DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease

Abstract

Background: Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted postprandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography in patients with coronary artery disease.

Methods and results: Fourteen patients with coronary artery disease and preserved LV function awaiting revascularization were studied. After either a single dose of 100 mg sitagliptin or placebo, 75 g of glucose was given orally to promote GLP-1 secretion and dobutamine stress echocardiography was conducted with tissue Doppler imaging at rest, peak stress, and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5+/-10.7 versus 9.7+/-8.7 pg/mL; P=0.003) and in recovery (12.4+/-5.5 versus 9.0+/-5.5 pg/mL; P=0.01), and the LV response to stress was enhanced (ejection fraction, 72.6+/-7.2 versus 63.9+/-7.9%, P=0.0001; mitral annular systolic velocity, 12.54+/-3.18 versus 11.49+/-2.52 cm/s; P=0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired nonapical segments assessed by peak systolic tissue Doppler (velocity, 10.56+/-4.49 versus 9.81+/-4.26 cm/s, P=0.002; strain, -15.9+/-6.3 versus -14.6+/-6.6%, P=0.01; strain rate, -2.04+/-1.04 versus -1.75+/-0.98 s(-1), P=0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments, 9.77+/-4.18 versus 8.74+/-3.87, P=0.007; velocity in nonischemic segments, 11.51+/-4.70 versus 11.14+/-4.38, P=0.14). In recovery, sitagliptin attenuated the postischemic stunning seen after the control study.

Conclusions: The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates postischemic stunning in humans with coronary artery disease. Clinical Trial Registration- URL: http://www.isrctn.org. Unique identifier: ISRCTN78649100.