Review
This 2026 American College of Physicians (ACP) living clinical guideline synthesizes systematic reviews on pharmacologic treatments combined with lifestyle modifications for weight management in nonpregnant adults with overweight or obesity in outpatient settings, using the GRADE framework. For adults with obesity (BMI ≥30 kg/m²), the ACP issued conditional recommendations favoring semaglutide and tirzepatide as first-line agents (moderate-certainty evidence), phentermine-topiramate as second-line (low-certainty), liraglutide as third-line (low-certainty), and naltrexone-bupropion as fourth-line (low-certainty). For adults with overweight (BMI ≥27–30 kg/m²) who also have type 2 diabetes, dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease, the guideline conditionally recommends semaglutide and tirzepatide as first-line and liraglutide as second-line. All recommendations are conditional, reflecting the importance of shared decision-making around benefits, harms, costs, access, comorbidities, contraindications (e.g., cardiovascular contraindication and monthly pregnancy-test requirement for phentermine-topiramate; suicidal ideation risk with naltrexone-bupropion), and patient preferences. The living guideline format signals ongoing updates as new evidence emerges.
Annals of internal medicine · Jun 2026DOI ↗ Strong · human
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Annals of internal medicine · Jun 2026DOI ↗ Review
This systematic review, conducted for the American College of Physicians, evaluated the cost-effectiveness of pharmacologic treatments for overweight or obesity in U.S. adults. Researchers searched MEDLINE, Embase, and economic databases through October 2025, ultimately including 9 studies encompassing 42 pairwise treatment comparisons. Study quality was assessed using the CHEQUE tool, value was measured via incremental cost-effectiveness ratios (ICERs) against established willingness-to-pay thresholds, and certainty of evidence was graded using GRADE. Key findings from the 6 moderate-certainty studies suggested that liraglutide had low value compared with lifestyle modification, while phentermine-topiramate and tirzepatide showed high value versus lifestyle modification. Semaglutide demonstrated low value compared with naltrexone-bupropion and phentermine-topiramate, but high value compared with liraglutide. Important limitations include that all 9 included studies were model-based rather than empirical trial-based analyses, only 4 of 9 were at low risk of bias, none of the 42 comparisons reached high certainty, and reporting was frequently incomplete. The authors conclude that current U.S. evidence on cost-effectiveness of obesity pharmacotherapy is significantly hampered by poor study quality, restricting the strength of any conclusions that can be drawn.
Annals of internal medicine · Jun 2026DOI ↗ Review
This review synthesizes evidence from randomized controlled trials and high-quality meta-analyses on approved and investigational obesity medications, examining their effects beyond weight loss alone. Medications reviewed include phentermine-topiramate, naltrexone-bupropion, GLP-1 receptor agonists (liraglutide, semaglutide), and newer multiagonist agents (tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). The authors evaluated impacts across a broad range of obesity-related comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnea, polycystic ovary syndrome, osteoarthritis, muscle mass, depression, quality of life, food cravings, binge-eating disorders, substance use disorders, and neurodegenerative diseases. The review concludes that GLP-1-based and multiagonist therapies demonstrate beneficial effects across these conditions. Notably, the authors report that while many benefits appear to be mediated through weight reduction, accumulating evidence suggests weight loss-independent mechanisms, particularly for GLP-1 receptor agonist-based therapies. Key limitations include its reliance on synthesized rather than primary data and variability in evidence quality across the individual conditions reviewed.
The lancet. Diabetes & endocrinology · May 2026DOI ↗ Review
This narrative review examines the relationship between diabetes mellitus (DM) and stroke, and evaluates the cerebrovascular potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide). The authors summarize evidence from large cardiovascular outcome trials (CVOTs), noting that agents such as semaglutide and liraglutide were associated with reductions in non-fatal stroke incidence, fewer hospitalizations, and improved neurological outcomes in patients with prior stroke or high cardiovascular risk. The review highlights that stroke reduction may represent a class effect of GLP-1 RAs, though differences between individual agents exist, attributed to variations in pharmacokinetics, receptor affinity, and study populations. Evidence in the acute stroke setting is described as preliminary, coming largely from early-phase or ongoing trials. The authors also discuss emerging agents—orforglipron, retatrutide, Maridebart cafraglutide, and CagriSema—as potential future options. Limitations acknowledged include the narrative (non-systematic) design, reliance on trial-level rather than individual patient data, and the absence of large-scale, long-term randomized trials specifically targeting post-stroke populations. The authors conclude that GLP-1-based therapies should currently be considered tools for long-term vascular risk reduction rather than established acute stroke treatments.
