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Commentary on the Results and Clinical Implications of the PROactive Study

The first 300 words of the full text of this article appear below.

	Introduction

 
Thiazolidinediones (TZDs), or glitazones, are a relatively new class of oral drugs that are used to treat type 2 diabetes.^1-4 They lower blood glucose by targeting insulin resistance, one of the major underlying causes of the disease. In addition to their ability to lower blood glucose, TZDs also display a wide range of effects on lipids, blood pressure, weight, and other cardiovascular and metabolic risk factors. As with all other drugs, they can be associated with undesirable side effects.

By virtue of their glucose-lowering properties, all such agents will significantly reduce the risk of the microvascular complications associated with diabetes. On the other hand, no glucose-lowering agent has clearly been shown to significantly reduce macrovascular disease.

Since TZDs, in general, have a net favorable impact on blood lipid levels, may be associated with a reduction in blood pressure, and have positive effects on other physiological parameters associated with vascular disease (e.g., decreasing vascular inflammation, reducing insulin resistance), they have the potential to slow the progression of cardiovascular disease (CVD) in addition to lowering blood glucose.

Because of the above favorable actions of TZDs, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) was initiated to assess the effects of pioglitazone (Actos; Takeda Pharmaceuticals and Eli Lilly) on the secondary prevention of macrovascular events in type 2 diabetic patients.

	Study design

 
PROactive was a randomized, double-blind, placebo-controlled study in 5,238 patients with type 2 diabetes who were managed with diet and/or glucose-lowering medications and who had a history of macrovascular disease.⁵

Male or female patients, aged 35-75 years, were randomized to receive placebo or pioglitazone titrated over 2 months to its maximally approved dosage (45 mg/day). Because study participants had preexisting CVD and diabetes of long duration (average 8 years), virtually all subjects at the time of enrollment were taking a glucose-lowering . . . [Full Text of this Article]

	What were the results of the PROactive study?

 

	Are the results of the PROactive study clinically meaningful?

 

	What adverse events were observed in the trial, and should they influence decisions regarding therapy?

 

	Can the results of PROactive be extrapolated to all people with diabetes?

 

	Do the results of PROactive apply to all TZDs?

 

	Uncertainties and areas that require future research

 

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PROactive: A Sad Tale of Inappropriate Analysis and Unjustified Interpretation

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Clin. Diabetes 2006 24: 63-65. [Extract] [Full Text] [PDF]