The Efficacy and Safety of GLP-1 RAs in the Modification of Cardiovascular Morbidity in Patients with Obesity Without Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials Involving 32,884 Patients.

Background: Although the cardioprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well documented in patients with diabetes mellitus, their impact on cardiovascular outcomes in patients with obesity without diabetes remains under debate. Therefore, we conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) to investigate the effects of GLP-1 RAs on cardiovascular outcomes in patients with obesity without diabetes.

Methods: We systematically searched PubMed, Web of Science, SCOPUS, and Cochrane databases through December 26, 2023. We pooled dichotomous data using risk ratios (RRs) and continuous data using mean differences with 95% confidence intervals (CIs). We evaluated the quality of each study using the Cochrane RoB2 method, and the study protocol was registered on PROSPERO ID: CRD42024498538.

Results: We included 19 RCTs with a total of 32,884 patients. Of these, 15 had a low overall risk of bias, two raised concerns, and two had a high risk of bias. There was no difference between GLP-1 RAs and placebo regarding cardiovascular mortality (RR 0.85; 95% CI 0.71-1.01; p = 0.07). However, compared with placebo, GLP-1 RAs significantly decreased the incidence of all-cause mortality (RR 0.82; 95% CI 0.72-0.93; p < 0.0001), non-cardiovascular mortality (RR 0.77; 95% CI 0.63-0.95; p = 0.01), and myocardial infarction (RR 0.73; 95% CI 0.62-0.86; p < 0.0001). Additionally, patients receiving GLP-1 RAs experienced significant overall weight loss (- 8.53 kg; 95% CI - 12.38 to - 4.68; p < 0.0001) and improvements in lipid profiles, including lower levels of total cholesterol (- 0.77 %; 95% CI - 1.03 to - 0.50; p < 0.0001), triglycerides (- 6.78 %; 95% CI - 8.11 to - 5.46; p < 0.0001), low-density lipoproteins (- 2.85 %; 95% CI - 3.74 to - 1.96; p < 0.0001), and very low-density lipoproteins (- 4.47 %; 95% CI - 5.56 to - 3.38; p < 0.0001). GLP-1 RAs also significantly increased the incidence of any adverse events (RR 1.11; 95% CI 1.05-1.16; p < 0.0001), with no difference regarding the incidence of serious adverse events. However, gastrointestinal adverse events were significantly more frequent in patients receiving GLP-1 RAs, with a higher risk of any gastrointestinal adverse events (RR 2.83; 95% CI 1.86-4.3; p < 0.001), nausea (RR 2.70; 95% CI 2.18-3.33; p < 0.001), diarrhea (RR 1.97; 95% CI 1.68-2.31; p < 0.001), vomiting (RR 3.85; 95% CI 3.32-4.48; p < 0.001), and constipation (RR 2.35; 95% CI 1.94-2.85; p < 0.001) than in those receiving placebo.

Conclusion: In obese patients without diabetes, GLP-1 RAs demonstrated substantial benefits in reducing cardiovascular risks, including all-cause mortality and myocardial infarction, and effectively promoted weight loss and improved lipid profiles and blood pressure control. However, their use is accompanied by a higher incidence of gastrointestinal adverse effects and heterogeneity in outcomes, highlighting the need for individualized treatment approaches.

Registration: PROSPERO identifier number: CRD42024498538.