135 Chronic DPP-4 inhibition by sitagliptin enhances both global and regional myocardial function during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease

Background Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut in response to the oral ingestion of nutrients. Through augmentation of myocardial glucose uptake and subsequent reduction in fatty acid oxidation, GLP-1 modulation therapy has emerged as a potential target for improving myocardial oxygen efficiency at times of ischaemic stress, such as occurs in obstructive coronary artery disease (CAD). Sitagliptin is a DDP-4 inhibitor licensed for the treatment of Type 2 Diabetes Mellitus (T2DM) that reduces degradation of plasma GLP-1 (7–36). We investigated whether sitagliptin improved myocardial performance during dobutamine stress echocardiography (DSE) in patients with T2DM and CAD. Methods 12 patients (aged 69±9 years, 9 men) with T2DM on oral hypoglycaemic therapy (OHT), obstructive CAD and preserved left ventricular (LV) systolic function were studied. Each subject underwent DSE on two separate occasions after an overnight fast; the first (control) while receiving standard OHT and the second after the addition of sitagliptin (100 mg od) for 4 weeks. Tissue Doppler imaging was acquired in three apical views at rest, peak stress and 30 min recovery. Global function was assessed by ejection fraction (EF) using the Simpson's biplane method and mitral annular peak systolic velocity (MASV) averaged over six sites. Regional LV wall motion was assessed using a 12-segment model comprising the base and mid-level of six regional walls. Peak systolic tissue velocity (Vs), strain (S) and strain rate (SR) were calculated for each region from tissue Doppler velocity data averaged over three consecutive beats using an off-line workstation (EchoPac, GE Medical Systems). Results At rest, all parameters of both global and regional LV performance were unchanged after sitagliptin. At peak stress, the rate-pressure product attained was the same for both DSE studies but those after sitagliptin demonstrated significantly enhanced myocardial performance in both global (LVEF 69.9±6.5 vs 63.9±6.2%, p=0.001; MASV 12.69±3.0 vs 11.65±3.5 cm/s, p=0.003) and regional parameters (data for 12 segments; vs 10.8±4.4 vs 9.9±4.4 cm/s, p 50% stenosis than in those supplied by a non-obstructed artery. At 30 min recovery, ischaemic LV dysfunction did not occur after sitagliptin (LVEF 55.6±3.5 vs 49.7±2.6%, p=0.0001; MASV 5.55±1.2 vs 5.20±1.0 cm/s, p=0.003). Conclusion In patients with CAD and T2DM receiving OHT, DPP-4 inhibition by sitagliptin improves both global and regional myocardial performance during demand ischaemia (with greater benefit seen in ischaemic vs non-ischaemic segments), and mitigates post-ischaemic stunning.