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

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.