Moderate · humanPreprint
This Bayesian network meta-analysis systematically evaluated the dose-dependent efficacy and safety of mazdutide — a dual GLP-1 receptor and glucagon receptor agonist — in adults with obesity or overweight, with or without type 2 diabetes. Researchers searched five major databases through January 2026 and included nine randomized controlled trials comprising 2,292 participants. The study found that, compared with placebo, multiple mazdutide doses were associated with statistically significant improvements across a broad range of cardiometabolic outcomes, including body weight, waist circumference, BMI, HbA1c, fasting plasma glucose, blood pressure, LDL cholesterol, and liver enzymes (ALT). Subgroup analyses suggested that weight loss effects were more pronounced in non-diabetic individuals, while glycemic benefits were greater in those with type 2 diabetes. Gastrointestinal adverse events were notably more frequent with mazdutide relative to placebo, though serious adverse events were not significantly elevated. Key limitations include the relatively small number of included trials (n=9) and total participants, the indirect comparisons inherent to network meta-analysis methodology, potential heterogeneity across trial populations, and the preprint status of this work, meaning it has not yet undergone formal peer review.
Unknown journal · Jun 2026DOI ↗ Moderate · human
The SYNCHRONIZE-MASLD trial investigated survodutide — a dual glucagon receptor/GLP-1 receptor agonist — in 216 adults with obesity and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD). Participants were randomized 2:1 to once-weekly subcutaneous survodutide 6.0 mg (n=146) or placebo (n=70) for 48 weeks. The trial had two co-primary endpoints: ≥30% reduction in MRI-assessed liver fat content (LFC) and percentage change in body weight from baseline to week 48. Both endpoints were met. The study found that 84.2% of survodutide-treated participants achieved ≥30% LFC reduction versus 24.3% on placebo. Mean body weight decreased by 12.2% with survodutide compared to 1.0% with placebo. The most common adverse events were gastrointestinal in nature, typically mild-to-moderate and concentrated during dose escalation. Key limitations include the relatively short 48-week duration, which precludes conclusions about long-term outcomes such as fibrosis regression or cardiovascular events, a modest sample size, and recruitment restricted to the United States and Spain, limiting generalizability. The study was funded by the manufacturer and used surrogate endpoints rather than hard clinical outcomes.
Nature medicine · Jun 2026DOI ↗ Moderate · human
REIMAGINE 1 was a randomised, double-blind, placebo-controlled phase 3a trial evaluating once-weekly subcutaneous cagrilintide-semaglutide (CagriSema) — a combination of an amylin receptor agonist (cagrilintide) and a GLP-1 receptor agonist (semaglutide) — in 189 adults with type 2 diabetes inadequately controlled by diet and exercise alone. Conducted across 42 sites in six countries over 40 weeks, participants were assigned to one of two active dose levels or matched placebo. The primary endpoint was change in HbA1c from baseline to week 40. The study found that both active dose levels produced statistically significant and clinically meaningful reductions in HbA1c compared to placebo (estimated treatment differences of −1.7 and −1.4 percentage points for the higher and lower doses, respectively; p<0.0001 for both). Body weight reduction was a notable secondary finding. The safety profile was described as consistent with the GLP-1 receptor agonist class. Key limitations include the relatively small sample size (n=189), short 40-week duration, an early-stage diabetes population not on background glucose-lowering medications, and industry funding from Novo Nordisk, which may introduce bias. These results suggest CagriSema may be a promising therapeutic option for early-stage type 2 diabetes.
The lancet. Diabetes & endocrinology · Jun 2026DOI ↗ Moderate · humanPreprint
This systematic review and meta-analysis, conducted following PRISMA 2020 guidelines, examined the effects of GLP-1 receptor agonists (semaglutide, liraglutide) and the dual GIP/GLP-1 receptor agonist tirzepatide on obstructive sleep apnea (OSA) severity, as measured by apnea-hypopnea index (AHI). The authors searched PubMed, Google Scholar, and SciSpace through May 2026 and included 40 studies involving adults with OSA receiving GLP-1–based therapies with quantitative AHI outcomes. The review found that tirzepatide was associated with greater AHI reductions (−25.3 to −29.3 events/h; approximately 50.7%–58.7%) compared with liraglutide (−12.2 events/h; ~25%), and a pooled meta-analytic estimate showed an overall AHI reduction of −16.57 events/h across therapies. The authors attributed these effects primarily to weight loss, while noting emerging evidence for potential weight-independent mechanisms. Limitations include the heterogeneity of included studies, reliance on a preprint-stage document, and the inability to fully disentangle weight-mediated versus direct effects. The authors conclude that GLP-1–based therapies, particularly tirzepatide, may represent meaningful treatment options for obesity-related OSA, especially among patients with poor CPAP adherence.
