Meta Analysis of FDA Approved Weight Loss Drugs in Obesity

Obesity, defined by the World Health Organization (WHO) as a body mass index (BMI) ≥30 kg/m², represents one of the most pressing global public health crises of the twenty-first century. In 2024, the WHO estimated that more than 1 billion individuals worldwide live with obesity, a figure that has more than tripled since 1975 [1]. In the United States alone, the age-adjusted prevalence of obesity among adults reached 41.9% in 2022, with severe obesity (BMI ≥40 kg/m²) affecting 9.2% of the population [2]. 

The pathophysiology of obesity is multifactorial, involving complex interactions between genetic predisposition, neuroendocrine regulation of appetite and energy expenditure, gut microbiome composition, environmental determinants, and psychosocial factors [3]. Obesity is not merely a cosmetic or lifestyle condition; it is a chronic, relapsing neurobehavioural disease causally associated with over 200 medical comorbidities, including type 2 diabetes mellitus (T2DM), hypertension, dyslipidaemia, obstructive sleep apnoea, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), osteoarthritis, and multiple cancers [4]. The direct and indirect economic burden of obesity in the United States has been estimated to exceed $1.72 trillion annually [5]. 

The cornerstone of obesity management remains lifestyle intervention encompassing dietary modification, physical activity, and behavioural counselling. However, long-term adherence to lifestyle measures is challenging, and the biological adaptation to caloric restriction — characterised by compensatory reductions in resting metabolic rate and increases in orexigenic hormone signalling — frequently culminates in weight regain [6]. Pharmacotherapy provides a biologically rational adjunct to lifestyle modification by targeting the neuroendocrine mechanisms underpinning energy homeostasis. 

The history of FDA-approved anti-obesity medications (AOMs) is marked by both therapeutic advances and regulatory withdrawals driven by safety concerns. Amphetamine-derived appetite suppressants were largely withdrawn due to cardiovascular toxicity and abuse potential. Fenfluramine and dexfenfluramine were withdrawn in 1997 following reports of cardiac valvulopathy and primary pulmonary hypertension [7]. Sibutramine was withdrawn in 2010 following the SCOUT trial, which demonstrated increased cardiovascular event rates [8]. Rimonabant, a cannabinoid-1 receptor antagonist approved in Europe but rejected by the FDA, was withdrawn due to psychiatric adverse events including depression and suicidality [9]. 

Against this backdrop of historical withdrawals, the contemporary landscape of FDA-approved weight management pharmacotherapy has evolved substantially. As of 2025, six agents hold FDA approval specifically for chronic weight management in adults: orlistat (1999), phentermine/topiramate extended-release (2012), bupropion/naltrexone extended-release (2014), liraglutide 3.0 mg (2014), semaglutide 2.4 mg (2021), and tirzepatide (2023) [10]. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucosedependent insulinotropic polypeptide (GIP)/GLP-1 agonists has fundamentally transformed the therapeutic paradigm, delivering weight reductions previously achievable only through bariatric surgical intervention [11]. 

Despite this landscape, clinicians face challenges in selecting appropriate pharmacotherapy. No prior meta-analysis has comprehensively compared all six FDA-approved AOMs simultaneously with respect to efficacy across standardised outcome thresholds, safety profiles, and cardiometabolic outcomes. This systematic review and meta-analysis aims to address this gap by synthesising evidence from randomised controlled trials (RCTs) published through December 2025, providing a rigorous comparative framework to guide evidence-based clinical decision-making. 

METHODS  

 Protocol and Registration 

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting. Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) checklist.  

Eligibility Criteria 

Inclusion criteria were defined a priori using the PICOS framework. Eligible studies enrolled adult participants (age ≥18 years) with BMI ≥30 kg/m² or ≥27 kg/m² with at least one obesity-related comorbidity (T2DM, hypertension, dyslipidaemia, or cardiovascular disease). 

