Response to Letter Regarding Article, "Heart Failure, Saxagliptin and Diabetes Mellitus: Observations From the SAVOR-TIMI 53 Randomized Trial".

We thank Drs Muskiet, Tonneijck, and van Raalte for calling attention to the potentially detrimental consequences of simultaneous inhibition of dipeptidyl peptidase 4 and angiotensin-converting enzyme (ACE).1,2 They note correctly that in Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications (SAVOR-TIMI 53), more patients treated with ACE inhibitors at baseline were subsequently hospitalized for heart failure. However, this observation alone is likely a result of confounding by indication, because patients at highest risk of heart failure are more likely to be treated with this class of drug in the first place. A similar observation was seen with β-blockers.3 Despite elegant physiological studies suggesting a potential hemodynamic interaction between dipeptidyl peptidase 4 inhibitors and ACE inhibitors, there were no differences in heart or blood pressure changes after randomization according to baseline ACE inhibitor use in patients treated with saxagliptin or placebo (all P for interaction >0.10). Nor were there any clinical consequences of baseline ACE inhibitor use on the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke (baseline ACE inhibitor: saxagliptin, 7.3% versus placebo, 7.5%; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.81–1.09; P =0.41 in comparison with no baseline ACE inhibitor: saxagliptin, 7.3% versus placebo, 6.9%; HR, 1.08; 95% CI, 0.91–1.27; P =0.39; P for interaction=0.23), the secondary end point, which included the primary end point plus hospitalization for unstable angina, heart failure, or coronary revascularization (baseline ACE inhibitor: saxagliptin, 12.9% versus placebo, 13.2%; HR, 0.95; 95% CI, 0.85–1.07; P =0.41 in comparison with no baseline ACE inhibitor: saxagliptin, 12.7% versus placebo, 11.5%; HR, 1.11; 95% CI, 0.98–1.27; P =0.11; P for interaction=0.08), or hospitalization for heart failure alone (baseline ACE inhibitor: saxagliptin, 3.6% versus placebo, …