Moderate · human
This network meta-analysis systematically evaluated the comparative efficacy and safety of four investigational glucagon receptor agonist (GRA)-based agents — retatrutide, cotadutide, mazdutide, and survodutide — in adults with type 2 diabetes, overweight, or obesity. Researchers searched PubMed, Cochrane, Embase, and Scopus, ultimately including 14 randomised controlled trials analyzed using frequentist network meta-analysis with random-effects models. Key outcomes included absolute and percent body weight change, HbA1c reduction, adverse events, and treatment discontinuation due to adverse events. The study found that retatrutide produced the greatest absolute weight reduction versus placebo (MD −13.44 kg), followed by survodutide (MD −10.74 kg) and mazdutide (MD −6.47 kg); cotadutide's effect did not reach statistical significance. Retatrutide also showed the largest HbA1c reduction, though only its effect was statistically significant among the agents. Regarding tolerability, mazdutide demonstrated the most favorable safety profile, while retatrutide and cotadutide were associated with comparatively lower tolerability. The authors acknowledge limitations inherent to network meta-analysis, including reliance on early- and mid-phase trial data and the absence of direct head-to-head comparisons between agents.
Endocrinology, diabetes & metabolism · 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
This systematic review and meta-analysis evaluated the efficacy and safety of retatrutide — a novel triple agonist (GIP/GLP-1/glucagon receptor) — specifically in patients with type 2 diabetes and/or obesity comorbid with chronic kidney disease (CKD). Researchers conducted a comprehensive literature search and ultimately included eight randomized controlled trials. The study found that retatrutide was associated with a statistically significant mean reduction in HbA1c of -1.04% (95% CI: -1.42 to -0.67) and body weight reductions of up to -24.2%. A subgroup analysis suggested a dose-dependent pattern in glycemic outcomes, with lower doses appearing to produce greater HbA1c reductions than higher doses, though this finding warrants cautious interpretation. Secondary analyses indicated possible renoprotective effects, reflected by reductions in albuminuria. Gastrointestinal adverse events were the most commonly reported safety concern, consistent with the broader drug class. Key limitations include the small number of included studies (n=8), potential heterogeneity across trials, and the fact that CKD-specific data may have been drawn from subgroup analyses of broader trials rather than CKD-dedicated studies. The overall evidence base for retatrutide in CKD patients remains early-stage.
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 network meta-analysis evaluated the comparative efficacy and safety of dual and triple incretin-based agonists — compounds targeting combinations of GLP-1, GIP, and glucagon receptors — versus standard therapies for type 2 diabetes mellitus (T2DM). Researchers searched PubMed, Web of Science, Cochrane Library, and Embase through July 2024, identifying randomized controlled trials assessing outcomes including body weight, HbA1c, fasting blood glucose (FBG), adverse events (AEs), and serious adverse events (SAEs). The analysis found that Retatrutide (a triple agonist) was associated with the greatest weight reduction, while Tirzepatide (a dual GLP-1/GIP agonist) showed the largest reductions in both FBG and HbA1c. Regarding safety, Tirzepatide and Cotadutide were associated with increased AEs, whereas Semaglutide was associated with reduced SAEs. The authors suggest that receptor-specific targeting may help personalize T2DM treatment. Key limitations include small sample sizes in some included trials, short study durations, and reliance on indirect comparisons in the network meta-analysis. The authors acknowledge that direct head-to-head trials are needed to confirm these findings. The study was prospectively registered (PROSPERO: CRD42024532368).
Acta diabetologica · Jun 2025DOI ↗