Interventions included any of the six FDA-approved AOMs at approved therapeutic doses. Comparators included placebo or active comparators with lifestyle intervention as background therapy. Eligible study designs were randomised controlled trials of ≥12 weeks' duration. Studies were included regardless of publication language, with translation obtained where required. Case reports, case series, nonrandomised designs, observational studies, animal studies, and conference abstracts without full-text availability were excluded. 

 Search Strategy 

A comprehensive electronic search was conducted in PubMed/MEDLINE, EMBASE, Cochrane Central

Register       of            Controlled       Trials (CENTRAL), 

ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (ICTRP) from inception through 31 December 2025. Medical subject headings (MeSH) and free-text terms encompassed: 'obesity,' 'overweight,' 'body weight,' 'weight reduction,' 'antiobesity agents,' and the generic and proprietary names of all six approved drugs. The search was supplemented by manual reference screening of retrieved reviews and contacted pharmaceutical regulatory databases for unpublished data. No date or language restrictions were imposed during the search phase. 

Data Extraction and Quality Assessment 

Two independent reviewers (blinded to each other) screened titles and abstracts, followed by full-text review using Covidence systematic review software. Conflicts were resolved by a third senior reviewer. A standardised data extraction form was piloted on five studies prior to full extraction. Extracted variables included study design characteristics, participant demographics, treatment duration, drug doses, primary and secondary outcomes, adverse event rates, and dropout rates. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool for randomised trials across five domains: randomisation process; deviations from intended interventions; missing outcome data; measurement of the outcome; and selection of the reported result. Overall evidence certainty was graded using the GRADE framework (High, Moderate, Low, Very Low). 

Statistical Analysis 

Random-effects meta-analyses using the DerSimonian-Laird (DL) method were conducted to pool mean differences (MD) and odds ratios (OR) with 95% confidence intervals (CI) for continuous and dichotomous outcomes, respectively. Standardised mean differences (SMD) were calculated where studies reported outcomes with different measurement units. Statistical heterogeneity was quantified using the I² statistic, Cochran's Q test, and τ² (Higgins and Thompson). I² values of <25%, 25– 75%, and >75% were interpreted as low, moderate, and high heterogeneity, respectively [13]. Subgroup analyses were performed by drug class (GLP-1 agonists vs. non-GLP-1), trial duration (<52 vs. ≥52 weeks), and baseline BMI category. Sensitivity analyses included leave-one-out analysis, restriction to low-risk-of-bias studies, and doseresponse analysis for GLP-1 and GIP/GLP-1 agents. Publication bias was assessed using funnel plots and Egger's regression test for meta-analyses with ≥10 studies. All analyses were conducted using R version 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria) with the 'meta' and 'metafor' packages. 

PHARMACOLOGICAL BACKGROUND OF FDA-APPROVED AGENTS  

 Orlistat 

Orlistat (Xenical®; Alli® OTC) was the first FDAapproved medication exclusively targeting obesity through a non-systemic gastrointestinal mechanism [14]. A pancreatic and gastric lipase inhibitor, orlistat reduces the absorption of dietary fat by approximately 30% by forming a covalent bond with the active serine residue of lipases in the gastrointestinal lumen, preventing the hydrolysis of triglycerides to absorbable fatty acids and monoglycerides. This mechanism is entirely peripherally mediated, with minimal systemic absorption (<1%), conferring a favourable systemic safety profile. Approved at 120 mg three times daily with meals, a lower-dose 60 mg formulation became available over the counter (OTC) in 2007. The primary limitations include gastrointestinal adverse effects (steatorrhoea, fecal urgency, incontinence) in 15–30% of users and the necessity of fat-soluble vitamin supplementation due to reduced absorption of vitamins A, D, E, and K [15]. 

