Moderate · human
This network meta-analysis (NMA) systematically synthesized evidence from 25 randomized controlled trials across 12 interventions to compare the weight-loss efficacy and safety of four advanced anti-obesity medications — tirzepatide, semaglutide, cagrilintide, and the combination CagriSema (cagrilintide + semaglutide) — in adults with overweight or obesity. Searches were conducted across PubMed, Scopus, and Cochrane Central. Using random-effects NMA models, the study found that tirzepatide 15 mg produced the greatest mean percent body weight reduction (−17.97%), closely followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). For achieving ≥20% body weight loss, CagriSema showed the highest relative risk (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). All agents increased gastrointestinal adverse events (RR 1.33–1.91) relative to placebo, with the highest treatment discontinuation seen with semaglutide 7.2 mg (RR 3.09). Serious adverse events were comparable to placebo across all regimens. Key limitations include reliance on indirect comparisons due to absence of head-to-head trials, potential heterogeneity across trial populations and follow-up durations, and the emerging/limited trial data for CagriSema specifically. The authors conclude that both tirzepatide and CagriSema represent leading options for substantial weight loss but call for direct comparative trials.
Endocrinology, diabetes & metabolism · Jul 2026DOI ↗ 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
This updated systematic review and meta-analysis evaluated the efficacy and safety of semaglutide — a GLP-1 receptor agonist — in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). Following PRISMA guidelines and registered on PROSPERO, the authors searched multiple databases through January 2026, ultimately pooling data from 10 studies comprising 1,908 participants. The primary outcomes were histological MASH resolution without worsening of fibrosis and improvement in fibrosis stage; secondary outcomes included liver stiffness and biochemical markers. The meta-analysis found that semaglutide was significantly associated with MASH resolution without fibrosis worsening (OR 3.48; 95% CI: 2.68–4.53). However, the anti-fibrotic effect appeared to be both stage-dependent and time-dependent, with meaningful histological fibrosis reversal observed primarily in non-cirrhotic patients within the durations of the included trials. Improvements in liver stiffness and biochemical markers were also reported. Limitations include the relatively short durations of the constituent trials and heterogeneity across included studies, which may limit generalizability to advanced or cirrhotic disease stages.
British journal of clinical pharmacology · 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 network meta-analysis (NMA) evaluated the comparative efficacy of pharmacological interventions—at specific dosages—for improving liver fibrosis in adults with metabolism-associated steatotic liver disease (MASLD) and fibrosis stages F1–F3. Researchers searched three databases through July 2025, identifying 13 randomized controlled trials encompassing 3,871 patients and 12 distinct drug regimens. Using both direct comparisons and network meta-analysis, the study found that six interventions—resmetirom (two doses), survodutide, and tirzepatide (three doses)—were significantly more effective than placebo at achieving NASH resolution without worsening fibrosis. Surface Under the Cumulative Ranking (SUCRA) analysis ranked survodutide 6 mg/week highest, followed by tirzepatide 15 mg/week; emricasan 10 mg/day ranked lowest. The authors concluded that survodutide, efruxiferimin, resmetirom, and denifanstat showed the most promise for this population, while emricasan was not supported. Limitations include the moderate number of included trials, potential heterogeneity across study populations and outcome definitions, and the indirect nature of many NMA comparisons, which may limit the precision of the relative effect estimates.
Journal of translational medicine · May 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 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 ↗ Moderate · human
This observational study used two target-trial emulations to compare cardiovascular outcomes among commercially insured U.S. adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) who initiated tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. Using propensity-score (PS) 1:1 matching to reduce confounding, the researchers formed two cohorts: 9,233 tirzepatide–dulaglutide pairs and 25,266 tirzepatide–semaglutide pairs. The primary outcome was a modified MACE composite (nonfatal myocardial infarction, nonfatal stroke, and all-cause death). The study found that tirzepatide initiators had a statistically significantly lower rate of modified MACE compared with dulaglutide initiators (HR 0.80; 95% CI 0.65–0.99), largely driven by reduced all-cause mortality (HR 0.60; 95% CI 0.43–0.83); tirzepatide was also associated with fewer pneumonia-related hospitalizations versus dulaglutide. No significant difference in modified MACE was observed between tirzepatide and semaglutide initiators (HR 1.03; 95% CI 0.90–1.17). Key limitations include the observational design, potential residual confounding, reliance on administrative claims data, and a relatively short follow-up window.
Diabetes care · 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 open-label randomized controlled trial (NCT03082885) enrolled 73 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), randomizing them to standard medical therapy (SMT, n=38) or SMT plus Thymosin α1 (Tα1, n=35), with a primary endpoint of 90-day transplant-free survival. Using flow cytometry and ELISA, researchers characterized peripheral immune cell subsets and serum cytokines at baseline and over follow-up. The study found that 90-day survivors had higher baseline effector T (TE) cell proportions, lower regulatory T cells (Tregs), and higher pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) compared to non-survivors. Non-survivors developed a progressive hyperinflammatory trajectory over time. Tα1 treatment was associated with improved 90-day transplant-free survival, reduced Treg frequencies (including CD226 low/- Treg subsets) at weeks 4–8, and moderation of late-stage hyperinflammation without suppressing early immune activation. The authors conclude Tα1 may rebalance immune responses in ACLF. Key limitations include the open-label design, relatively small sample size, and a single-center context, which may limit generalizability.
Immunopharmacology and immunotoxicology · 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 systematic review and meta-analysis evaluated the efficacy and safety of cagrisema (a fixed-ratio combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide) and cagrilintide monotherapy compared with semaglutide monotherapy for obesity management. Researchers searched five major databases and ClinicalTrials.gov, ultimately including three randomized controlled trials comprising 3,545 participants. Using a random-effects model, the study found that cagrisema produced statistically significantly greater reductions in percentage body weight (mean difference –7.47%, 95% CI: –10.58 to –4.36) and absolute body weight compared with semaglutide alone. Cagrisema also demonstrated superior improvements in glycemic markers, including fasting plasma glucose and HbA1c, and in BMI. Lipid parameters and safety profiles were reported as broadly comparable between groups. The authors concluded that cagrisema showed greater weight-loss efficacy and glycemic benefit than semaglutide, with an acceptable tolerability profile. Limitations include the small number of included trials (n=3), potential heterogeneity across trial designs, and the relatively short follow-up durations typical of early-phase RCTs in this therapeutic area.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used electronic health records from a large health system in Ohio and Florida (January 2021–June 2025) to examine real-world obesity treatment patterns and weight changes among adults who discontinued injectable semaglutide or tirzepatide within 3–12 months of initiation. A total of 7,938 patients (mean age ~56 years; ~64% female) were included. The study found that within one year of discontinuation, roughly 19.6% restarted the same medication and 35.2% received an alternative obesity treatment (most commonly another medication). Patients treated for obesity lost a mean of 8.4% of body weight before discontinuation, while those treated for type 2 diabetes lost 4.4%. In the year following discontinuation, the average weight change was modest (+0.5% for obesity indication; −1.3% for T2D indication), but with considerable individual-level variability—meaning some patients regained weight substantially while others did not. Key limitations include the retrospective, observational design (precluding causal inference), potential confounding by unmeasured factors, and restriction to a single health system in two U.S. states, which may limit generalizability.
Diabetes, obesity & metabolism · Mar 2026DOI ↗