DPP-4 inhibition with sitagliptin has cardioprotective effects in diabetics with CAD
Chronic DPP-4 Inhibition with Sitagliptin Is Associated with Sustained Protection Against Ischemic Left Ventricular Dysfunction in a Pilot Study of Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease
McCormick LM, Kydd AC, Read PA, et al.
Circ Cardiovasc Imaging. 2014 Feb 6
BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors reduce the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1), which leads to increased insulin secretion, suppression of glucagon release, and a lower hepatic production of glucose and higher peripheral glucose uptake and metabolism. The pancreatic effects depend on the glucose concentration, which reduces the risk of hypoglycaemia. They were found to be safe and well-tolerated in clinical studies .
Modulation of GLP-1 may influence cardiovascular (CV) risk. To date, only one study has investigated the cardioprotective effects of DPP-4 inhibition in humans, which found an acute improvement in myocardial performance during dobutamine stress in non-diabetic patients with coronary artery disease (CAD) after a single dose of sitagliptin and an oral glucose load .
This study aimed to determine if patients with type 2 diabetes mellitus (T2DM) will also benefit from these favourable CV effects. To this extent, 19 patients with T2DM and CAD received DPP-4 inhibition with sitagliptin for about four weeks, and left ventricular (LV) function and myocardial response to demand in dobutamine stress echocardiography (DSE) was evaluated.
- The number of patients experiencing ischemic chest pain did not differ between the control-DSE (on regular oral hypoglycemic agents) and the DSE after sitagliptin, nor were differences seen in ST segment shift or segmental motion abnormalities at peak stress.
- Plasma GLP-1 levels at baseline, during peak dobutamine stress and during recovery were 5 to 8 times higher after sitagliptin than control, while plasma glucose levels were not significantly different.
- No statistically significant differences in plasma concentrations of insulin or free fatty acids were seen at baseline, nor at peak stress and in the recovery phase 30 minutes after cessation of dobutamine.
- At baseline there was no difference in ejection fraction at rest. At peak stress, DPP-4 inhibition gave a greater increase in LV function (70.5+7.0 vs 65.7+8.0% in control DSE, P<0.0001), an improvement that persisted into recovery (56.0+6.2 vs. 51.2+6.0%, P<0.0001). The control DSE showed evidence of post-ischaemic LV dysfunction (stunning) when compared to baseline, which was not seen after sitagliptin.
- Myocardial performance as measured by mitral annular systolic velocity was also enhanced after DPP-4 inhibition, both at peak stress (11.69+2.64 vs. 10.9+2.29cm/s, P=0.01) and at 30 minutes after dobutamine stress (5.81+1.16 vs. 5.53+1.12cm/s, P=0.03).
- DPP-4 inhibition was associated with a small improvement of peak systolic tissue velocity at rest, and at peak dobutamine stress, which persisted into recovery.
With regard to regional wall LV motion, sitagliptin had a greater beneficial effect on ischaemic than on non-ischaemic segments.
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ConclusionThis pilot study suggests that addition of DPP-4 inhibitor therapy with sitagliptin to regular treatment of patients with T2DM and CAD can give improvement of both global and regional LV performance during dobutamine stress and a reduction in post-ischaemic stunning. Ischemic regional wall segments benefitted most from the cardioprotective effects.
These cardioprotective effects of sitagliptin treatment in diabetic patients need to be confirmed in large, prospective, randomised studies, and clinical endpoints need to be also evaluated.
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1. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011; 13:7-18.
2. Read PA, Khan FZ, Heck PM, et al. 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. Circ Cardiovasc Imaging. 2010; 3:195-201.