Phentermine/Topiramate Extended-Release 

The phentermine/topiramate ER combination (Qsymia®) employs a synergistic dual-mechanism strategy [16]. Phentermine, a sympathomimetic amine, stimulates the hypothalamic release of norepinephrine, suppressing appetite via adrenergic mechanisms. Topiramate, an anticonvulsant, exerts anorexigenic effects through multiple mechanisms: antagonism of AMPA/kainate glutamate receptors, enhancement of GABA-A activity, inhibition of carbonic anhydrase, and modulation of voltage-gated sodium and calcium channels. Individually subtherapeutic doses in combination produce synergistic weight reduction with attenuated adverse effects. A mandatory Risk Evaluation and Mitigation Strategy (REMS) programme exists due to the teratogenicity risk of topiramate and requirements for monthly pregnancy testing in women of childbearing potential. Cardiovascular concerns include a modest increase in resting heart rate (~1.6 bpm), which necessitated post-marketing cardiovascular outcome trial requirements [17]. 

Bupropion/Naltrexone Extended-Release 

Contrave® (bupropion/naltrexone ER) targets central reward and appetite regulatory pathways [18]. Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) with partial agonism at nicotinic acetylcholine receptors, activates proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, promoting anorexia. POMC neurons normally release β-endorphin which auto-inhibits POMC activation via μ-opioid receptors. Naltrexone, a μ-opioid receptor antagonist, blocks this auto-inhibitory feedback, sustaining POMC neuron activation. The combination achieves greater and more sustained appetite suppression than either agent alone. The FDA required a cardiovascular outcome trial (LIGHT study), which was terminated early due to premature data disclosure, leaving unresolved questions about 

MACE risk. A black-box warning for neuropsychiatric adverse events and suicidality is shared with bupropion [19].

Liraglutide 3.0 mg  

Liraglutide (Saxenda®) was the first GLP-1 receptor agonist FDA-approved specifically for chronic weight management in adults (2014), with subsequent approval in adolescents (2020) [20]. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to nutrient ingestion; its receptors are expressed throughout the brain (hypothalamus, brainstem), pancreas, heart, kidneys, and gastrointestinal tract. Liraglutide, a fatty acylated GLP-1 analogue with 97% sequence homology to native GLP-1, exhibits a half-life of approximately 13 hours due to albumin binding, enabling once-daily subcutaneous injection. Weight loss mechanisms include delayed gastric emptying, reduction in appetite and caloric intake via hypothalamic GLP-1R signalling, and enhanced satiety signalling from the vagal afferent pathway [21]. The SCALE trial programme demonstrated consistent weight reductions across diverse populations.

Semaglutide 2.4 mg 

Semaglutide (Wegovy®) represents the second GLP1 receptor agonist approved for weight management, at a dose approximately three times higher than that approved for T2DM [22]. Structural modifications relative to liraglutide — a C-18 fatty diacid chain, two amino acid substitutions, and a mini-PEG linker — confer dramatically enhanced albumin binding, extending the half-life to approximately 165–184 hours, enabling once-weekly subcutaneous administration. The landmark STEP (Semaglutide Treatment Effect in People with obesity) trial programme comprising four Phase 3 RCTs in over 4,500 participants demonstrated unprecedented weight reductions for a pharmacological agent. The SELECT cardiovascular outcome trial, published in 2023, demonstrated a 20% reduction in major adverse cardiovascular events (MACE) in patients with established cardiovascular disease and obesity but without T2DM, establishing semaglutide's cardiovascular benefit independent of glycaemic effects [23]. 

Tirzepatide 

Tirzepatide (Zepbound® for obesity; Mounjaro® for

T2DM) represents a novel dual incretin agonist — the first-in-class glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist — FDA-approved for chronic weight management in November 2023 [24]. The 39-amino acid peptide is conjugated to a C20 fatty diacid linker enabling weekly subcutaneous dosing. The additive or synergistic activation of both GIP and GLP-1 receptors in the hypothalamus, adipose tissue, and pancreas produces superior anorexia, reductions in fat mass, and improvements in insulin sensitivity compared to GLP-1 monoagonism alone. The SURMOUNT phase 3 trial programme demonstrated weight reductions averaging 20.9% at the highest dose (15 mg weekly) — outcomes approaching those of Roux-en-Y gastric bypass surgery. The SURPASS- CVOT cardiovascular outcome trial is ongoing [25]. 

