclinm.2023.101882. PMID 36915759 Check |pmid= value (help).
  24. ↑ Wilding JPH, Batterham RL, Calanna S; et al. (2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity". N Engl J Med. 384 (11): 989–1002. doi:10.1056/NEJMoa2032183. PMID 33567185 Check |pmid= value (help).
  25. ↑ Garvey WT, Batterham RL, Bhatta M; et al. (2022). "Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial". Nat Med. 28 (10): 2083–2091. doi:10.1038/s41591-022-02026-4. PMID 36216945 Check |pmid= value (help).
  26. ↑ 26.0 26.1 Rubino DM, Greenway FL, Khalid U; et al. (2022). "Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial". JAMA. 327 (2): 138–150. doi:10.1001/jama.2021.23619. PMID 35015037 Check |pmid= value (help).
  27. ↑ 27.0 27.1 27.2 Wharton S, Freitas P, Hjelmesæth J; et al. (2025). "Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial". Lancet Diabetes Endocrinol. 13 (11): 949–963. doi:10.1016/S2213-8587(25)00226-8. PMID 40961952 Check |pmid= value (help).
  28. ↑ 28.0 28.1 Lingvay I, Bergenheim SJ, Buse JB; et al. (2025). "Once-weekly semaglutide 7.2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial". Lancet Diabetes Endocrinol. 13 (11): 935–948. doi:10.1016/S2213-8587(25)00225-6. PMID 40961953 Check |pmid= value (help).
  29. ↑ 29.0 29.1 29.2 Lincoff AM, Brown-Frandsen K, Colhoun HM; et al. (2023). "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes". N Engl J Med. 389 (24): 2221–2232. doi:10.1056/NEJMoa2307563. PMID 37952131 Check |pmid= value (help).
  30. ↑ Deanfield J, Lincoff AM, Kahn SE; et al. (2025). "Semaglutide and Cardiovascular Outcomes by Baseline and Changes in Adiposity Measurements: A Prespecified Analysis of the SELECT Trial". Lancet. 406 (10516): 2257–2268. doi:10.1016/S0140-6736(25)01375-3.
  31. ↑ 31.0 31.1 "FDA approves treatment for serious liver disease known as MASH". U.S. Food and Drug Administration. August 15 2025. Retrieved May 27 2026. Check date values in: |accessdate=, |date= (help)
  32. ↑ 32.0 32.1 "FDA Approves First Medication for Obstructive Sleep Apnea". U.S. Food and Drug Administration. December 20 2024. Retrieved May 27 2026. Check date values in: |accessdate=, |date= (help)
  33. ↑ Jastreboff AM, Aronne LJ, Ahmad NN; et al. (2022). "Tirzepatide Once Weekly for the Treatment of Obesity". N Engl J Med. 387 (3): 205–216. doi:10.1056/NEJMoa2206038. PMID 35658024 Check |pmid= value (help).
  34. ↑ Garvey WT, Frias JP, Jastreboff AM; et al. (2023). "Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial". Lancet. 402 (10402): 613–626. doi:10.1016/S0140-6736(23)01200-X. PMID 37385275 Check |pmid= value (help).
  35. ↑ Aronne LJ, Horn DB, le Roux CW; et al. (2025). "Tirzepatide as Compared with Semaglutide for the Treatment of Obesity". N Engl J Med. 393 (1): 26–36. doi:10.1056/NEJMoa2416394.
  36. ↑ 36.0 36.1 Wharton S, Blevins T, Connery L; et al. (2023). "Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity". N Engl J Med. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564 Check |pmid= value (help).
  37. ↑ Wharton S, Aronne LJ, Stefanski A; et al. (2025). "Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment". N Engl J Med. 393 (18): 1796–1806. doi:10.1056/NEJMoa2511774.
  38. ↑ Horn DB, Ryan DH, Kis SG; et al. (2026). "Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial". Lancet. 406 (10522): 2927–2944. doi:10.1016/S0140-6736(25)02165-8.
  39. ↑ Aronne LJ, Horn DB, le Roux CW; et al. (2026). "Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial". Nat Med. doi:10.1038/s41591-026-04386-7. PMID 42120723 Check |pmid= value (help).