Unknown journal · Jun 2026DOI ↗ Moderate · human
This systematic review and meta-analysis synthesized evidence from three placebo-controlled randomized controlled trials (total n = 258) examining semaglutide in adults with schizophrenia spectrum disorders (SSDs). The authors conducted a preregistered search, pooled outcomes using random-effects meta-analysis, and assessed evidence certainty using GRADE criteria. The included trials tested semaglutide over 26–36 weeks. The study found that, compared to placebo, semaglutide was associated with statistically significant reductions in body weight (approximately −11.3 kg), BMI (approximately −3.6 kg/m²), HbA1c (approximately −0.37%), and fasting glucose. On the safety side, semaglutide was associated with meaningfully higher risks of abdominal pain, vomiting, and constipation, consistent with the known gastrointestinal profile of GLP-1 receptor agonists; no elevated risk of serious adverse events was observed. The authors note that the overall evidence base is limited by a small number of trials, modest combined sample size, and relatively short follow-up durations. No trials of tirzepatide in this population were identified. The authors conclude that semaglutide shows promise as an adjunctive metabolic treatment in SSDs but call for larger, longer trials.
BJPsych open · May 2026DOI ↗ Moderate · human
This systematic review and meta-analysis investigated whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with hair loss. Researchers searched four electronic databases through August 2025, identifying nine interventional studies (seven RCTs and two prospective non-randomized trials) involving 4,114 GLP-1 RA users. Using a random-effects model, the pooled analysis found that GLP-1 RA users had a significantly higher risk of hair loss compared to placebo users (risk ratio: 3.252; 95% CI: 1.437–7.358). This association remained significant in a subgroup analysis restricted to RCTs enrolling patients with overweight or obesity (RR: 3.587; 95% CI: 2.100–6.124). A single-arm analysis estimated the overall event rate of hair loss at approximately 3.9%. Limitations of this study include the relatively small number of included studies (n=9), potential variability in how hair loss was defined and reported across trials, and the inability to fully disentangle hair loss attributable to the drug itself versus rapid weight loss—a known independent trigger of telogen effluvium. The authors conclude that GLP-1 RA use is significantly associated with an increased risk of hair loss.
Diabetes research and clinical practice · May 2026DOI ↗ Moderate · human
This study aimed to indirectly compare the efficacy and safety of injectable tirzepatide (a dual GIP/GLP-1 receptor agonist) with oral semaglutide (a GLP-1 receptor agonist) for weight management in adults with overweight or obesity but without type 2 diabetes. Because no head-to-head trial exists, researchers used multilevel network meta-regression (ML-NMR) to adjust for baseline differences in sex, ethnicity, and outcome measures between two pivotal trials: SURMOUNT-1 (tirzepatide, 72 weeks) and OASIS 1 (oral semaglutide, 68 weeks). After adjustment, the analysis found that tirzepatide at two of the three doses studied was associated with statistically significantly greater reductions in body weight and waist circumference compared with oral semaglutide. Tirzepatide was also associated with higher odds of achieving clinically meaningful weight-loss thresholds (≥5%, ≥10%, ≥15%, and ≥20% body weight reduction). Cardiometabolic outcomes and safety profiles were reported as improved or broadly comparable for tirzepatide versus oral semaglutide. Key limitations include the indirect nature of the comparison, differences in trial duration and populations, and the inability to fully control for all confounders across separate trials. The findings should be interpreted cautiously pending direct head-to-head evidence.
Diabetes, obesity & metabolism · Apr 2026DOI ↗ Moderate · human
This large genome-wide association study (GWAS) investigated whether genetic variants explain why people respond differently to GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide and tirzepatide. Researchers analyzed self-reported weight loss and side effects in 27,885 individuals on GLP-1 RA therapy. The study identified a missense variant in the GLP1R gene significantly associated with greater weight loss efficacy, with carriers of the effect allele losing an additional estimated 0.76 kg per copy. Separate genetic associations were found linking variants in both GLP1R and GIPR to nausea or vomiting during GLP-1 RA treatment; notably, the GIPR association appeared specific to tirzepatide users, consistent with tirzepatide's dual GLP-1/GIP receptor mechanism. The authors built a broader predictive model incorporating these findings, suggesting the potential to stratify patients by expected efficacy and side effect risk—a step toward precision medicine for obesity. Key limitations include reliance on self-reported outcomes, which may introduce recall and reporting bias, and the observational nature of the design, which limits causal inference beyond the genetic associations themselves.
