Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation - PERISCOPE


The goal of this trial was to compare the effectiveness of pioglitazone with glimepiride in reducing progression of atherosclerosis in patients with type 2 diabetes and coexisting coronary artery disease (CAD).


Pioglitazone, being an insulin sensitizer, is associated with a reduction in the progression of atherosclerosis in patients with type 2 diabetes and CAD, compared with glimepiride, which is an insulin secretagogue.

Study Design

Study Design:

Patients Screened: 1,636
Patients Enrolled: 543
Mean Follow Up: 18 months
Mean Patient Age: 59.9 years
Female: 33

Patient Populations:

• Age 35-85 years
• Baseline glycohemoglobin level of 6.0-9.0%, if taking an antidiabetic medication, or 6.5-10%, if not currently receiving drug therapy
• Coronary angiography done for clinical indications that demonstrated at least one angiographic stenosis with at least 20% narrowing


• Type 1 diabetes
• Taking ≥3 antidiabetic medications
• Any thiazolidinedione within the past 3 months
• Serum creatinine >2.0 mg/dl
• Triglyceride level >500 mg/dl
• Uncontrolled hypertension (blood pressure >160/100 mm Hg despite treatment)
• Active liver disease
• Left main disease of more than 50%

Primary Endpoints:

Change in percent atheroma volume

Secondary Endpoints:

• Change in average maximum atheroma thickness
• Normalized total atheroma volume
• Change in atheroma volume in the most diseased 10 mm subsegment
• Changes in glycohemoglobin levels
• Change in insulin levels

Drug/Procedures Used:

Patients with CAD and diabetes were randomized to receive either glimepiride 1-4 mg or pioglitazone 15-45 mg and titrated to maximum dosage, if tolerated by 16 weeks. Baseline intravascular ultrasound (IVUS) was performed to determine atheroma volume. After 18 months, IVUS of the originally examined coronary artery was performed in 360 patients.

Concomitant Medications:

Aspirin (90.8%), statins (81.8%), insulin (20.6%), metformin (64.5%), angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (82.1%), and beta-blockers (76.6%)

Principal Findings:

A total of 543 patients were randomized, 270 to the pioglitazone arm, and 273 to the glimepiride arm. The baseline clinical characteristics were fairly comparable between the two arms, except hypertension and former smokers, which were more frequent in the glimepiride arm. The mean baseline glycosylated hemoglobin (HbA1C) was 7.4% in both arms. The levels of fasting blood glucose, insulin, low-density lipoprotein (LDL), triglycerides, and C-reactive protein were similar between the two arms; high-density lipoprotein (HDL) cholesterol was slightly higher in the glimepiride arm (43.4) compared with the pioglitazone arm (40.8).

The primary efficacy endpoint, least square mean change in percent atheroma volume from baseline, increased significantly in the glimepiride arm (0.73%, 95% confidence interval [CI] 0.33-1.12%, p < 0.001), whereas it decreased slightly in the pioglitazone arm (0.16%, 95% CI -0.57 to 0.25%, p = 0.44) (p = 0.002 between the two arms). Similarly, the change in maximum atheroma thickness increased by 0.011 mm (95% CI -0.0002 to 0.022 mm) in the glimeperide arm, and decreased by 0.011 mm (95% CI -0.002 to 0.0004 mm) in the pioglitazone arm (p = 0.006 between the two arms). Another secondary outcome, the change in 10 mm of the most diseased segment, showed no difference between the two groups.

There was a 0.19% greater reduction in mean HbA1c levels in the pioglitazone arm compared with glimepiride (-0.55% vs. -0.36%, p = 0.03), although this difference was not apparent until 2 years of follow-up. Compared with baseline, there was a greater reduction in fasting insulin levels (-5.0 µU/ml vs. 1.33 µU/ml, p < 0.001), a greater increase in HDL (5.7 vs. 0.9, p < 0.001), a greater reduction in triglycerides (-16.3 vs. 3.3, p < 0.001), a greater reduction in hs-CRP (-1.0 vs. -0.4, p < 0.001), a smaller increase in systolic blood pressure (0.1 vs. 2.3, p = 0.03), a greater decrease in diastolic blood pressure (-0.9 vs. 0.9, p = 0.003), but no significant increase in LDL cholesterol (2.1 vs. 1.1, p = 0.69) in the pioglitazone arm compared with the glimepiride arm, respectively.

The composite endpoint of cardiovascular death, nonfatal myocardial infarction, or stroke was similar between the glimepiride and pioglitazone arms (2.2% vs. 1.9%, respectively; p = 0.78). Similarly, the incidence of hospitalization for congestive heart failure and coronary revascularization was 1.8% and 1.5% (p = 1.0), and 11.0% and 10.7% (p = 0.93), for glimepiride and pioglitazone, respectively. The incidence of side effects between pioglitazone and glimepiride, respectively, was: hypoglycemia (15.2% vs. 37.0%, p < 0.001), bone fractures (3.0% vs. 0%, p = 0.004), peripheral edema (17.8% vs. 11.0%, p = 0.02), and angina (7.0% vs. 12.1%, p = 0.05). Serum urea nitrogen >30 mg/dl was significantly higher in the pioglitazone arm (10.7%) compared with the glimepiride arm (4.8%) (p = 0.009), although serum creatinine >2.0 mg/dl was similar between the two arms (1.1% vs. 0.7%, p = 0.12). Hemoglobin decrease >3 g/dl was also significantly higher in the pioglitazone arm (4.1%) compared with the glimepiride arm (0.7%) (p = 0.01).


The results of this surrogate endpoint study seem to indicate that pioglitazone is better than glimepiride in reducing the progression of CAD in diabetic patients, in the background of optimal medical therapy. Pioglitazone also has a favorable impact on biochemical parameters such as HDL cholesterol, triglycerides, hs-CRP, and HbA1c compared with glimepiride, although side effects such as hypoglycemia, bone fractures, angina, and peripheral edema were more common. Further studies, powered to study specific clinical differences between the two classes of drugs, are warranted.


Nissen SE, Nicholls SJ, Wolski K, et al., on behalf of the PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: The PERISCOPE randomized controlled trial. JAMA 2008;299:1561-73.

Effect of Pioglitazone Versus Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes. Presented by Dr. Steven Nissen at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Keywords: Coronary Artery Disease, Follow-Up Studies, Diabetes Mellitus, Type 2, Edema, Blood Pressure, Creatinine, Hypoglycemia, Sulfonylurea Compounds, Glycated Hemoglobin A, Biomarkers, Cholesterol, HDL, Confidence Intervals, Hypertension, Thiazolidinediones, Myocardial Infarction, Stroke, Plaque, Atherosclerotic, Atherosclerosis, Cholesterol, LDL, Nitrogen, Fractures, Bone, Constriction, Pathologic, Insulins, Least-Squares Analysis, Lipoproteins, LDL, C-Reactive Protein, Coronary Angiography, Blood Glucose, Heart Failure, Hypoglycemic Agents, Triglycerides, Lipoproteins, HDL, Fasting

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