Thiazolidinediones, Insulin Resistance And Obesity: Finding A Balance

J. Wilding

Disclosures

Int J Clin Pract. 2006;60(10):1272-1280. 

In This Article

Summary and Introduction

The clinical efficacy of currently available thiazolidinediones (TZDs) in improving glycaemic control and ameliorating several risk factors for cardiovascular disease (linked to their insulin-sensitising actions as well as direct vascular effects) is well established. Treatment-associated weight gain, however, which has been identified as a class effect of the TZDs, is seen in a number of patients. The magnitude of weight gain correlates in part with improved metabolic control, i.e. better responders are more prone to increases in body weight. The cardiovascular risk associated with obesity appears to be depot specific; while peripheral obesity is associated with a low risk of cardiovascular complications, central obesity confers a greater degree of risk. Evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, the adipose depot that is associated with central obesity.

The thiazolidinediones (TZDs; rosiglitazone and pioglitazone) are a class of oral antidiabetic agents that exert their glucose-lowering effects by reducing insulin resistance,[1] an important underlying factor in the development of type 2 diabetes.[2] The clinical efficacy of the TZDs in improving glycaemic control, either as monotherapy or in combination with other agents such as metformin, sulphonylureas or insulin, is well documented in patients with type 2 diabetes.[3,4,5,6,7,8,9,10,11] Furthermore, the impact of TZDs on insulin resistance and associated risk factors for cardiovascular disease (CVD) and data from the PROactive trial[12] suggest that these agents may improve some cardiovascular outcomes in patients with type 2 diabetes. Insulin resistance, which is recognised as being a risk factor for CVD in its own right,[13] is also closely associated with a cluster of cardiovascular risk factors, including abdominal obesity, that are collectively labelled the metabolic syndrome.[14] Through their effects in reducing insulin resistance, the TZDs may favourably impact on other risk factors for CVD, including hypertension, dyslipidaemia and microalbuminuria, as well as non-traditional cardiovascular risk factors, such as markers of hypofibrinolysis (plasminogen activator inhibitor-1) and systemic inflammation (C-reactive protein).[15,16,17,18,19] In addition, the TZDs have direct actions at the level of the vessel wall.[20,21]

While the potential of the TZDs to improve the cardiovascular risk profile is apparent, data from clinical trials and post-marketing experience indicate that TZD therapy is associated with weight gain in some patients; although fluid retention may contribute, it is partly attributable to increase in fat mass.[22] At first, this appears to present a paradox, as obesity is closely related to insulin resistance[23] and is a significant risk factor for CVD.[24] However, it is now recognised that fat distribution is important in determining the risk of CVD.[25] In this article, evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, which is widely regarded as being a risk factor for CVD. In addition, possible mechanisms to explain TZD-associated weight gain and the benefits of implementing concomitant lifestyle intervention measures are discussed.

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