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 · 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
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 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 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 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 ↗ Moderate · human
This large retrospective cohort study examined real-world trends in 1-year treatment persistence and adherence among commercially insured adults without diabetes who newly initiated high-potency, weight loss-indicated GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) — between January 2021 and June 2024. Using integrated medical and pharmacy claims data from approximately 17.9 million members, researchers identified 33,607 eligible new initiators. The study found that 1-year persistence nearly doubled over the observation period, rising from 33.2% in 2021 to 60.9% in the first half of 2024. Tirzepatide demonstrated notably higher persistence (approximately 64%) compared to semaglutide during overlapping availability years. The authors suggest that resolution of GLP-1RA product shortages, improved side effect and dose escalation management, and lifestyle support programs may have contributed to improving persistence trends. Key limitations include reliance on claims data (which cannot capture clinical nuance or patient-reported reasons for discontinuation), a commercially insured-only population limiting generalizability, and the inability to distinguish voluntary discontinuation from access-related gaps. The authors call for further research into discontinuation reasons and long-term cost-effectiveness.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Moderate · human
This systematic review and meta-analysis examined the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and heart rate (HR) changes in people with overweight or obesity who do not have diabetes. Researchers searched four major databases (PubMed, Web of Science, Embase, and Cochrane Library) and ultimately included 12 randomized controlled trials. Using both pairwise and network meta-analysis methods, the study calculated mean differences (MDs) in HR compared to placebo. Pairwise meta-analysis found that all analyzed GLP-1RAs — including liraglutide, semaglutide, orforglipron, oral semaglutide, tirzepatide, retatrutide, and the drug class overall — were associated with statistically significant increases in heart rate versus placebo. Network meta-analysis, which allows indirect comparisons across agents, suggested that orforglipron 36 mg was associated with the most pronounced HR increase, while tirzepatide 5 mg showed the least increase (and its result was not statistically significant). Key limitations include the indirect nature of network comparisons, variability in trial designs and follow-up durations, and the restriction to a non-diabetic population, which limits generalizability. The clinical significance of the observed HR increases was not fully addressed.
European journal of medical research · Jan 2026DOI ↗ Moderate · human
The REDEFINE 1 trial was a phase 3a, 68-week randomized controlled trial that evaluated the blood pressure (BP) effects of CagriSema (a fixed-dose combination of semaglutide 2.4 mg and cagrilintide 2.4 mg) in 3,417 adults without diabetes who had overweight or obesity, with or without obesity-related complications. Participants were randomized to once-weekly CagriSema, semaglutide alone, cagrilintide alone, or placebo, alongside lifestyle intervention. Secondary and post hoc analyses focused on antihypertensive outcomes. The study found that CagriSema was associated with greater reductions in systolic BP (−10.9 vs. −2.8 mmHg) and diastolic BP (−5.4 vs. −1.7 mmHg) compared to placebo at week 68. A higher proportion of CagriSema participants reached BP targets (63.0% vs. 32.0%). Among those with resistant hypertension at baseline, BP target attainment was 42.0% vs. 29.3% (OR 1.7; 95% CI 0.7–4.4), though the confidence interval crossed 1. Notably, 39.6% of CagriSema participants on antihypertensive medications reduced or stopped treatment versus 18.8% with placebo. Limitations include that BP outcomes were secondary/post hoc endpoints, not primary, which limits causal inference strength for these specific findings.
Hypertension (Dallas, Tex. : 1979) · Dec 2025DOI ↗ Moderate · humanPreprint
This systematic review and meta-analysis (PROSPERO-registered) pooled data from four randomized controlled trials (n = 4,810 adults with overweight or obesity) to compare the fixed-dose combination of cagrilintide and semaglutide (CagriSema) against semaglutide alone, cagrilintide alone, or placebo. The authors found that, across all comparators, CagriSema was associated with statistically greater percent body weight reduction: approximately 7.4 percentage points more than semaglutide, 8.8 percentage points more than cagrilintide, and 13.9 percentage points more than placebo. The likelihood of achieving ≥15% or ≥20% weight loss was reported to be 2–3 times higher with the combination. Waist circumference was also significantly reduced with CagriSema versus placebo (mean difference approximately −10.9 cm). No consistent differences in HbA1c were observed across comparisons. Gastrointestinal adverse events were more frequent with CagriSema, and treatment discontinuation rates were correspondingly higher in the combination group. Limitations include the small number of included trials (four), preprint status introducing risk of non-peer-reviewed data, and potential heterogeneity across trial designs and populations.
Unknown journal · Nov 2025DOI ↗ 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 · human
This systematic review and meta-analysis examined the risk of pancreatitis and pancreatic cancer associated with GLP-1 receptor agonists (GLP-1 RAs), including dulaglutide, exenatide, liraglutide, semaglutide, beinaglutide, retatrutide, and tirzepatide. Following PRISMA guidelines, the authors searched PubMed, Embase, and the Cochrane Library, ultimately including 62 randomised controlled trials encompassing 66,232 patients with a mean age of 58.3 years and a mean follow-up of approximately 43.5 weeks. The pooled analysis found a statistically significant increase in pancreatitis risk overall (RR: 1.44, 95% CI 1.09–1.89); however, this significance disappeared when results were stratified by background medication use, suggesting that concomitant medications may be a confounding factor. For pancreatic cancer, no significant overall association was identified (RR: 1.30, 95% CI 0.86–1.97), though a significant signal emerged in the subgroup taking background medications (RR: 1.85, 95% CI 1.05–3.26). The authors note this subgroup finding may be an artifact, as many excluded trials had zero events in both arms. Key limitations include variable follow-up durations, heterogeneous patient populations, and the influence of concomitant therapies, which complicate causal attribution to GLP-1 RAs alone.
Endocrinology, diabetes & metabolism · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from 33 randomized controlled trials (n = 12,028 adults with overweight or obesity) to evaluate whether combining lifestyle modifications with GLP-1 receptor agonists (GLP-1RAs) produces greater improvements in body weight and cardiometabolic markers than lifestyle modification plus placebo. Searches covered PubMed, Embase, and the Cochrane Library through May 2025, and the protocol was pre-registered on PROSPERO. The study found that the combination therapy was associated with a statistically significant mean weight reduction of 7.13 kg, along with improvements in waist circumference, fat mass, systolic blood pressure, fasting blood glucose, glycated hemoglobin, total cholesterol, triglycerides, and LDL cholesterol. HDL cholesterol did not show a significant change. Subgroup analyses suggested that longer treatment duration, use of semaglutide or tirzepatide, weekly dosing, and trials conducted in North America were associated with larger weight loss effects. No included trials were rated high risk of bias. GRADE certainty ranged from low to high across outcomes, with heterogeneity and potential publication bias limiting confidence in several findings. The authors conclude that results should be interpreted cautiously given this variability in evidence certainty.
EClinicalMedicine · Aug 2025DOI ↗