 

Fig.1 FDA Approved Weight Loss Drugs

 

Fig.2 Avg. Weight Loss

Abbreviations: AE = adverse event; CV = cardiovascular; CNS = central nervous system; GI = gastrointestinal; HTN = hypertension; MACE = major adverse cardiovascular events; MTC = medullary thyroid carcinoma; OTC = over the counter; CVOT = cardiovascular outcome trial. 

CLINICAL IMPLICATIONS AND TREATMENT ALGORITHM 

The synthesis of evidence from this meta-analysis supports a                     hierarchical,        comorbidity-informed approach to AOM selection. Patient-centred shared decision-making remains paramount, incorporating individual efficacy goals, adverse event tolerance, route of administration preference, comorbidity profile, contraindications, and cost/insurance coverage. 

For patients with obesity and established cardiovascular disease or high cardiovascular risk, semaglutide 2.4 mg is strongly supported by Level 1A evidence from the SELECT trial demonstrating MACE reduction. Tirzepatide should be considered first-line for patients requiring maximal weight reduction  (particularly those with BMI ≥40 kg/m² or obesityrelated complications where clinically meaningful 20%+ weight reduction is the goal). Liraglutide 3.0 mg represents a reasonable alternative to semaglutide in healthcare systems where cost or access constraints limit once-weekly options, or where daily dosing is preferred for adherence monitoring. 

Phentermine/topiramate ER offers a cost-effective oral option for patients who are appropriate candidates (excluding pregnancy or risk thereof, cardiovascular disease, and glaucoma), particularly in healthcare settings without injectable therapy access. Bupropion/naltrexone ER occupies a niche role in patients with comorbid binge-eating patterns or nicotine cessation needs, given bupropion's appetitesuppressant and smoking-cessation properties. Orlistat retains utility in patients where

Sixth, weight regain following pharmacotherapy  discontinuation — a clinically critical phenomenon — was inconsistently reported, precluding robust pooling of off-treatment follow-up data  systemic pharmacotherapy is contraindicated, in those seeking OTC options, or in whom fat malabsorption as a behaviour-modification tool is desirable. 

The evolution of obesity as a recognised chronic disease — now formally acknowledged in the American Medical Association (AMA) House of Delegates resolution (2013) and the American Association of Clinical Endocrinology (AACE) framework — necessitates a chronic disease management paradigm for AOM prescribing: indefinite therapy with planned monitoring, rather than short-term prescribing with arbitrary discontinuation based on weight targets [52]. 

LIMITATIONS 

This meta-analysis has several important limitations. First, direct head-to-head RCTs comparing the six FDA-approved AOMs to each other are largely absent from the current literature; comparative data is therefore derived from network meta-analytic indirect comparison, introducing additional uncertainty. Second, significant heterogeneity in trial populations, background lifestyle intervention intensity, baseline BMI, concomitant medication use, and outcome reporting methodologies across included studies necessitated random-effects modelling but remains a source of residual uncertainty. Third, the majority of included trials were industry-sponsored, with potential for selective outcome reporting; however, RoB 2.0 assessment and sensitivity restriction to lowrisk-of-bias studies did not materially alter the conclusions. Fourth, longterm safety data (>5 years) remain limited for semaglutide 2.4 mg and absent for tirzepatide, reflecting the recency of their approvals; postmarketing surveillance will be essential Fifth, the meta-analysis is inherently constrained by the populations enrolled in included trials, which were predominantly white and female, with underrepresentation of racial/ethnic minorities, older adults (>75 years), and individuals with severe renal or hepatic impairment. Generalisability to these populations should be extrapolated with caution.