  40. ↑ Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M; et al. (2015). "A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management". N Engl J Med. 373 (1): 11–22. doi:10.1056/NEJMoa1411892. PMID 26132939.
  41. ↑ Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML; et al. (2011). "Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial". Lancet. 377 (9774): 1341–1352. doi:10.1016/S0140-6736(11)60205-5. PMID 21481449.
  42. ↑ "Diethylpropion hydrochloride prescribing information". U.S. Food and Drug Administration. 2019. Check date values in: |accessdate= (help); Missing or empty |url= (help); |access-date= requires |url= (help)
  43. ↑ Greenway FL, Aronne LJ, Raben A; et al. (2019). "A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss". Obesity (Silver Spring). 27 (2): 205–216. doi:10.1002/oby.22347. PMID 30694541.
  44. ↑ 44.0 44.1 44.2 Mozaffarian D, Agarwal M, Aggarwal M; et al. (2025). "Nutritional Priorities to Support GLP-1 Therapy for Obesity: A Joint Advisory From the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society". Am J Clin Nutr. 122 (1): 344–367. doi:10.1016/j.ajcnut.2025.04.023.
  45. ↑ 45.0 45.1 Perkovic V, Tuttle KR, Rossing P; et al. (2024). "Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes". N Engl J Med. 391 (2): 109–121. doi:10.1056/NEJMoa2403347. PMID 38785209 Check |pmid= value (help).
  46. ↑ Colhoun HM, Lingvay I, Brown-Frandsen K; et al. (2024). "Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial". Nat Med. 30 (7): 2058–2066. doi:10.1038/s41591-024-03015-5.
  47. ↑ Mendonça L, Moura H, Chaves PC, Neves JS, Ferreira JP (2025). "The Impact of Glucagon-Like Peptide-1 Receptor Agonists on Kidney Outcomes: A Meta-Analysis of Randomized Placebo-Controlled Trials". Clin J Am Soc Nephrol. 20 (2): 159–168. doi:10.2215/CJN.0000000584.
  48. ↑ Kunutsor SK, Seidu S (2025). "Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists: A State-of-the-Art Narrative Review". Drugs. doi:10.1007/s40265-025-02263-0.
  49. ↑ Chiang CH, Jaroenlapnopparat A, Colak SC; et al. (2025). "Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis". Gastroenterology. doi:10.1053/j.gastro.2025.06.003.
  50. ↑ 50.0 50.1 Rosen CJ, Ingelfinger JR (2026). "GLP-1 Receptor Agonists". N Engl J Med. 394 (13): 1313–1324. doi:10.1056/NEJMra2500106.
  51. ↑ Fotheringham P, McGee RG, Chang R, Kennedy D, Simmons D (2026). "Pharmacological Management of Obesity in Pregnancy: A Review of Current and Emerging Therapies". Drugs. 86 (3): 321–333. doi:10.1007/s40265-025-02279-6.
  52. ↑ Wilding JPH, Batterham RL, Davies M; et al. (2022). "Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension". Diabetes Obes Metab. 24 (8): 1553–1564. doi:10.1111/dom.14725. PMID 35441470 Check |pmid= value (help).
  53. ↑ Aronne LJ, Sattar N, Horn DB; et al. (2024). "Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial". JAMA. 331 (1): 38–48. doi:10.1001/jama.2023.24945. PMID 38078870 Check |pmid= value (help).
  54. ↑ 54.0 54.1 54.2 Perdomo CM, Cohen RV, Sumithran P, Clément K, Frühbeck G (2023). "Contemporary medical, device, and surgical therapies for obesity in adults". Lancet. 401 (10382): 1116–1130. doi:10.1016/S0140-6736(22)02403-5. PMID 36958749 Check |pmid= value (help).
  55. ↑ 55.0 55.1 55.2 De Luca M, Cohen RV, Belluzzi A; et al. (2026). "Efficacy and Safety of Pharmacological, Endoscopic, and Surgical Treatments for Obesity: A GRADE-Based Network Meta-Analysis". Obesity (Silver Spring). doi:10.1002/oby.70083.