Moderate · human
This systematic review and meta-analysis pooled data from three head-to-head randomized or controlled trials comparing tirzepatide (a dual GIP/GLP-1 receptor agonist) with semaglutide (a selective GLP-1 receptor agonist) in adults with obesity and/or type 2 diabetes. Studies were identified through searches of PubMed, Embase, and ScienceDirect up to February 2026. Using a random-effects model, the authors found that tirzepatide was associated with significantly greater weight reduction compared to semaglutide (pooled mean difference: −5.19 kg) and a higher likelihood of achieving ≥10% weight loss (pooled risk ratio: 1.50). No statistically significant differences were observed in overall adverse events or gastrointestinal events between the two agents; however, serious adverse events were reported more frequently with tirzepatide (risk ratio: 1.83). Key limitations include a very small number of included studies (n=3), substantial statistical heterogeneity in weight-related outcomes (I² >86%), and insufficient follow-up duration to draw conclusions about long-term cardiovascular safety. The authors note that further studies with longer follow-up are needed to confirm the cardiometabolic safety profile of tirzepatide relative to semaglutide.
Nepal journal of epidemiology · Apr 2026DOI ↗ Moderate · human
This systematic review and meta-analysis (PRISMA 2020, PROSPERO-registered) pooled three randomized controlled trials (N = 13,590 adults with type 2 diabetes) comparing once-weekly tirzepatide — a dual GIP/GLP-1 receptor agonist — against dulaglutide (a GLP-1 receptor agonist) over at least 26 weeks. The primary safety outcome was overall adverse event incidence, which the study found did not differ significantly between treatments (RR 1.04; moderate-certainty evidence). However, discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32; high-certainty evidence), suggesting a tolerability-persistence trade-off. Glycemic target achievement (HbA1c) was population-dependent: tirzepatide showed consistent benefit at the primary threshold in treatment-naïve patients receiving lower-dose dulaglutide, while the advantage narrowed in patients with established cardiovascular disease on higher-dose dulaglutide; heterogeneity was extreme at the strictest threshold. Weight-loss threshold achievement favored tirzepatide, though evidence certainty was very low due to substantial heterogeneity. Serious adverse events did not differ significantly. Key limitations include only three included trials, high heterogeneity for several outcomes, and restricted generalizability across patient subgroups. GRADE certainty ranged from very low to high across outcomes.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used the TriNetX global federated electronic health record (EHR) database to compare real-world cardiovascular outcomes between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in non-diabetic adults treated for obesity. Patients who initiated either medication between November 2023 and August 2024 were included, with individuals having recent atherosclerotic events, prior heart failure, or treatment crossovers excluded. After 1:1 propensity score matching yielding 35,336 pairs, the study found that tirzepatide was associated with a statistically significantly lower incidence of the composite primary endpoint — all-cause death, acute coronary syndrome, stroke, or new-onset heart failure — at 12 months (1.90% vs. 2.18%; HR 0.86). This difference was primarily driven by a reduction in new-onset heart failure (both reduced and preserved ejection fraction). No significant differences were observed for all-cause mortality, acute coronary syndrome, or stroke individually. Tirzepatide also produced greater mean weight loss. Limitations include the retrospective observational design, reliance on EHR coding accuracy, inability to confirm medication adherence, short follow-up duration, and potential for residual confounding despite propensity matching.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Moderate · human
This phase 2 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of mazdutide 9 mg — a once-weekly dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist — in Chinese adults with obesity (BMI ≥30 kg/m²) without diabetes over 24 weeks. Eighty participants were randomized 3:1 to receive mazdutide 9 mg (n=60) or placebo (n=20). The primary endpoint was percentage change in body weight from baseline to week 24. The study found that participants receiving mazdutide 9 mg experienced a mean body weight reduction of approximately 12.78%, compared to a gain of 1.80% in the placebo group, representing a treatment difference of approximately −14.58% (95% CI: −18.00 to −11.16). The authors concluded that mazdutide 9 mg was safe and produced substantial weight reductions in this population. Key limitations include the relatively small sample size, the short 24-week duration, the single-country (China) population limiting generalizability, the phase 2 (exploratory) design, and industry sponsorship by Innovent Biologics. The findings are described as supportive of further clinical development.
