Metformin Use May Moderate the Effect of DPP-4 Inhibitors on Cardiovascular Outcomes

OBJECTIVE To explore prevalent metformin use as a potential moderator of the cardiovascular effects of dipeptidyl peptidase 4 inhibitors (DPP-4i). RESEARCH DESIGN AND METHODS We performed a meta-analysis of the three major cardiovascular outcomes trials examining DPP-4i. We used meta-regression to examine how the cardiovascular effects of DPP-4i differ between prevalent metformin users and baseline nonusers. RESULTS While prevalent metformin users experienced a trend toward improved cardiovascular outcomes with DPP-4i (summary hazard ratio HR 0.92 95% CI 0.84, 1.01), baseline metformin nonusers showed a trend toward harm (HR 1.10 95% CI 0.97, 1.26). The difference in overall DPP-4i effect between metformin user and nonuser subgroups was statistically significant (P = 0.036). CONCLUSIONS Baseline metformin status may have a moderating effect on cardiovascular outcomes with DPP-4i use. This hypothesis-generating analysis suggests there is residual uncertainty as to how DPP-4i affect cardiovascular outcomes, depending on concurrently prescribed medications.