  56. ↑ 56.0 56.1 56.2 56.3 Dhippayom T, Meraz M, Lee H; et al. (2026). "GLP-1 receptor agonists for treating obesity without diabetes: A systematic review and meta-analysis of economic evaluations". Diabetes Obes Metab. 28 (2): 1339–1349. doi:10.1111/dom.70322.
  57. ↑ 57.0 57.1 57.2 Klebanoff MJ, Li P, Long JA, Doshi JA (2025). "Medicare Part D Coverage and Costs for Glucagon-Like Peptide-1 Receptor Agonists". JAMA. 334 (20): 1848–1850. doi:10.1001/jama.2025.15841.
  58. ↑ Neumiller JJ, Bajaj M, Bannuru RR; et al. (2025). "Compounded GLP-1 and Dual GIP/GLP-1 Receptor Agonists: A Statement From the American Diabetes Association". Diabetes Care. 48 (2): 177–181. doi:10.2337/dci24-0091.
  59. ↑ McCall KL, Mastro Dwyer KA, Casey RT; et al. (2026). "Safety Analysis of Compounded GLP-1 Receptor Agonists: A Pharmacovigilance Study Using the FDA Adverse Event Reporting System". Expert Opin Drug Saf. 25 (3): 581–588. doi:10.1080/14740338.2025.2499670.
  60. ↑ "FDA's Concerns with Unapproved GLP-1 Drugs Used for Weight Loss". U.S. Food and Drug Administration. February 4 2026. Retrieved May 27 2026. Check date values in: |accessdate=, |date= (help)
  61. ↑ Garvey WT, Blüher M, Osorto Contreras CK; et al. (2025). "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity". N Engl J Med. 393 (7): 635–647. doi:10.1056/NEJMoa2502081.
  62. ↑ Davies MJ, Bajaj HS, Broholm C; et al. (2025). "Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes". N Engl J Med. 393 (7): 648–659. doi:10.1056/NEJMoa2502082.
  63. ↑ Jastreboff AM, Kaplan LM, Frías JP; et al. (2023). "Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial". N Engl J Med. 389 (6): 514–526. doi:10.1056/NEJMoa2301972. PMID 37366315 Check |pmid= value (help).
  64. ↑ Kokkorakis M, Chakhtoura M, Rhayem C; et al. (2025). "Emerging Pharmacotherapies for Obesity: A Systematic Review". Pharmacol Rev. 77 (1): 100002. doi:10.1124/pharmrev.123.001045.
  65. ↑ Harrison SA, Ruane PJ, Freilich B; et al. (2025). "Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on liver fat content and body weight in metabolic dysfunction-associated steatotic liver disease: a randomized, placebo-controlled trial". J Hepatol. 82 (1): 58–69. doi:10.1016/j.jhep.2024.06.014. PMID 39002641 Check |pmid= value (help).
  66. ↑ Buch A, Eldor R, Brown R, Zonszein J (2025). "Novel oral agents in anti-obesity pharmacotherapy: A narrative review". Diabetes Obes Metab. 27 (10): 5409–5417. doi:10.1111/dom.16618. PMID 40662383 Check |pmid= value (help).
  67. ↑ "Pfizer Provides Update on Oral GLP-1 Receptor Agonist Danuglipron". Pfizer. April 14 2025. Retrieved May 27 2026. Check date values in: |accessdate=, |date= (help)
  68. ↑ Knop FK, Vilsbøll T, Wewer Albrechtsen NJ; et al. (2025). "Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial". Lancet Diabetes Endocrinol. 13 (11): 906–918. doi:10.1016/S2213-8587(25)00216-5. PMID 41038215 Check |pmid= value (help).
  69. ↑ Bays HE, Biesbroeck E, Hatorp V; et al. (2026). "Weekly Subcutaneous VK2735, a GIP/GLP-1 Receptor Dual Agonist, for Weight Management: Phase 2, Randomized, 13-Week VENTURE Study". Obesity (Silver Spring). 34 (3): 537–549. doi:10.1002/oby.70106. PMID 41508550 Check |pmid= value (help).


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