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Pioglitazone May Prevent Progression of Atherosclerosis in Patients With Type 2 Diabetes: Presented at ACC

By Mike Fillon

CHICAGO -- April 2, 2008 -- Antidiabetic therapy does not appear to reduce the progression of coronary atherosclerosis, and there is little evidence to support a preference for one class of glucose-lowering medication over any other as a means to reduce atherosclerotic disease burden.

The Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial compared the effects of 2 widely used classes of oral hypoglycaemic agents on the rate of progression of coronary atherosclerosis.

Results of the prospective, randomised, multicentre, double-blind, clinical trial were presented here on March 31 at the American College of Cardiology (ACC) 57th Annual Scientific Session and were published in the March 31 issue of the Journal of the American Medical Association [299(13):1561-1573].

Sulfonylureas have been available for decades; they lower blood glucose by acting as insulin secretagogues and are one of the most commonly used classes of antidiabetic therapy. Thiazolidinediones (TZDs) are a relatively new class of antidiabetic agents that reduce glucose levels primarily by increasing insulin sensitivity in peripheral tissues.

Lead author Steven E. Nissen, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, said these 2 approaches to management of hyperglycaemia have important differences in their metabolic and physiological effects. Two TZD agents are currently on the market -- pioglitazone and rosiglitazone. Both agents reduce inflammatory biomarkers, while pioglitazone also produces elevation of high-density lipoprotein cholesterol (HDL-C) and reduction of triglyceride levels.

For their study, Dr. Nissen and colleagues used intravascular ultrasonography (IVUS) to evaluate the effect of treatment on progression of coronary atherosclerosis, said Dr. Nissen, and added that pioglitazone was selected to represent the TZD class and glimepiride chosen as a representative of the sulfonylurea class. "The goal of this study was to directly compare the effectiveness of these 2 alternative approaches, an insulin-providing versus an insulin-sensitising strategy, in reducing progression of atherosclerosis in patients with type 2 diabetes and coexisting coronary artery disease," Dr. Nissen said.

Participants aged 35 to 85 years were eligible if they had a baseline glycated haemoglobin (HbA) level of 6.0% to 9.0% if taking a glucose-lowering medication, or 6.5% to 10.0% if not currently receiving drug therapy. Patients were required to have coronary angiography performed for clinical indications that demonstrated at least 1 angiographic stenosis with at least 20% narrowing. A target vessel for IVUS examination was required to have less than 50% obstruction throughout a 40-mm or longer segment.

Patients were excluded if they had type 1 diabetes, were taking 3 or more antidiabetic medications, or if they had received any TZD within the past 12 weeks.

The study included 273 patients randomised to glimepiride treatment and 270 to pioglitazone treatment. Patients were enrolled between August 5, 2003, and March 31, 2006, at 97 centres in North and South America. Evaluable baseline and follow-up IVUS examinations were available for 360 patients (66%) -- 181 in the glimepiride group and 179 in the pioglitazone group.

Most demographic characteristics and baseline medications were similar in the 2 treatment groups. However, despite randomisation, small but statistically significant imbalances were observed for 2 characteristics, Dr. Nissen said. Patients randomised to receive glimepiride were more likely to report a history of hypertension, although baseline blood pressures were similar between treatment groups. Patients randomised to receive pioglitazone were more likely to be former smokers, whereas patients randomised to receive glimepiride were more likely to be current smokers. Characteristics were similar in the 360 patients who completed the trial and the 183 patients who did not.

The primary efficacy measure was least square mean change in percent atheroma volume. Secondary efficacy measures were change in maximum atheroma thickness and normalised total atheroma volume.

Results showed an increase from baseline in the primary efficacy measure of 0.73% in the glimepiride group (95% confidence interval [CI], 0.33%-1.12%; P < .001 from baseline). There was also a decrease of 0.16% in the pioglitazone group (95% CI, -0.57% to 0.25%; P = .44 from baseline; between-treatment groups, P = .002).

Analysis of the primary endpoint adjusting for baseline differences in smoking did not alter the results significantly.

Maximum atheroma thickness in the glimepiride group increased by 0.011 mm (95% CI, -0.0002 to 0.022 mm) and decreased in the pioglitazone group by -0.011 mm (95% CI, -0.022 to 0.0004 mm; between groups, P = .006).

Normalised total atheroma volume showed a greater reduction with pioglitazone than with glimepiride, but the difference was not significant (-5.5 vs -1.5 mm³; P = .06). However, there was a significant within-group decrease from baseline in the pioglitazone group (P < .001) and no change for the glimepiride group (P = .34).

Patients randomised to pioglitazone exhibited a lower rate of progression of coronary atherosclerosis across a wide array of prespecified and exploratory subgroups.

Dr. Nissen said the findings of the PERISCOPE study support the conclusion that treatment with pioglitazone can prevent the progression of atherosclerosis in patients with type 2 diabetes during 18 months of treatment. These findings may have important implications for defining the optimal strategy for management of patients with type 2 diabetes and coronary atherosclerosis, he added.


[Presentation title: Effect of Pioglitazone Versus Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes.]

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