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.

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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. 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. 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. 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. PROSPERO identifier number: CRD42024498538.