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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 ↗ Strong · human
The GLORY-2 trial was a double-blind, placebo-controlled, phase 3 randomized clinical trial evaluating the efficacy and safety of mazdutide — a once-weekly subcutaneous glucagon and GLP-1 receptor dual agonist — for weight reduction in Chinese adults with obesity (BMI ≥30). Conducted across 27 hospitals in China from December 2023 to November 2025, the trial enrolled 461 participants (64% female; mean age ~34 years; mean BMI ~34.3), including 16.1% with type 2 diabetes. Participants were randomized 2:1 to receive 9 mg mazdutide or placebo weekly for 60 weeks alongside lifestyle interventions. The co-primary outcomes were percentage change in body weight and proportion achieving ≥5% weight loss at week 60. The mazdutide group achieved a mean body weight reduction of approximately 16.65% from baseline, compared with 1.50% in the placebo group — a statistically significant between-group difference of approximately 15.15%. Gastrointestinal adverse reactions were more common in the mazdutide group than in the placebo group. Key limitations include the single-ethnicity (Chinese) population, limiting generalizability, and a relatively young mean participant age. The trial was industry-relevant and registered on ClinicalTrials.gov (NCT06164873).
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The SYNCHRONIZE-1 trial was a phase 3, double-blind, randomized controlled trial evaluating survodutide — an investigational dual glucagon receptor and GLP-1 receptor agonist — for weight management in adults with obesity (BMI ≥30, or ≥27 with an obesity-related complication) who did not have diabetes. A total of 725 participants were randomized 1:1:1 to one of two dose levels of once-weekly subcutaneous survodutide or placebo, alongside lifestyle counseling, over 76 weeks. The study found that both survodutide groups achieved significantly greater mean body weight reductions compared to placebo (-12.2% and -13.0% versus -5.4%). Approximately 72% of participants in each survodutide group achieved at least 5% body weight reduction, compared to about 46% in the placebo group. The primary analysis used a treatment-regimen estimand accounting for early discontinuations and protocol deviations. Limitations include the relatively short 76-week duration for a chronic condition, the exclusion of people with diabetes, and industry funding by Boehringer Ingelheim. Long-term cardiovascular and safety outcomes remain to be established in ongoing or future trials.
The New England journal of medicine · Jun 2026DOI ↗ Strong · human
The REIMAGINE 2 trial was a phase 3, double-blind, randomised, placebo- and active-controlled study evaluating the fixed-dose combination of cagrilintide (an amylin receptor agonist) and semaglutide (a GLP-1 receptor agonist), known as CagriSema, in 2,713 adults with inadequately controlled type 2 diabetes and overweight or obesity across 30 countries. Participants were on background metformin with or without an SGLT2 inhibitor and were followed for 68 weeks. The primary endpoint was change in HbA1c from baseline. The study found that the higher-dose CagriSema combination produced a statistically significantly greater reduction in HbA1c compared with semaglutide alone (-1.91 vs. -1.75 percentage points; treatment difference -0.16 percentage points; p=0.0035). Adverse events were more frequent in the combination group (86.9%) than in the semaglutide monotherapy group (81.2%), with gastrointestinal disorders being the most common across active treatment arms. Limitations include the relatively modest absolute difference in HbA1c reduction, a predominantly White study population, and industry funding by Novo Nordisk, which may introduce sponsorship bias.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Strong · human
The REIMAGINE 3 trial investigated the combination of cagrilintide and semaglutide (CagriSema) as a weekly add-on to daily basal insulin in adults with type 2 diabetes and suboptimal glycaemic control (HbA1c 7.0–10.5%). In this 40-week, double-blind, placebo-controlled phase 3 study conducted across 46 centres in six countries, 274 participants were randomised to one of two active dose combinations (2.4 mg each or 1.0 mg each) or pooled placebo. The primary endpoint—change in HbA1c from baseline to week 40—was significantly greater with both CagriSema doses (–2.33% and –2.10%, respectively) compared with placebo (–0.66%). Both active groups also achieved substantial bodyweight reductions versus placebo, and no additional hypoglycaemia risk was observed. The safety profile was consistent with the GLP-1 receptor agonist class. Limitations include a relatively short 40-week duration, a moderately sized sample, and industry funding by Novo Nordisk. The study authors conclude that CagriSema meaningfully improved glycaemic control when added to basal insulin, without increasing hypoglycaemia risk.
