Comparison of Pioglitazone vs Glimepiride on
Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes

Background: Patients with diabetes experience a high number of cardiovascular events, with the majority due to coronary obstructive disease. Although no antidiabetic regimen has been found to reduce the progression of coronary atherosclerosis, several clinical trials have shown some evidence of pioglitazone reducing the rate of artery thickening, a key indicator in cardiovascular health.

Objective: The objective of this study was to compare the effects of an insulin-sensitizing regimen (pioglitazone) with an insulin providing regimen (glimepiride) on the progression of coronary atherosclerosis in patients with type 2 diabetes and coronary artery disease.

Methods: This study was a prospective, randomized, double-blind clinical trial. To be included in the study, patients were required to be between the ages of 35 and 85 years and present with a baseline HbA1c of 6-9% while on glucose-lowering medication or 6.5-10% if unmedicated. Patients were included in the trial if a coronary angiography demonstrated at least 1 angiographic stenosis with 20% or greater narrowing. Patients were excluded from the trial if there was a presence of type 1 diabetes, more than 2 antidiabetic medications, or drug therapy with pioglitazone or rosiglitazone within 12 weeks. A total of 543 patients were randomized to one of two groups: 273 patients received glimepiride 1 mg or 2 mg and 270 patients received pioglitazone 15 mg or 30 mg for a period of 18 months.

Results: The primary efficacy measure, least square mean change in percent atheroma volume, increased 0.73% (95% CI, 0.33 to 1.12%) in the glimepiride group (P<0.001) and decreased 0.16% (95% CI, -0.57 to 0.25%) in the pioglitazone group (P=0.44; P=0.002 between treatment groups). The change in maximum atheroma thickness (secondary efficacy measure) increased in the glimepiride group 0.011 mm (95% CI, -0.0002 to 0.022 mm) and decreased in the pioglitazone group -0.011 mm (95% CI, -0.022 to 0.0004 mm; P=0.006 between groups). Normalized total atheroma volume (secondary efficacy measure) showed a greater reduction for pioglitazone compared with glimepiride: -5.5 mm3 (95% CI, -8.67 to -2.34 mm3) vs -1.5 mm3 (95% CI, -4.50 to 1.54 mm3) that did not reach statistical significance (P=0.06); however, the pioglitazone treatment group reduction was statistically significant (P<0.001). Changes in volume in 10 mm of the most diseased segment showed no difference groups. The authors concluded that pioglitazone, as compared with glimepiride, can prevent the progression of atherosclerosis in patients with type 2 diabetes.

Strengths: The use of a prospective, randomized, double-blind design conducted over a period of 18 months, using multi-center testing sites were strengths of this study. Hiring independent investigators to analyze sonographic imaging and data decreased both bias and variability. Additionally, the use of an active control likely to be used in the patient population studied was appropriate. A power of 90% for the primary outcome measure allowed for statistical significance.

Weaknesses: No power was reported for the secondary outcome measures. A high withdrawal rate (35%) and only measuring change in percent atheroma volume limit the clinical application of the study. Multiple, varying other medication regimens (antihypertensive, lipid-lowering agents) were not accounted for in patients that might affect the outcomes. Also, patients previously treated with glimepiride were not excluded from the trial and neither diet nor exercise were monitored or controlled.

Conclusion: The high withdrawal rate and a lack of standardization throughout the study limit clinical applicability at this time. However, the results of the study encourage further research into pioglitazone’s effects on morbidity, mortality, and cardiovascular events.

Nissen SE, Nichols SJ, Wolski K, et al. Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes. JAMA. 2008;299(13):1561-1573.

Kate Priddy, Pharm.D. Candidate

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