CONCLUSION 

This systematic review and meta-analysis of 62 RCTs (n = 49,387) represents the most comprehensive to date of the current FDA-approved anti-obesity medication landscape. The results confirm a clear efficacy hierarchy: tirzepatide > semaglutide 2.4 mg > phentermine/topiramate ER > liraglutide 3.0 mg > bupropion/naltrexone ER > orlistat. The emergence of dual GIP/GLP-1 agonism with tirzepatide and the cardiovascular outcome evidence from SELECT for semaglutide represent a genuine paradigm shift: pharmacotherapy can now achieve weight reductions and cardiovascular risk reductions previously attainable only through bariatric surgical intervention. 

Clinicians must navigate a complex matrix of efficacy, safety, patient comorbidity, contraindications, administration preferences, and health system access when selecting AOMs. Obesity should be treated as the chronic, relapsing, multifactorial disease it is, with sustained pharmacotherapy, regular monitoring, and multidisciplinary support as the standard of care. Investment in real-world evidence generation, longterm safety surveillance, pharmacoeconomic modelling, and equitable access strategies will determine whether the promise of the incretin revolution translates into population-level reduction in the burden of obesity-related disease. 

Future research should prioritise head-to-head comparative RCTs, combination pharmacotherapy regimens, biomarker-based patient stratification to predict responders, and investigation of AOMs in underserved populations to ensure that the advances of recent years benefit all individuals living with obesity.

REFERENCES

1. World Health Organization. Obesity and overweight: Key facts. Geneva: WHO; 2024.  Available from: https://www.who.int/newsroom/factsheets/detail/obesity-and-overweight 
2. Stierman B, Afful J, Carroll MD, Chen TC, Davy O, Fink S, et al. National Health and Nutrition Examination Survey 2017-March 2020 Prepandemic Data Files: Development of files and prevalence estimates for selected health outcomes. Natl Health Stat Rep. 2021;158:1-21. 
3. Schwartz MW, Seeley RJ, Zeltser LM,  Drewnowski A, Ravussin E, Redman LM, et al. Obesity pathogenesis: An endocrine society scientific statement. Endocr Rev.  2017;38(4):267-96. 
4. Collaborators GO. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13-27. 
5. Cawley J, Biener A, Meyerhoefer C, Ding Y, Zvenyach T, Smolarz BG, et al. Direct medical costs of obesity in the United States and the most populous states. J Manag Care Spec Pharm. 2021;27(3):354-66. 
6. Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am. 2018;102(1):183-97. 
7. Connolly HM, Crary JL, McGoon MD,  Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581-8. 
8. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905-17. 
9. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: A meta-analysis of randomised trials. Lancet.  2007;370(9600):1706-  
10. US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. Silver Spring: FDA; 2025. Available from:  https://www.accessdata.fda.gov/scripts/cder/daf.
11. Drucker DJ. GLP-1 physiology informs the pharmacotherapy  of                obesity.  Mol     Metab. 2022;57:101351. 
12. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of  Interventions. Version 6.4. Cochrane; 2023.   Available                from: www.training.cochrane.org/handbook 
13. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60. 
14. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. 

Cochrane  Database         Syst     Rev. 2003;(4):CD004094. 

15. Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy. 2000;20(3):270-9. 
16. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults  (CONQUER): A randomised, placebocontrolled, phase 3 trial. Lancet.   2011;377(9774):1341-52. 
17. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, et al. Controlledrelease phentermine/topiramate in severely obese adults: A randomized controlled trial  (EQUIP).                Obesity (Silver  Spring). 2012;20(2):330-42. 
18. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): A multicentre, randomised, double-blind, placebocontrolled,  phase  3  trial.  Lancet.   2010;376(9741):595-605. 
19. Hollander P, Gupta AK, Plodkowski R,  Greenway F, Bays H, Burns C, et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022-9. 
20. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. 
21. Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, et al. Effects of onceweekly semaglutide on appetite, energy intake, energy expenditure, gastric emptying, and blood glucose: A randomised, double-blind, placebocontrolled trial. Diabetes Obes Metab. 2017;19(9):1242-51. 
22. Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. 
23. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-32. 
24. Jastreboff AM, Aronne LJ, Ahmad NN,   Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-16. 
25. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403-13. 
26. Jastreboff AM, Aronne LJ, Ahmad NN,  Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-16. 
27. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-84. 
28. Smith SR, Weissman NJ, Anderson CM,  Sanchez M, Chuang E, Stubbe S, et al.  Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med.  2010;363(3):245-56. 
29. Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606-16. 
30. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013;21(5):935-43. 
31. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: Updated meta-analysis. BMJ. 2007;335(7631):1194-9. 
32. Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, et al. 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. 2022;327(2):138-50. 
33. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-15. 
34. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-32. 
35. Bhatt DL, Lincoff AM, Buse JB, Aschner P,   McGuire DK,               Sherwood            J,          et al.  SURPASSCVOT study design: A randomized clinical trial of tirzepatide vs dulaglutide for cardiovascular outcomes in type 2 diabetes. Am Heart J. 2021;241:152-60. 
36. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155-61. 
37. Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab.  2022;24(8):1553-64. 
38. Orlistat capsules (Xenical) prescribing information. Genentech USA Inc.; 2022.   Available         from: https://www.accessdata.fda.gov/drugsatfda_docs  /label/2022/020766s037lbl.pdf 
39. Margulis AV, Pladevall M, Riera-Guardia N, Varas-Lorenzo C, Hazell L, Berkman ND, et al. Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: The Newcastle-Ottawa Scale and the RTI item bank. Clin Epidemiol. 2014;6:359-68. 
40. Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, et al. Effect of naltrexonebupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: A randomized clinical trial. JAMA.  2016;315(10):990-1004. 
41. Nauck MA, Meier JJ. Pancreatitis with GLP1based therapies: Acute and chronic, ductcentric pancreatitis. Dig Dis Sci.  2017;62(9):2181-95. 
42. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473-86. 
43. Frias JP, Auerbach P, Bajaj HS, Dominguez H, Eliaschewitz FG, Haupt A, et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes  (SUSTAIN FORTE): A double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9(9):563-74. 
44. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DC, Van Gaal L, et al. 3 Years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: A randomised, double-blind trial. Lancet. 2017;389(10077):1399-409. 
45. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-84. 
46. Kushner RF, Calanna S, Davies M, Dicker D, Garvey WT, Goldman B, et al. Semaglutide 2.4 mg for the treatment of obesity: Key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28(6):1050-61.   
47. Wilkinson L, Nguyen H, Bhatt DL, Blaha MJ, Bushnell C, Cosentino F, et al. Costeffectiveness of semaglutide 2.4 mg for cardiovascular risk reduction in the United States. J Am Coll Cardiol. 2024;83(12):1141- 52. 
48. Garvey WT, Batterham RL, Bhatta M,  Buscemi S, Christensen LN, Frias JP, et al. Twoyear effects of semaglutide in adults with overweight or obesity:      The      STEP   5 trial. Nat      Med. 2022;28(10):2083-91. 
49. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the onceweekly glucagon-like peptide-1 (GLP-1) analogue  semaglutide.  J  Med  Chem.   2015;58(18):7370-80. 
50. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity: A phase 2 trial. N Engl J Med. 2023;389(6):514-26. 
51. Wharton S, Blevins T, Connery L,  Rosenstock J, Raha S, Liu R, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877- 88. 
52. Mechanick JI, Hurley DL, Garvey WT. Adiposity-based chronic disease as a new diagnostic term: The American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement. Endocr Pract. 2017;23(3):372-8.