A randomized placebo controlled double blind crossover study of pioglitazone on left ventricular diastolic function in type 2 diabetes

Abstract

Background/Objectives

Thiazolidinediones (TZDs), such as pioglitazone, are widely used to treat type 2 diabetes but there is evidence that their use is associated with an increased risk of heart failure. We compared the effect of pioglitazone vs. placebo on left ventricular (LV) diastolic and systolic function in people with type 2 diabetes.

Methods and results

24 male or female patients with type 2 diabetes were randomized to pioglitazone (45 mg/day) or placebo in addition to current therapy for 12 weeks using a prospective double blind crossover protocol following a run-in period > 1 week and a 2 week washout period at crossover. Tissue Doppler early peak velocity (e′), a measure of LV diastolic function, was the primary outcome. Pioglitazone significantly increased e′ by 0.7(0.1, 1.3) cm/s (mean (95% confidence interval); p = 0.02) compared with placebo. Pioglitazone also increased E/A and mitral deceleration index, ejection fraction, stroke volume and weight, whereas fasting glucose, HbA1c, total peripheral resistance and LV meridional end systolic stress were decreased.

Conclusions

Treatment with pioglitazone for 12 weeks improves left ventricular diastolic and systolic function in people with type 2 diabetes.

Introduction

Diabetes is a major risk factor for death and disability, principally from cardiovascular disease (CVD). Thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, are agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ) that act as insulin-sensitizing agents. TZDs are used either as monotherapy or in combination with other hypoglycemic agents in diabetes [1], and recently pioglitazone has also been reported to markedly reduce the risk of type 2 diabetes in people with impaired glucose tolerance [2]. Nevertheless, there have been increasing concerns about adverse cardiovascular effects of TZDs, specifically myocardial infarction and congestive heart failure (CHF) for rosiglitazone [3]. These have led to the removal of rosiglitazone from diabetes management guidelines [1], and a dramatic reduction in use. Instead, pioglitazone is being more widely recommended and used. Yet concerns have also been raised regarding the risks of heart failure with pioglitazone [4].

Diabetes is a major risk factor for heart failure [5], and diabetes is associated with impaired systolic [6] and particularly diastolic function [[6], [7]], which may antedate impaired systolic function [8]. Current evidence on the effects of TZDs on left ventricular (LV) function is contradictory [[9], [10], [11], [12], [13], [14], [15]]; most studies show little or no adverse effect on systolic function, but the effects of TZDs on diastolic function are less well studied. Meta-analyses indicate that TZD use is associated with increased rates of reporting of CHF in clinical trials [4], [16], but it has been suggested that this may be due to edema as a result of fluid retention induced by TZDs [17]. This has implications for the use of TZDs given the likely reversibility and lack of adverse outcomes associated with fluid retention per se [18], [16]. Establishing the effects of TZDs, specifically pioglitazone, on LV diastolic function is therefore important to define the appropriate role for pioglitazone in the management of diabetes.

The aim of this study, therefore, was to determine the effect of pioglitazone on LV diastolic function in people with type 2 diabetes in a prospective randomized placebo-controlled double blind trial.