A Methodological Framework for Meta-analysis and Clinical Interpretation of Subgroup Data: The Case of Major Adverse Cardiovascular Events with GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes

We present a methodological framework for conducting and interpreting subgroup meta-analyses. Methodological steps comprised evaluation of clinical heterogeneity regarding the definition of subpopulations, credibility assessment of subgroup meta-analysis, and translation of relative into absolute treatment effects. We used subgroup data from type 2 diabetes cardiovascular outcomes trials (CVOTs) with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, for patients with established cardiovascular disease and those at high cardiovascular risk without manifest cardiovascular disease. First, we evaluated the variability in definitions of the subpopulations across CVOTs using major adverse cardiovascular events (MACE) incidence in the placebo arm as a proxy for baseline cardiovascular risk. As baseline risk did not differ considerably across CVOTs, we conducted subgroup meta-analyses of hazard ratios (HRs) for MACE and assessed the credibility of a potential effect modification. Results suggested using the same overall relative effect for each of the two subpopulations (HR 0.85, 95% CI 0.80 to 0.90 for GLP-1 receptor agonists, and HR 0.91, 95% CI 0.85 to 0.97 for SGLT2 inhibitors). Finally, we calculated five-year absolute treatment effects (number of fewer patients with event per 1000 patients). Treatment with GLP-1 receptor agonists resulted in 30 fewer patients with event in the subpopulation with established cardiovascular disease, and 14 fewer patients with event in patients without manifest cardiovascular disease. For SGLT2 inhibitors, the respective absolute effects were 18 and 8 fewer patients with event per 1000 patients. This framework can be applied to subgroup meta-analyses regardless of outcomes or modification variables.