Med (New York, N.Y.) · Mar 2026DOI ↗ Moderate · human
This meta-analysis pooled data from five randomised controlled trials to evaluate the efficacy and safety of mazdutide — a dual GLP-1 and glucagon receptor agonist — for weight management in non-diabetic adults with overweight or obesity. Searches were conducted across Cochrane Library, PubMed, Google Scholar, and ClinicalTrials.gov, and analyses were performed using random-effects models in RevMan 5.4. The pooled results reported by the study authors indicate that mazdutide was associated with significant reductions in percentage body weight (mean difference –12.42%), absolute body weight (–9.76 kg), and waist circumference (–7.98 cm) compared with control conditions. Secondary cardiometabolic outcomes — including systolic blood pressure (–7.68 mmHg), total cholesterol (–0.57 mmol/L), and LDL cholesterol (–0.37 mmol/L) — also showed reductions. Adverse events were slightly more frequent in the mazdutide groups (RR = 1.12), described as mild to moderate. A dose-wise meta-regression suggested a significant dose-dependent relationship. The authors acknowledge that findings are constrained by the small number of included trials (n = 5), which limits the robustness and generalisability of conclusions.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Moderate · human
This systematic review and nonlinear meta-regression examined how body weight changes after people stop taking GLP-1 receptor agonists (GLP-1RAs), a class of medications widely used for obesity management. Researchers searched five major databases through August 2025 and identified 48 eligible studies. The core quantitative analysis focused on six randomised controlled trials (n = 3,236 participants) and applied a mixed-effects exponential recovery model to characterise the trajectory of weight regain over time. The study found that weight regain after GLP-1RA discontinuation follows a predictable, decelerating pattern: approximately 60% of treatment-related weight loss was regained within one year of stopping. The modelled plateau of regain was estimated at 75.3% (95% CI 68.9–81.6%) of lost weight, suggesting a residual but substantially attenuated long-term benefit. The rate constant of 0.0302 per week corresponded to a regain half-life of roughly 23 weeks. Secondary outcomes (HbA1c, systolic blood pressure) were explored but not the primary focus. Limitations include that most included studies carried moderate risk of bias, weight trajectories beyond 52 weeks were extrapolated rather than directly observed, and heterogeneity across study populations, GLP-1RA agents, and treatment durations may affect generalisability.
EClinicalMedicine · Mar 2026DOI ↗ Moderate · human
This systematic review and frequentist network meta-analysis (NMA) examined the comparative cardiovascular efficacy of tirzepatide (a dual GIP/GLP-1 receptor agonist) versus GLP-1 receptor agonists (GLP-1RAs) and placebo in adults with type 2 diabetes (T2D) and established or high-risk atherosclerotic cardiovascular disease (ASCVD). Eleven randomized controlled trials were included — ten evaluating GLP-1RAs and one evaluating tirzepatide (SURPASS-CVOT). In the class-level analysis, the study found that tirzepatide was associated with statistically significant reductions in MACE, cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke compared to placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo and lixisenatide specifically, while appearing broadly comparable to other individual GLP-1RAs. Subgroup and leave-one-out sensitivity analyses were consistent with primary findings. A key limitation is that only one tirzepatide RCT (SURPASS-CVOT) was available, constraining direct head-to-head NMA comparisons between tirzepatide and individual GLP-1RAs and reducing the precision of tirzepatide-specific estimates. The authors concluded that tirzepatide may provide cardiovascular benefit at least comparable to established GLP-1RAs, though this inference is based on indirect comparisons.
Cardiovascular diabetology · Feb 2026DOI ↗ Moderate · human
This secondary analysis pooled data from two randomized, double-blind, placebo-controlled crossover trials to examine whether the GLP-1 receptor agonist (RA) dulaglutide affects copeptin — a stable surrogate marker for vasopressin (antidiuretic hormone) — in euvolemic individuals. A total of 54 participants were included: 34 with primary polydipsia and 20 healthy volunteers. Participants received three weeks of either subcutaneous dulaglutide or saline placebo once weekly before crossing over. Fasting blood samples for copeptin were collected after each treatment phase. The study found that dulaglutide was associated with a statistically significant suppression of copeptin levels, with a median within-subject difference of −0.7 pmol/L (p = .047), representing approximately a 12% reduction relative to placebo. This effect was not significantly correlated with dulaglutide-related changes in blood pressure, BMI, or nausea frequency. The authors suggest this finding may help explain GLP-1's known role in fluid and sodium homeostasis. Key limitations include the secondary-analysis design (not pre-specified as the primary outcome), modest sample size, a mixed population (healthy and polydipsic participants), and the reliance on copeptin as a proxy rather than directly measured vasopressin.
