Abstract
Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions may be mediated by changes in hemoglobin A1c (HbA1c), bodyweight, systolic blood pressure (SBP), hematocrit, and urine albumin-creatinine ratio (uACR). We evaluated the heterogeneity of CV benefits by these potential mediators for sodium-glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a meta-analytic approach. Methods: We performed a systematic review and meta-regression analyses of 12 SGLT2i and 9 GLP-1RA CV outcome trials using linear mixed models of treatment efficacy measured as log hazard ratios (HRs) vs changes in potential mediators. We extracted follow-up mediator data for treatment and control, preferably at 12 months post randomization. Outcomes included MI, stroke, and MACE (a composite of MI, stroke, or CV death). We investigated slope differences between drug classes using interaction terms and likelihood-ratio tests. Results: Treatment efficacy for MACE improved with more HbA1c reduction among GLP-1RA (slope .26; P slope .02) but not among SGLT2i trials (slope -.22; P slope .39; P interaction .06), see Figure . Treatment efficacy for MACE, MI, and stroke decreased with more weight loss for SGLT2i (slope –.17, –.29, –.39; P slope <.05) but not for GLP-1RA trials (slope .05, .03, .07; P slope .30, .62, .32). Slopes differed significantly between drug classes: P interaction <.05. For stroke, we observed a trend of less treatment efficacy with increases in hematocrit among five SGLT2i trials with available data (slope .96; P slope .07). We did not find any indication of mediation effects by SBP and uACR for SGLT2i or GLP-1RAs (slopes -.11 -.07; P slopes ≥ .05). Conclusion: We confirm previous findings of increased CV benefits with reductions in HbA1c for GLP1-RAs. Further research is needed to investigate the potential loss of SGLT2i efficacy with greater weight loss and increase in hematocrit.
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