Lancet (London, England) · Jun 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from four randomized controlled trials (n = 5,023 adults with overweight or obesity) to evaluate the efficacy and safety of cagrilintide — a long-acting amylin analogue — and its combination with semaglutide (CagriSema) versus placebo. The primary outcome was percent change in body weight. The authors followed PRISMA 2020 and AMSTAR 2 guidelines and used Cochrane RoB 2 for bias assessment, with random-effects models throughout. Key findings: cagrilintide alone was associated with a mean body weight reduction of approximately 6.1% versus placebo (95% CI: −8.0% to −4.1%), and CagriSema with approximately 6.0% (95% CI: −10.6% to −1.3%). CagriSema also significantly reduced waist circumference and HbA1c; cagrilintide alone showed modest blood pressure improvements without significant glycemic effects. Adverse events were more frequent with active treatment, though discontinuation rates were comparable to placebo. Notable limitations include the small number of pooled trials (n = 4) and potential heterogeneity across study populations and durations. The authors conclude that both therapies show clinically meaningful weight loss and acceptable tolerability, positioning them as emerging options in obesity pharmacotherapy.
Journal of diabetes and metabolic disorders · May 2026DOI ↗ Strong · human
This network meta-analysis pooled data from 11 randomized controlled trials (n = 83,215) to compare the cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes and established cardiovascular disease or high CV risk. Trials were identified through a systematic search of five major databases up to December 2025. Using a frequentist random-effects framework, the authors found that several GLP-1RAs — including subcutaneous semaglutide, efpeglenatide, albiglutide, tirzepatide, oral semaglutide, liraglutide, and dulaglutide — significantly reduced three-point major adverse cardiovascular events (MACE) compared with placebo, with no detected heterogeneity or inconsistency. Subcutaneous semaglutide, efpeglenatide, and albiglutide ranked highest by P-score. No agent significantly reduced all-cause or CV mortality versus placebo. Tirzepatide and dulaglutide were associated with reduced stroke risk. Tolerability signals showed higher rates of discontinuation due to gastrointestinal adverse events with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. The authors concluded that MACE reduction is the most consistent efficacy signal across GLP-1RAs in this population. Limitations include the indirect nature of network comparisons and differing trial designs and populations across included studies.
Canadian journal of diabetes · Apr 2026DOI ↗ Strong · human
This systematic review and network meta-analysis compared the weight-loss efficacy and safety of three FDA-approved agents—tirzepatide (a dual GIP/GLP-1 agonist), semaglutide, and liraglutide—in non-diabetic adults with obesity. Researchers searched four major databases through May 2025 and identified 15 Phase 3 RCTs encompassing 14,059 patients. Using a frequentist random-effects network meta-analysis, the authors found that all three agents produced statistically significant body weight reductions compared to placebo. Ranking by magnitude of effect, the highest tolerated dose of tirzepatide demonstrated the greatest weight reduction, followed by lower tirzepatide doses, then semaglutide, and finally liraglutide. On the safety side, tirzepatide and semaglutide were each associated with a higher risk of any adverse event compared to placebo, while liraglutide was not. The authors note that the analysis was limited to Phase 3 RCTs and did not assess long-term outcomes such as weight regain after discontinuation, metabolic endpoints, cost-effectiveness, or patient preferences, which they identify as priorities for future research.
Obesity (Silver Spring, Md.) · Apr 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled evidence from 21 randomized controlled trials (n = 7,024 participants) to evaluate the weight-loss efficacy of GLP-1 receptor agonists (GLP-1 RAs) compared with placebo or active comparators. Across 16 placebo-controlled trials, the study found that a substantially higher proportion of participants achieved weight loss with GLP-1-based agents (78.54%) than with placebo (26.53%), yielding a pooled odds ratio of 11.37 (95% CI: 8.10–15.98). A frequentist network meta-analysis using SUCRA rankings suggested that tirzepatide and semaglutide demonstrated the greatest relative efficacy among agents evaluated. The authors concluded that GLP-1 RAs significantly increase the likelihood of weight loss and support their role in clinical obesity management. Notable limitations include the use of a fixed-effect model despite potential heterogeneity across trials, a binary primary endpoint (any weight loss) rather than magnitude of weight loss, the absence of a pre-registered protocol, and inclusion criteria restricted to the past five years in English only. These methodological choices may affect the precision and generalizability of the pooled estimates.
