Glycemic control, weight-loss effects, and safety of cotadutide in individuals with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Cotadutide (MEDI0382) is a twincretin that acts as an agonist for both the glucagon-like peptide-1 and glucagon receptors. Several randomized controlled trials (RCTs) have been published evaluating the use of cotadutide in individuals with type 2 diabetes (T2D), showing promising results. However, the efficacy and safety of the drug use have been inadequately explored by systematic reviews and meta-analyses. AIM: To assess the clinical efficacy and safety of cotadutide in individuals with T2D having overweight or obesity. METHODS: The systematic reviews and meta-analyses have been registered with International Prospective Register of Systematic Reviews (CRD42024511703), and the protocol summary can be accessed online. Several databases and registries, including MEDLINE (via PubMed), Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, were systematically searched using related terms from their inception to May 15, 2025, for RCTs involving individuals with T2D receiving cotadutide in the intervention group. Review Manager web was used to conduct meta-analysis using random-effects models. The co-primary outcomes of interest were the changes in glycated hemoglobin (HbA1c) and the percent changes in body weight from baseline. The results of the outcomes were expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). The analysis of outcomes was stratified according to whether the control group received a placebo, denoted as the placebo control group (PCG), or an active comparator, referred to as the active control group (ACG). RESULTS: Nine RCTs (mostly phase 2 RCTs, n = 1525) with study durations varying from 28 days to 54 weeks that met all the inclusion criteria were analyzed; five studies had a low overall risk of bias, while the other four had some concerns. Compared to the PCG, greater reductions in HbA1c were achieved with cotadutide 100 μg (MD -0.77%, 95%CI: -1.06 to -0.47), 200 μg (MD -0.68%, 95%CI: -1.12 to -0.23), 300 μg (MD -0.67%, 95%CI: -0.79 to -0.56), and 600 μg (MD -0.69%, 95%CI: -0.97 to -0.41). Cotadutide 100 μg (MD -1.74%, 95%CI: -3.23 to -0.25), 200 μg (MD -2.56%, 95%CI: -3.37 to -1.75), 300 μg (MD -3.49%, 95%CI: -4.14 to -2.84), and 600 μg (MD -5.45%, 95%CI: -7.17 to -3.73) achieved greater percent reductions in body weight from baseline. However, the certainty of evidence for HbA1c and percent body weight reductions was very low to low. Cotadutide, at all doses, also outperformed PCG in reducing fasting plasma glucose and absolute body weight. The changes in HbA1c, percent body weight, fasting plasma glucose, and absolute body weight were similar between the cotadutide group and the ACG. Compared to PCG, pooled doses of cotadutide increased the risks of treatment-emergent adverse events (AEs), treatment-related AEs, and discontinuation of the study drug due to AEs, but not for serious AEs. More subjects experienced overall gastrointestinal AEs, dyspepsia, nausea, vomiting, constipation, and decreased appetite with cotadutide than with PCG. Compared to the ACG, none of the AEs showed increased risk in the cotadutide group. CONCLUSION: Cotadutide demonstrated glycemic control and weight-loss benefits in short-term, small RCTs (mostly phase 2). However, small sample sizes, very low to low certainty of evidence, and the absence of data on long-term cardiovascular and renal outcomes highlight substantial uncertainties, warranting cautious interpretation and further investigation in larger, longer-term trials to establish its safety and efficacy profile.