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 (Pϭ0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (PϽ0.001), 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 (Pϭ0.006), 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 (PϽ0.001). 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.

Impact of sex on the heart's metabolic and functional responses to diabetic therapies

“…This finding in men makes sense given that their palmitate clearance decreased, and they had slightly higher plasma FA levels. These myocardial FA findings are in contrast with another study, which demonstrated a decline in FA oxidation with metformin (23). The reasons for this dis- …”

“…Alternatively and/or in addition, some studies suggest sexrelated differences in the generation of oxidative stress and the response to oxidative stress (6,11), and oxidative stress is linked to cardiac dysfunction (1). The lack of correlation between functional and metabolic changes is at odds with studies in experimental models of T2DM (25) but consistent with reports in T2DM patients (23). The lack of correlation may reflect the fact that our patients were relatively healthy, well-controlled, and only exhibited mild diastolic dysfunction.…”

“…This increase may be related to the volume retention effects of the thiozoladinedione agents (17). Although a consistent increase in LV mass is not observed in all studies of thiozoladinedione treatment (23), there are reports of increases in LV mass in animal studies (17). Alternatively, there may be a potential synergistic effect on LV mass when metformin and rosiglitazone are given concomitantly.…”

“…Animals with T2DM treated with omega-3E fatty acids, which typically lower plasma triglyceride levels, also improved cardiac dysfunction, but only in the males (22). A study in T2DM men showed that lowering plasma FA levels (via weight loss) was associated with lower myocardial fat accumulation and improved diastolic function (23).…”

Nonalcoholic fatty liver disease is independently associated with early left ventricular diastolic dysfunction in patients with type 2 diabetes

“…Moreover, it is also important to note that the use of hypoglycemic, lipidlowering and anti-hypertensive drugs was not significantly different between patients with and without NAFLD. Again, no patients were treated with pioglitazone or glucagon-like peptide-1 receptor agonists, which have been shown to reduce hepatic steatosis [1,9,25] and improve cardiac function [26,27]. Finally, our novel finding of a significant association between NAFLD and larger left atrial volume might also be of pathophysiological relevance in the explanation of recent observations documenting that type 2 diabetic patients with NAFLD are at risk of atrial fibrillation [28,29].…”