Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta‐Regression Analysis

Background Prior research suggests clinical effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin‐creatinine ratio. We aimed to confirm these findings using a meta‐analytic approach. Methods and Results We updated a systematic review of 9 GLP‐1RA and 13 SGLT2i trials and summarized longitudinal mediator data. We obtained hazard ratios (HRs) for cardiovascular, renal, and mortality outcomes. We performed linear mixed‐effects modeling of LogHRs versus changes in potential mediators and investigated differences in meta‐regression associations among drug classes using interaction terms. HRs generally became more protective with greater glycated hemoglobin reduction among GLP‐1RA trials, with average HR improvements of 20% to 30%, reaching statistical significance for major adverse cardiovascular events (ΔHR, 23%; P =0.02). Among SGLT2i trials, associations with HRs were not significant and differed from GLP1‐RA trials for major adverse cardiovascular events ( P interaction =0.04). HRs for major adverse cardiovascular events, myocardial infarction, and stroke became less efficacious (ΔHR, −15% to −34%), with more weight loss for SGLT2i but not for GLP‐1RA trials (ΔHR, 4%−7%; P interaction <0.05). Among 5 SGLT2i trials with available data, HRs for stroke became less efficacious with larger increases in hematocrit (ΔHR, 123%; P =0.09). No changes in HRs by systolic blood pressure (ΔHR, −11% to 9%) and urine albumin‐creatinine ratio (ΔHR, −1% to 4%) were found for any outcome. Conclusions We confirmed increased efficacy findings for major adverse cardiovascular events with reduction in glycated hemoglobin for GLP1‐RAs. Further research is needed on the potential loss of cardiovascular benefits with increased weight loss and hematocrit for SGLT2i.