Role of Incretin Mimetics in Cardiovascular Outcomes and Other Classical Cardiovascular Risk Factors beyond Obesity and Diabetes Mellitus in Nondiabetic Adults with Obesity: a Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Emerging data on cardiovascular outcomes, specifically major adverse cardiovascular events (MACE), are being reported from various trials involving incretin mimetics, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and glucose-dependent insulinotropic polypeptide (GIP), especially among patients with obesity and diabetes. Our aim was to evaluate this matter, while also involving various traditional cardiovascular risk factors [e.g., several body weight (BW) parameters, blood pressure (BP), lipid profile]. METHODS: A search of PubMed, Europe PMC, ScienceDirect, Cochrane, and ClinicalTrials.gov up to September 2024 was performed to identify GLP-1 RA and GIP trials in MACE risk reduction as a primary endpoint. Our secondary endpoints included a reduction in BW, waist circumference (WC), body mass index (BMI), BP changes, and lipid modifying effects, while also yielding safety concerns surrounding the use of these pharmaceutical agents. Mean differences (MD) and risk ratios (RR) were summarized using random-effects model. RESULTS: A total of 11 eligible randomized controlled trials (RCTs) comprising 8 GLP-1 RA trials and 3 dual GLP-1 RA/GIP (tirzepatide) trials were included. Compared with control groups, GLP-1 RA significantly reduced the MACE risk by 32% [RR 0.68 (95% CI 0.53-0.87); P = 0.002; I= 73%, P-heterogeneity < 0.001] and 59% for tirzepatide [RR 0.41 (95% CI 0.18-0.92); P = 0.03; I= 0%, P-heterogeneity = 0.96]. Incretin mimetics also substantially reduced BW, BP, and improved lipid panel measures. However, there was an increased risk of adverse events, specifically gastrointestinal disorders within the incretin mimetics subset. CONCLUSIONS: Incretin mimetics have shown promise in reducing MACE risk while also enhancing cardiovascular risk factors, including blood pressure and lipid profile, in adults with obesity without diabetes.