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This systematic review and meta-analysis evaluated the efficacy and safety of CagriSema — a dual therapy combining the GLP-1 receptor agonist semaglutide with the amylin analogue cagrilintide — compared to semaglutide monotherapy or placebo in adults with obesity. The authors searched four major databases through July 2025 and identified four eligible randomized controlled trials encompassing 4,419 participants (CagriSema: 3,055; controls: 1,364). Pooled analyses found that CagriSema was associated with significantly greater percent body weight loss (Cohen's d: −1.38; 95% CI: −1.84 to −0.91), greater absolute weight reduction (mean difference: −11 kg), reductions in waist circumference (−9.41 cm), and lower systolic blood pressure (−7.06 mmHg) versus comparators. However, gastrointestinal adverse events occurred more frequently with CagriSema (relative risk: 1.32). Notable limitations include high statistical heterogeneity (I² = 94.8%) across the included trials, the small number of studies (n = 4), and the absence of long-term safety and cardiovascular outcomes data. The authors conclude that CagriSema demonstrates superior weight reduction compared with semaglutide or placebo, but that tolerability monitoring and longer-term evidence are warranted.
The American journal of cardiology · Feb 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 10 randomized controlled trials (3,236 participants) to evaluate the efficacy and safety of incretin-based dual and triple receptor agonists — specifically tirzepatide, retatrutide, and mazdutide — in overweight or obese adults. The authors searched PubMed, the Cochrane Library, and Google Scholar through June 2025 and applied a random-effects model to pool outcomes. The study found that these agents were associated with statistically significant reductions in body weight (mean difference: −11.47 kg), waist circumference (−9.40 cm), glycated hemoglobin (−0.96%), and fasting plasma glucose (−26.89 mg/dL) compared to placebo. On the safety side, treatment was associated with a higher risk of any adverse event (RR 1.13), gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation), treatment discontinuation due to adverse events (RR 1.96), and hypoglycemic episodes (RR 3.08). No significant difference in serious adverse events was observed. Limitations include the relatively small number of pooled trials, heterogeneity inherent across different agents and doses, and the restriction to placebo-controlled comparisons, which limits conclusions about comparative effectiveness between agents.
Cardiology in review · Feb 2026DOI ↗ Strong · human
This meta-analysis pooled data from five randomized controlled trials (RCTs) to evaluate the effects of tesamorelin — a synthetic growth hormone-releasing hormone (GHRH) analogue — compared with placebo in adults living with HIV who have lipodystrophy. The authors conducted a systematic search of five major databases through July 2025 and applied a random-effects meta-analysis model, assessing risk of bias with RoB 2.0 and certainty of evidence using GRADE. The analysis found that tesamorelin was associated with a statistically significant reduction in visceral adipose tissue (mean difference of approximately −27.71 cm²), as well as improvements in hepatic fat content, lean body mass, and IGF-1 levels. The study authors reported that these benefits occurred without clinically significant adverse effects on glucose metabolism or serious safety signals. Limitations of the analysis include the small number of included trials (n=5), potential variability across trial populations and durations, and the inherent constraints of meta-analytic methodology in establishing causality. The findings suggest tesamorelin may offer metabolic and body composition benefits in HIV-associated lipodystrophy, though the authors note the results should be interpreted within the context of the underlying evidence base.
Obesity research & clinical practice · Jan 2026DOI ↗ Strong · human
This systematic review and network meta-analysis examined the renal effects of three classes of novel antidiabetic agents—DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors—in adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Researchers searched four major databases through July 2025 and identified 20 randomized controlled trials enrolling 80,670 participants, with a minimum follow-up of 24 weeks. Key outcomes assessed were composite renal outcomes, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). The study found that several agents significantly reduced composite renal outcomes compared with placebo; dapagliflozin demonstrated the largest effect (high-certainty evidence), followed by canagliflozin, empagliflozin, and select GLP-1 agonists (efpeglenatide, sotagliflozin, semaglutide, dulaglutide). Canagliflozin most strongly reduced UACR, while dapagliflozin showed no significant effect on this measure. No agent significantly altered eGFR. DPP-4 inhibitors showed no renal benefit. Certainty of evidence, assessed via GRADE, was high for direct placebo-controlled comparisons but fell to low or very low for indirect network estimates. A key limitation is that conclusions about head-to-head drug comparisons rely on indirect evidence, which carries greater uncertainty.
