Pioglitazone Improves Cardiac Function and Alters Myocardial Substrate Metabolism Without Affecting Cardiac Triglyceride Accumulation and High-Energy Phosphate Metabolism in Patients With Well-Controlled Type 2 Diabetes Mellitus

Abstract

Background— Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients. Methods and Results— Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [ 18 F]-2-fluoro-2-deoxy- d -glucose and [ 11 C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate ( P =0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake ( P <0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone ( P =0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content ( P <0.001). Conclusions— In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.