Pharmaceutics · May 2026DOI ↗ Insufficient
This review article addresses the safety profile of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, specifically in the context of breastfeeding. The authors note that no empirical data are currently available on liraglutide use during lactation. The discussion is grounded in pharmacokinetic reasoning: liraglutide is a large peptide molecule with a molecular weight of 3,751 daltons, which suggests that transfer into breast milk would likely be minimal. Furthermore, even if trace amounts were present in milk, oral absorption by the nursing infant is considered unlikely, as the peptide would probably be degraded by proteolytic enzymes in the infant's gastrointestinal tract. Despite this theoretically low risk, the authors recommend caution when using liraglutide during breastfeeding, with particular attention to newborns and preterm infants, who may have less developed gastrointestinal and metabolic systems. The article acknowledges the absence of clinical or experimental data as a key limitation, meaning conclusions are based on indirect, mechanistic reasoning rather than direct observation or controlled study.
Unknown journal · May 2026Source ↗ Moderate · human
This network meta-analysis (NMA) synthesized evidence from six randomized controlled trials (N = 4,642; durations 12–68 weeks) to compare novel amylin-based therapies (ABTs) — amycretin, eloralintide, and cagrilintide/semaglutide (CagriSema) — against placebo and established anti-obesity agents (semaglutide 2.4 mg, liraglutide 3.0 mg) in adults with overweight or obesity without diabetes. Using a frequentist random-effects framework, the study found that high-dose subcutaneous amycretin produced the largest estimated reduction in percent body weight versus placebo (mean difference approximately −24%), followed by high-dose eloralintide (−18%) and high-dose CagriSema (−17%), all exceeding reductions seen with semaglutide 2.4 mg (−11%) and liraglutide 3.0 mg (−6%). Similar ranking patterns emerged for absolute weight, BMI, waist circumference, and categorical weight-loss thresholds. Gastrointestinal adverse events — particularly nausea, vomiting, and constipation — were more frequent with high-dose ABTs, and only high-dose CagriSema significantly increased treatment-discontinuation due to adverse events. The authors acknowledge that the included trials are few, relatively short-to-medium term, and carry low certainty of evidence, characterizing findings as preliminary and requiring confirmation in larger trials.
Endocrinology, diabetes & metabolism · May 2026DOI ↗ Limited · human
This cross-sectional study conducted in Saudi Arabia (January–June 2025) investigated the frequency, characteristics, and predictors of hair loss among 254 adults using GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Ozempic), tirzepatide (Mounjaro), liraglutide (Saxenda), or liraglutide (Victoza) — primarily for weight loss. Data were collected via structured questionnaires covering demographics, clinical characteristics, and hair loss details such as timing, severity, and progression. The majority of participants were female (71.3%), with a mean age of approximately 33 years. The study found that overall hair loss prevalence did not differ significantly across GLP-1RA types (p = 0.116); however, severe hair loss was reported significantly more often among Mounjaro (43.4%) and Saxenda (42.9%) users. Female sex and Mounjaro use were identified as notable predictors of hair loss. The authors noted that the hair loss observed was generally non-scarring and potentially reversible, but associated with psychological distress and possible impacts on treatment adherence. Key limitations include the cross-sectional design (precluding causal inference), reliance on self-reported data, the single-country sample limiting generalizability, and the absence of a control group not using GLP-1RAs.
Journal of cosmetic dermatology · Apr 2026DOI ↗ Review
This narrative review synthesizes the evolution of incretin-based pharmacotherapies for metabolic disorders, drawing on literature from PubMed, Scopus, and Google Scholar up to July 2025. The authors trace the trajectory from DPP-4 inhibitors—noted for modest glycaemic benefits—through GLP-1 receptor agonists (GLP-1RAs) such as liraglutide and semaglutide, which pivotal trials have associated with meaningful weight loss and cardiometabolic protection, to next-generation agents. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide are highlighted as demonstrating particularly substantial efficacy, with the review citing up to 24% body weight reduction alongside improvements in hepatic and inflammatory markers in included trials. Agents such as cotadutide and efinopegdutide are discussed in the context of expanding indications to MASLD and MASH. The authors acknowledge several limitations across the field: high cost and accessibility barriers, underrepresentation of low- and middle-income country populations in major trials, and pharmacogenomic variability that may modify therapeutic response. As a review, this paper does not generate new primary data. Its conclusions depend on the quality and representativeness of the underlying trials it synthesizes, and no independent meta-analytic pooling appears to have been conducted.
