Cardiovascular and Renal Benefits of Novel Diabetes Drugs by Baseline Cardiovascular Risk: A Systematic Review, Meta-analysis, and Meta-regression.

Objective Eligibility for glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but it is not clear whether expected treatment benefits differ by risk levels. We investigated whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RAs and SGLT2i using meta-analysis and meta-regression. Research Design and Methods We updated searches of recent meta-analyses using PubMed through November 7, 2022. We included reports of confirmatory randomized trials of GLP-1RA and SGLT2i in adult patients with safety or efficacy endpoint data. We extracted hazard ratio (HR) and event rate data for mortality, cardiovascular, and renal outcomes. Results We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA: 0.87; SGLT2i: 0.86), major adverse cardiovascular events (0.87; 0.88), heart failure (0.89; 0.70), and composite renal (0.84; 0.65) outcomes. For stroke, efficacy was significant for GLP-1RAs (0.84), but not for SGLT2i (0.92). We did not find statistically significant associations between control arm cardiovascular mortality rates and HRs. Five-year absolute risk differences ranged from -4.25% to -0.80%, with larger reductions (11.6%) for heart failure with SGLT2i in high risk (p for slope <.001). For GLP1-RAs, associations were nonsignificant. Conclusions Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making.