European journal of endocrinology · Feb 2026DOI ↗ Moderate · human
This Phase 3 randomized controlled trial evaluated mazdutide, a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist, as monotherapy versus placebo in 320 Chinese adults with type 2 diabetes (T2D) inadequately controlled by diet and exercise. Participants had a mean HbA1c of 8.24% and BMI of 28.2 kg/m². They were randomized 1:1:1 to weekly subcutaneous injections of mazdutide (4 mg or 6 mg) or placebo for 24 weeks, followed by a 24-week mazdutide extension phase. At week 24, the study found that both mazdutide doses significantly reduced HbA1c versus placebo (−1.57% and −2.15% for 4 mg and 6 mg, respectively, vs. −0.14% for placebo). Both doses also produced significantly greater body weight reductions and improved rates of composite endpoints (HbA1c <7.0% with ≥5% weight loss) compared to placebo. The most common adverse events—diarrhea, decreased appetite, and nausea—were consistent with the GLP-1R agonist class. Limitations include the single-ethnicity population (Chinese adults), the relatively short 24-week primary endpoint period, and the lack of an active comparator arm, which limits generalizability and comparative effectiveness conclusions.
Moderate · human
This Phase III randomized controlled trial evaluated mazdutide, a novel once-weekly dual glucagon and GLP-1 receptor agonist, compared to dulaglutide in 731 Chinese adults with type 2 diabetes (T2D) on background oral anti-diabetic therapy. Participants were randomized 1:1:1 to one of two mazdutide doses or dulaglutide (1.5 mg) for 28 weeks. The study found that both mazdutide doses demonstrated non-inferiority and superiority to dulaglutide in reducing HbA1c from baseline, with least-squares mean treatment differences of -0.24% and -0.30% for the lower and higher doses, respectively. Mazdutide also produced significantly greater reductions in body weight than dulaglutide, with differences of -3.78% and -5.76% for the two doses. The safety profile was generally acceptable, though gastrointestinal adverse events occurred more frequently with mazdutide than dulaglutide. Limitations include the relatively short 28-week duration, restriction to a Chinese population, and the lack of a placebo arm, which may limit generalizability of findings.
Moderate · human
This systematic review, following PRISMA 2020 guidelines, examined the frequency, severity, and types of gastrointestinal (GI) adverse effects associated with anti-obesity medications in non-diabetic adults with obesity. Researchers searched PubMed, Google Scholar, BMJ, and Web of Science through July 2025, ultimately including 12 studies from 733 screened articles. The evidence base included one large cohort of 18,386 participants alongside smaller randomized and observational trials. The review found that nausea, vomiting, diarrhea, and constipation were the most frequently reported GI symptoms, occurring predominantly with GLP-1 receptor agonists such as semaglutide and tirzepatide, particularly during dose escalation phases. Orlistat was commonly associated with steatorrhea and flatulence, while phentermine was linked to reduced GI motility. Newer investigational agents, including retatrutide and orforglipron, also demonstrated notable GI side effect profiles. Natural products and other investigational agents reported fewer adverse events but lacked long-term data and standardized reporting. Key limitations include heterogeneity in study designs and inconsistent GI outcome reporting across included studies. The authors concluded that GI side effects are common but generally mild to moderate, and that standardized reporting and proactive clinical management strategies may improve patient adherence and tolerability.
Medicina (Kaunas, Lithuania) · Nov 2025DOI ↗ Moderate · humanPreprint
This meta-analysis pooled data from four randomized controlled trials (n = 918) to evaluate the efficacy of mazdutide — a dual GLP-1 and glucagon receptor agonist — in nondiabetic adults with overweight or obesity. Researchers searched PubMed, Scopus, and Web of Science and applied a random-effects model to analyze primary outcomes including body weight, BMI, and waist circumference, along with secondary cardiometabolic markers. The pooled analysis found that, compared with placebo, mazdutide was associated with statistically significant reductions in body weight (mean difference: −7.72 kg), BMI (−2.84 units), waist circumference (−5.76 cm), HbA1c (−0.30%), LDL cholesterol (−10.59 mg/dL), total cholesterol (−18.61 mg/dL), and triglycerides (−49.87 mg/dL). The authors concluded that mazdutide shows promise as a pharmacotherapy option for this population. Key limitations include the small number of included trials (n = 4), the relatively modest total sample size, the lack of long-term follow-up data, and the preprint status of this analysis, meaning it has not yet undergone formal peer review. Findings should therefore be interpreted with caution pending publication.
Unknown journal · Oct 2025DOI ↗