The Indian journal of medical research · Apr 2026DOI ↗ Review
This review examines the landscape of next-generation glucagon-like peptide-1 (GLP-1)-based therapeutics in clinical development for type 2 diabetes and obesity, building on the established success of semaglutide and tirzepatide. The authors survey a broad range of investigational agents that target multiple gastro-entero-pancreatic hormone receptors simultaneously — including GIP, glucagon, amylin, and peptide YY receptors — to produce synergistic effects on energy intake, storage, and expenditure. Specific agents discussed include maridebart cafraglutide (GLP-1 agonism/GIP antagonism), survodutide and mazdutide (GLP-1/glucagon coagonists), cagrilintide combined with semaglutide (CagriSema), amycretin (amylin/GLP-1 dual agent), and retatrutide (GIP/GLP-1/glucagon triple agonist). The review also highlights the emergence of oral small-molecule GLP-1 receptor agonists such as danuglipron and orforglipron, which resist enzymatic degradation and may improve patient convenience. The paper does not present original clinical trial data; it synthesizes existing preclinical and clinical development evidence. As a narrative review, it does not meta-analytically pool outcomes, and the included agents are largely at Phase 1–3 stages, meaning long-term efficacy and safety data remain limited.
Endocrine reviews · Mar 2026DOI ↗ Review
This evidence review examines the evolving landscape of incretin-based pharmacotherapy, focusing on GLP-1 receptor agonists (GLP-1RAs) and newer multi-receptor co-agonists for cardiometabolic disease management. The paper surveys established GLP-1RAs — including liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide — noting their reported benefits on glycated hemoglobin, body weight, lipid profiles, liver fat, and cardiovascular outcomes (reduction in major adverse cardiovascular events, or MACE). It also covers emerging agents: dual GIP/GLP-1 agonist tirzepatide (approved for diabetes and obesity), dual GLP-1/glucagon co-agonists (notable for synergistic weight loss), and triple GLP-1/GIP/glucagon receptor agonists such as retatrutide and efocipegtrutide, described as achieving the highest pharmacotherapy-associated weight loss observed to date. Additional novel classes reviewed include GLP-1/amylin agonists (CagriSema, Amycretin), non-semaglutide oral GLP-1 agents, and peptide YY/GLP-1 dual agonists. As a narrative review, the paper does not present original trial data, and its conclusions are based on synthesized existing literature, which may introduce selection bias. The authors anticipate that metabolic benefits will translate into cardiometabolic outcomes, though direct evidence for many newer agents remains limited.
World journal of cardiology · Aug 2025DOI ↗ Limited · human
This cross-sectional study examined self-reported outcomes among 486 adults in Kuwait who were using or had previously used GLP-1 receptor agonist (GLP-1 RA) injections — Semaglutide (n=181), Liraglutide (n=152), or Tirzepatide (n=132) — for weight loss, surveyed between February and May 2024. Participants completed an online questionnaire covering demographics, weight change, side effects, and quality of life. The study found that Tirzepatide users reported the highest average monthly and annual weight loss, along with the greatest satisfaction (88%) and most frequently reported improvements in quality of life (60%) compared to the other two agents. Side-effect profiles differed across groups: Tirzepatide users more commonly reported belching, while Liraglutide users reported higher rates of anxiety and were more likely to switch medications. No statistically significant differences were observed between groups in BMI, dietary adherence, or treatment compliance. Key limitations include the cross-sectional, self-report design, recruitment via online survey (introducing selection bias), lack of clinical verification of outcomes, and the inability to establish causality. The study also does not account for differences in duration of use, dosing, or baseline characteristics across groups.
