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The PERISCOPE Randomized Controlled Trial

Steven E. Nissen, MD; Stephen J. Nicholls, MBBS, PhD; Kathy Wolski, MPH; Richard Nesto, MD; Stuart Kupfer, MD; Alfonso Perez, MD; Horacio Jure, MD; Robert De Larochellière, MD; Cezar S. Staniloae, MD; Kreton Mavromatis, MD; Jacqueline Saw, MD; Bo Hu, PhD; A. Michael Lincoff, MD; E. Murat Tuzcu, MD; for the PERISCOPE Investigators

JAMA. 2008;299(13):1561-1573. Published online March 31, 2008 (doi:10.1001/jama.299.13.1561).

Context  No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers.

Objective  To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes.

Design, Setting, and Participants  Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes.

Interventions  A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion.

Main Outcome Measure  Change in percent atheroma volume (PAV) from baseline to study completion.

Results  Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, –0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (–0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA_1c levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, –0.68% to –0.42%) with pioglitazone and 0.36% (95% CI, –0.48% to –0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, –0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, –27.7 to –11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, –10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group.

Conclusion  In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride.

Trial Registration  clinicaltrials.gov Identifier: NCT00225277

Author Affiliations: Department of Cardiovascular Medicine (Drs Nissen, Nicholls, Lincoff, and Tuzcu and Ms Wolski) and Department of Quantitative Health Sciences (Dr Hu), Cleveland Clinic, Cleveland, Ohio; Department of Cardiovascular Medicine, Lahey Clinic, Burlington, Massachusetts (Dr Nesto); Department of Clinical Science, Takeda Global Research and Development, Deerfield, Illinois (Drs Kupfer and Perez); Department of Cardiology, Clinica Chutro, Colon, Argentina (Dr Jure); Department of Cardiology, Quebec Heart Institute, Hôpital Laval, Quebec City, Quebec (Dr De Larochellière); Cardiovascular Division, St Vincent's Hospital Manhattan, New York, New York (Dr Staniloae); Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, Atlanta, Georgia (Dr Mavromatis), and Division of Cardiology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Saw).

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