Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone - CHICAGO – Presented at AHA 2006
The goal of the trial was to evaluate the effect of treatment with pioglitazone compared with glimepiride on carotid artery intima-media thickness (CIMT) among patients with type 2 diabetes.
Patients Screened: 1,346
Patients Enrolled: 462
Mean Follow Up: 18 months
Mean Patient Age: Mean age 60 years
Age 45-85 years with newly diagnosed type 2 diabetes per American Diabetes Association criteria that was diet-controlled or treated with sulfonylurea or metformin monotherapy, sulfonylurea/metformin combination therapy, or any of these plus insulin
Symptomatic coronary artery disease, cerebrovascular disease, or peripheral artery artery disease; functional New York Heart Association class III or IV heart failure; left ventricular dysfunction (ejection fraction <40%); use of diuretics or angiotensin-converting enzyme inhibitors for heart failure; significant cardiac valvular disease; use of thiazolidinedione within prior 12 weeks; intolerant or nonresponders to sulfonylurea or thiazolidinedione; required >2 oral agents for glycemic control; unexplained microscopic hematuria, triglycerides >500 mg/dl, elevated serum creatinine, decreased hemoglobin, alanine transaminase ≥2.5 times the upper limit of normal; active liver disease or jaundice; or weight >135 kg or body mass index >45
Change from baseline to final visit in mean posterior-wall CIMT in the right and left common carotid arteries
Absolute change in maximal CIMT from baseline to final visit
Patients were randomized in a double-blind manner to pioglitazone (15-45 mg/d; n = 232) or glimepiride (1-4 mg/d; n = 230). Patients were treated for 72 weeks and study drugs were titrated to maintain glycemic goals of fasting glucose ≤140 mg/dl. Patients underwent carotid artery ultrasound at baseline and 24-, 48-, and 72-week follow-up. A single reviewer blinded to treatment assignment analyzed the ultrasounds.
The study was completed in 68% of the pioglitazone group and 72% of the glimepiride group. Baseline mean HbA1c was 7.4% and fasting plasma glucose was 150 mg/dl. Average duration of diabetes was 7.7 years. Oral diabetic treatment regimen was used in 90% of patients at baseline. Baseline CIMT was 0.771 mm for pioglitazone and 0.779 mm for glimepiride.
The primary endpoint of mean change in CIMT at 72 weeks was smaller with pioglitazone compared with glimepiride (-0.001 mm vs. +0.012 mm, p = 0.02). Results were similar at 24 and 48 weeks. Maximum CIMT was also smaller with pioglitazone compared with glimepiride (0.002 mm vs. 0.026 mm, p = 0.008). Absolute difference in HbA1c levels at final visit between the pioglitazone and glimepiride groups was -0.32% (p = 0.002). For high-density lipoprotein cholesterol levels at final visit, the absolute difference was 6.4 mg/dl higher with pioglitazone (p < 0.001).
The composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization, carotid intervention, or hospitalization for unstable angina or congestive heart failure occurred in 1.7% of the pioglitazone group and 4.4% of the glimepiride group. Adverse events leading to study drug discontinuation were similar between groups (11.3% for pioglitazone vs. 8.3% for glimepiride). Weight gain was higher in the pioglitazone group (3.2 kg vs. 1.0 kg, p < 0.001). Peripheral edema was also more common with pioglitazone (13.0% vs. 7.0%).
Among patients with type 2 diabetes, treatment with pioglitazone for 18 months was associated with a reduction in CIMT progression compared with glimepiride.
Diabetics are at higher risk of development of cardiovascular disease. The effect of the slowing of CIMT progression with pioglitazone over glimepiride on clinical outcomes is not known from the present study, given the small sample size and low event rate.
A much larger trial would be necessary to evaluate the clinical efficacy of these therapies. The recent PROactive study demonstrated a reduction in death, MI, or stroke, but no significant difference in the primary endpoint with pioglitazone over placebo plus usual care, but large clinical studies of two active therapies are not yet available. Results of the present study are similar to those by Langenfeld et al., who also showed pioglitazone was associated with a greater reduction in carotid IMT at 24 weeks compared with glimepiride in diabetic patients.
Mazzone T, Meyer PM, Feinstein SB. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296:2572-81.
Presented by Dr. Theodore Mazzone at the American Heart Association Annual Scientific Sessions, Chicago, IL, November 2006.
Keywords: Myocardial Infarction, Stroke, Insulin, Carotid Intima-Media Thickness, Diabetes Mellitus, Type 2, Edema, Carotid Arteries, Weight Gain, Sulfonylurea Compounds, Cholesterol, Metformin, Blood Glucose, Heart Failure, Hypoglycemic Agents, Hospitalization, Thiazolidinediones, Fasting
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