Frontiers in nutrition · May 2025DOI ↗ Review
This scoping review systematically examined clinical research on anti-obesity medications (AOMs) conducted in Arab countries, drawing on five databases and covering publications up to October 2024. Researchers identified 59 eligible clinical studies published between 2014 and 2024, the large majority of which (89.8%) were observational in design. Most research originated from Saudi Arabia (40.7%) and the United Arab Emirates (20.3%). Glucagon-like peptide-1 (GLP-1) receptor agonists were the most studied drug class, appearing in 72.9% of studies, with liraglutide being the single most investigated agent (54.2%). The primary efficacy outcomes reported across studies were changes in total body weight, body mass index, and proportion of weight loss. Gastrointestinal side effects were noted in 32.2% of patients across studies. Risk of bias was assessed using the Newcastle-Ottawa scale and a modified randomized controlled trial tool. The authors highlight a notable gap: newer agents such as semaglutide and tirzepatide are underrepresented in the literature. Key limitations include the predominance of observational designs, geographic concentration, and limited data on diverse Arab subpopulations, which collectively constrain causal inference and generalizability.
Saudi medical journal · May 2025DOI ↗ Limited · human
This retrospective, non-interventional drug utilization cohort study examined real-world prescribing patterns of two liraglutide formulations in the United Kingdom: Saxenda® (3.0 mg, approved for weight management) and Victoza® (1.2/1.8 mg, approved for type 2 diabetes). Using anonymized primary care data from the Clinical Practice Research Datalink (CPRD Aurum and GOLD databases), researchers identified 604 Saxenda® initiators and 4,853 Victoza® initiators who had no prior liraglutide prescription in the preceding 12 months. Descriptive statistics characterized demographics and drug utilization patterns. The study found that, where body weight data were available, 96.4% of Saxenda® initiators met the weight loss indication criteria. Saxenda® users were predominantly female (86.4%), younger (mean age ~46.5 years), and had shorter follow-up periods compared to Victoza® users. The authors concluded that both formulations were mostly prescribed in line with their approved indications and that real-world use raised no new safety signals. Key limitations include incomplete weight data for approximately half of Saxenda® initiators, the observational nature of the study, and reliance on administrative/primary care records, which may not capture all clinical details or secondary care prescribing.
Diabetes, obesity & metabolism · Apr 2025DOI ↗ Review
This review article provides a comprehensive overview of approved and emerging hormone-based anti-obesity medications (AOMs), situating them within the broader context of obesity as a complex, chronic, global disease. The authors summarize the current regulatory landscape, noting that the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide have received FDA and EMA approval for weight management. The review also covers pipeline agents, including oral GLP-1RAs (semaglutide, danuglipron, orforglipron), the amylin receptor agonist cagrilintide (alone and in combination with semaglutide), and dual agonists such as tirzepatide (GIP/GLP-1), survodutide, mazdutide, and pemvidutide (GLP-1R/GCGR). The authors highlight tirzepatide's placebo-subtracted weight reduction of 17.8% in a 72-week RCT and retatrutide's (a GLP-1R/GCGR/GIPR tri-agonist) placebo-subtracted reduction of 22.1% in a 48-week phase-II trial. The review cautions that long-term safety and cardiovascular outcome data for many of these agents remain incomplete. As a narrative review, it does not conduct original research or meta-analysis, and conclusions are limited by the quality and heterogeneity of the underlying primary studies it synthesizes.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Moderate · human
This systematic review and meta-analysis examined the weight-loss efficacy and safety of cagrilintide (an amylin analogue) alone and in combination with semaglutide 2.4 mg (referred to as "Cagrisema") compared to placebo or active comparators (semaglutide or liraglutide) in adults with obesity. Researchers searched electronic databases and identified 3 eligible randomized controlled trials encompassing 430 participants. The pooled analysis found that Cagrisema was associated with significantly greater percentage and absolute body weight reduction compared to semaglutide 2.4 mg alone over 20–32 weeks, though with notably high statistical heterogeneity (I² up to 98%). Cagrilintide monotherapy showed statistically similar weight loss to semaglutide or liraglutide over 26–32 weeks. Regarding safety, treatment-emergent and serious adverse events were broadly comparable across groups; however, gastrointestinal adverse events and vomiting were significantly more frequent with Cagrisema versus semaglutide, while vomiting was significantly lower with cagrilintide monotherapy versus semaglutide or liraglutide. Key limitations include the very small number of included trials (n=3), limited total sample size, short-to-medium follow-up durations, and very high heterogeneity, which tempers confidence in the pooled estimates.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Animal only
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.
Molecular metabolism · Dec 2022DOI ↗