Efficacy of GLP-1 Receptor Agonist-Based Therapies on Cardiovascular Events and Cardiometabolic Parameters in Obese Individuals Without Diabetes: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background: The cardioprotective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA)-based therapies in nondiabetic individuals with overweight or obesity remain underexplored. This meta-analysis evaluates their impact on cardiovascular events and metabolic parameters in this population.

Methods: A meta-analysis was conducted using PubMed, Embase, Cochrane, and Web of Science databases from inception to June 18, 2024. Eligible studies were randomized controlled trials (RCTs) enrolling nondiabetic adults with overweight or obesity. These studies compared GLP-1RA-based therapies with placebo and reported cardiovascular events and metabolic parameters.

Results: A total of 29 RCTs involving 9 GLP-1RA-based drugs and 37 348 eligible participants were included. Compared to placebo, GLP-1RA-based therapies significantly reduced the risk of total cardiovascular events (relative risk: 0.81, 95% confidence interval [CI]: [0.76, 0.87]), major adverse cardiovascular events (0.80, [0.72, 0.89]), myocardial infarction (0.72, [0.61, 0.85]), and all-cause mortality (0.81, [0.71, 0.93]). No significant differences were observed in cardiovascular death or stroke. Additionally, GLP-1RA-based therapies were associated with significant reductions in some cardiometabolic parameters. Among GLP-1RA-based therapies, orfroglipron demonstrated strong benefits in reducing systolic blood pressure (mean difference: -7.10 mmHg, 95% CI: [-11.00, -2.70]). Tirzepatide induced the greatest reduction in body mass index (-6.50 kg/m², [-7.90, -5.10]) and hemoglobin A1c concentrations (-0.39%, [-0.52, -0.26]). Retatrutide and semaglutide were most effective in improving lipid profiles and reducing C-reactive protein levels (-1.20 mg/dL, [-1.80, -0.63]), respectively.

Conclusions: In nondiabetic individuals with overweight or obesity, GLP-1RA-based therapies significantly reduce cardiovascular events and improve cardiometabolic parameters. These findings underscore the potential for individualized GLP-1RA-based therapies targeting cardiovascular risk factors.

Keywords: GLP‐1 receptor agonist‐based therapies; GLP‐1RAs; cardiometabolic; cardiovascular disease; meta‐analysis; obesity or overweight.

FIGURE 1

Treatment effects of GLP‐1RA‐based therapies on cardiovascular events. Cardiovascular events include major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and cardiovascular death, as detailed in Table S1.

FIGURE 2

Risk ratios and 95% CI for MACE, MI, stroke, CV death, and all‐cause mortality. CV death, cardiovascular death; MACE, major adverse cardiovascular events; MI, myocardial infarction.

FIGURE 3

Mean difference and 95% CI for SBP, BMI, LDL‐c, TG, HbA1c, FBG, and CRP. BMI, body mass index; CRP, C‐reactive protein; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; LDL‐c, low‐density lipoprotein cholesterol; SBP, systolic blood pressure; TG, triglyceride. Units: SBP, mmHg; BMI, kg/m²; LDL‐c, TG, FBG, mmol/L; HbA1c, %; CRP, mg/L.

FIGURE 4

Network of available comparisons between GLP‐1RA‐based therapies and placebo for (a) systolic blood pressure, (b) BMI, (c) low‐density lipoprotein cholesterol, (d) triglyceride, (e) HbA1c, (f) fasting blood glucose, and (g) C‐reactive protein. The size of the nodes is proportional to the number of trial participants, and the thickness of the line connecting the nodes is proportional to the randomized number of trial participants directly comparing the two treatments. Numbers represent the number of trials contributing to each treatment comparison.

FIGURE 5

Forest plot of network effect sizes between GLP‐1RA‐based therapies and placebo for (a) systolic blood pressure, (b) BMI, (c) low‐density lipoprotein cholesterol, (d) triglyceride, (e) HbA1c, (f) fasting blood glucose, and (g) C‐reactive protein. Effect sizes are presented as mean differences with 95% confidence intervals. Units: SBP, mmHg; BMI, kg/m²; LDL‐c, TG, FBG, mmol/L; HbA1c, %; CRP, mg/L.

FIGURE 6

Mean difference and 95% confidence intervals (CIs) for comparisons between GLP‐1RA‐based therapies and placebo for (a) systolic blood pressure and fasting blood glucose, (b) BMI and HbA1c, (c) low‐density lipoprotein cholesterol and triglyceride, and (d) C‐reactive protein. Mean difference and 95% CIs for systolic blood pressure/BMI/low‐density lipoprotein cholesterol in upper cells (green or orange) and fasting blood glucose/HbA1c/triglyceride/C‐reactive protein in lower cells (blue or yellow). Cells are shaded according to mean difference, and the colors correspond to the legend on the side. For example, in the first cell of Figure 4a, the mean difference is −2.42 (−3.73, −1.12); it means liraglutide reduces the systolic blood pressure by −2.42 compared with placebo. Units: SBP, mmHg; BMI, kg/m²; LDL‐c, TG, FBG, mmol/L; HbA1c, %; CRP, mg/L.