Association Between the Magnitude of Glycemic Control and Body Weight Loss With GLP-1 Receptor Agonists and Risk of Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-analyses of Randomized Diabetes Cardiovascular Outcomes Trials

Purpose: Reduction of major atherosclerotic cardiovascular events (MACE) has not been consistent among different glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the association between the magnitude of glycemic control, body weight loss, and reductions in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) achieved through GLP-1 RA therapy and MACE.

Methods: Electronic databases (MEDLINE, CENTRAL, SCOPUS) were searched through March 2023. Studies were eligible if they were cardiovascular outcome trials (CVOTs) comparing GLP-1 RAs versus placebo in T2DM patients. The outcome of interest was 3-point MACE - cardiovascular death, myocardial infarction, or stroke. Random-effects meta-regression analyses evaluated the associations between reductions of HbA_1c, body weight, SBP and LDL-C and reduction of MACE.

Results: Overall, 8 CVOTs were included (60079 patients, 30693 with GLP-1 RAs). Reductions of HbA_1C were associated with the reduction of 3P-MACE (Log RR -0.290 [95% CI -0.515;-0.064], p = 0.012), with an estimated RR reduction of 25% for each 1% absolute reduction in HbA_1C levels. Body weight loss was associated with the reduction of 3P-MACE (Log RR -0.068 [95% CI -0.135;-0.001], p = 0.047), with an estimated RR reduction of 7% for each 1 kg reduction in body weight. Reductions of SBP (Log RR -0.058 [95% CI -0.192;0.076], p = 0.396) and LDL-C (Log RR -0.602 [95% CI -4.157;2.953], p = 0.740) were not associated with the reduction of 3P-MACE.

Conclusions: In T2DM patients, more potent GLP-1 RAs in reducing HbA1c and body weight were associated with greater reductions of MACE.