Diabetes, obesity & metabolism · Oct 2025DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 25 randomized controlled trials (RCTs) involving approximately 2,600 patients to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide — on metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Across a median treatment period of 24 weeks, the authors reported that GLP-1RAs were associated with a statistically significant mean reduction in liver fat content of 5.21%, with retatrutide showing the largest effect. Histological analyses suggested significant improvements in steatosis, hepatocellular ballooning, and lobular inflammation, though improvements in fibrosis did not reach statistical significance. Liver enzymes (ALT, AST, γ-GT) and liver stiffness also improved significantly, with semaglutide showing the most pronounced effect on stiffness. No liver-related adverse drug effects were identified. Limitations include heterogeneity across trials, variable treatment durations, and the relatively short median follow-up, which may be insufficient to capture fibrosis outcomes. The evidence base is derived entirely from RCTs in human populations.
The Journal of clinical endocrinology and metabolism · Sep 2025DOI ↗ Strong · human
This Bayesian network meta-analysis (NMA) synthesized evidence from 19 randomized controlled trials (RCTs) enrolling 29,506 adults with overweight or obesity (BMI ≥ 25 kg/m²) to compare the weight-loss efficacy and safety of GLP-1 receptor agonists (liraglutide, semaglutide), dual agonists (tirzepatide, survodutide), and the triple agonist retatrutide against placebo over at least 36 weeks. The study found that retatrutide and dual agonists achieved equivalent mean weight loss (approximately −11.0 kg), both outperforming GLP-1 receptor agonists (approximately −9.0 kg). Retatrutide showed the highest odds of achieving ≥15% weight loss (OR 54.6), followed by dual agonists (OR 16.4) and GLP-1 receptor agonists (OR 9.0). However, retatrutide was also associated with the highest adverse event risk. Meta-regression analyses indicated that type 2 diabetes mellitus attenuated weight loss across all drug classes, while female-dominant and higher-BMI cohorts showed enhanced outcomes. Limitations include indirect comparisons inherent to NMA methodology, heterogeneity across trials in baseline characteristics, and the fact that retatrutide data remain from earlier-phase trials. The authors recommend individualized treatment selection based on patient-specific factors.
Obesity (Silver Spring, Md.) · Jul 2025DOI ↗ Strong · human
The GLORY-1 trial was a phase 3, randomized, double-blind, placebo-controlled study conducted in China evaluating mazdutide — a once-weekly injectable glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist — for weight management in adults with overweight or obesity. A total of 610 participants (mean BMI 31.1, mean body weight 87.2 kg) were randomly assigned 1:1:1 to receive one of two doses of mazdutide or placebo for 48 weeks. The two co-primary endpoints at week 32 were percent change in body weight and the proportion achieving at least 5% weight reduction, analyzed using a treatment-policy estimand. The study found that both mazdutide groups achieved statistically significant and clinically meaningful reductions in body weight compared to placebo at week 32, with the higher dose group achieving a greater mean reduction than the lower dose group; the placebo group had a marginal mean weight gain. The proportions achieving ≥5% weight loss were substantially higher in both active treatment groups versus placebo. Limitations include the single-country (China) design, limiting generalizability, and the 32-week primary endpoint in a 48-week trial. Safety data were not detailed in the abstract.
The New England journal of medicine · May 2025DOI ↗ Strong · human
This network meta-analysis synthesized evidence from 39 randomized clinical trials (99,599 patients) to compare the efficacy and safety of three drug classes — SGLT-2 inhibitors, GLP-1 receptor agonists, and the non-steroidal mineralocorticoid receptor antagonist Finerenone — in adults with type 2 diabetes mellitus (T2DM) and non-dialysis chronic kidney disease (CKD). Databases were searched through November 2023, and methodological quality was assessed using the Cochrane RoB 2.0 tool. The study found that, compared to placebo, SGLT-2 inhibitors were most effective at reducing HbA1c, systolic and diastolic blood pressure, and body weight. Among GLP-1 receptor agonists, Liraglutide showed the greatest LDL-C reduction. Finerenone significantly reduced systolic blood pressure versus placebo. SUCRA rankings highlighted Empagliflozin for HbA1c and DBP reduction, Semaglutide for eGFR preservation, and Canagliflozin for blood pressure and weight loss. Safety profiles were generally favorable, with notable differences across agents in rates of urinary tract infection, hypoglycemia, and acute kidney injury. Limitations include indirect comparisons inherent to network meta-analysis, potential heterogeneity across trials, and the restriction to non-dialysis CKD populations, limiting broader generalizability.
Frontiers in pharmacology · Mar 2025DOI ↗