Therapy With a DPP-4 Inhibitor Increases Myocardial Glucose Uptake in Nonischemic Cardiomyopathy

Abstract

Introduction: Glucose and fatty acids comprise the primary substrates for myocardial energy metabolism. Because glucose is the more efficient fuel, the normal myocardium switches metabolism toward glucose in the setting of stress the inability to affect such a switch is a fundamental mechanism behind “diabetic” or “insulin-resistant” cardiomyopathy. We sought to evaluate the effects of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on myocardial glucose uptake in patients with nonischemic cardiomyopathy. Methods: Twelve patients with nonischemic dilated cardiomyopathy on stable medical therapy were enrolled in the trial. Because the goal of the study was to assess the direct actions of sitagliptin on myocardial glucose uptake rather than sitagliptin’s effects as a hypoglycemic therapy for diabetes, diabetic patients were excluded. At baseline, all subjects underwent fasting metabolic testing (glucose, insulin, lipids) and assessment of myocardial glucose uptake by 18F-FDG-PET/CT imaging. All subjects were then treated with sitagliptin (100 mg orally once daily) for four weeks, and metabolic testing and PET-CT imaging was repeated. The primary endpoint of the study was change in myocardial glucose uptake preand post-sitagliptin therapy, measured 10-30 minutes post-FDG injection. Results: Sitagliptin therapy resulted in a significant increase in myocardial glucose uptake (19% increase, P50.04). While most patients had at least a slight increase in glucose uptake, there was an overall bimodal response e with six patients (“responders”) demonstrating large increases (O20%) in glucose uptake and six patients (“nonresponders”) demonstrating !5% increases or slight decreases. There were no associations between increases in glucose uptake and levels of serum/plasma glucose, insulin, or insulin resistance. Triglyceride:HDL ratios significantly dropped in the six “responders” compared with the six “nonresponders” (P!0.02). Conclusions: Therapy with sitagliptin results in increased myocardial glucose uptake in nondiabetic patients with nonischemic cardiomyopathy. These results provide mechanistic evidence to support a trial assessing clinical heart failure endpoints.