Research Design and Methods
Subjects eligible for participation in this clinical trial were men or women ≥35 years of age with a diagnosis of type 2 diabetes (based on World Health Organization criteria) with fasting triglyceride levels ≥150 mg/dl and <600 mg/dl and fasting LDL cholesterol levels <130 mg/dl. Other inclusion criteria included fasting serum C-peptide levels ≥1 ng/ml and HbA1c (A1C) values ≥7 and ≤11% if nave to previous oral antihyperglycemic therapy or A1C values ≥7 and ≤9.5% if previously treated with oral antihyperglycemic monotherapy.
Subjects were excluded from participation in this study for any of the following: treatment within 60 days of screening with insulin, systemic glucocorticoid therapy, combination oral antihyperglycemic therapy, any lipid-lowering agent, or any weight loss agent; known allergy to any thiazolidinedione; serum creatinine ≥176.8 µmol/dl (≥2.0 mg/dl) or 2+ dipstick proteinuria at screening; alanine aminotransferase or aspartate aminotransferase ≥1.5 times the upper limit of normal or significant clinical liver disease; hemoglobin <10.5 g/dl (females) or <11.5 g/dl (males) at screening; abnormal thyrotropin; functional New York Heart Association Cardiac Disease Class III or IV, history of CVD, or heart surgery within 6 months of screening; receiving renal dialysis or having renal transplant; current therapy for malignancy other than basal cell or squamous cell skin cancer; known history of HIV infection; signs or symptoms of drug or alcohol abuse; and any condition or situation precluding adherence to and completion of the protocol. For female subjects, appropriate birth control was required, and pregnancy, breast-feeding, or the intent to become pregnant during the study period prohibited participation.
Subjects were enrolled from the U.S. (78 sites), Puerto Rico (11 sites), Mexico (4 sites), and Colombia (7 sites). Conducted in accordance with the Declaration of Helsinki guidelines on good clinical practice, this study was approved by each investigator's institutional ethical review board.
Screening for eligibility occurred at visit 1 after written informed consent was obtained. At visit 2, subjects were randomly assigned to one of the two treatment groups, although active study drug administration was not initiated until 4 weeks later (visit 3). Randomization occurred in a stratified fashion with four strata corresponding to previous oral antihyperglycemic treatment (previously treated or nave) and sex (male or female). Subjects discontinued any current oral antihyperglycemic therapy and received oral placebo therapy throughout the 4-week, single-blind, lead-in period. At visit 3, subjects received either 30 mg pioglitazone once daily or 4 mg rosiglitazone once daily for 12 weeks according to the randomization assigned at visit 2. Qualified personnel provided dietary counseling on the American Heart Association weight-maintaining Step I diet, and all subjects were instructed to follow this diet throughout the entire study. Clinic visits occurred every 4 weeks following visit 3 through visit 6. At visit 6 and for the final 12 weeks, the doses of pioglitazone and rosiglitazone were increased to the maximally effective doses (for monotherapy) of 45 mg once daily or 4 mg twice daily, respectively. Clinic visits occurred every 6 weeks (visits 7 and 8) for the remainder of the 24-week total study.
The following analyses were performed by Covance Central Laboratory Services (Indianapolis, IN): triglycerides, total cholesterol, and plasma glucose in blood samples (following at least 10 h of fasting) using standard enzymatic methods; HDL and LDL cholesterol (Roche Diagnostics, Indianapolis, IN) by direct methods; free fatty acid by the Wako enzymatic method (Wako Chemicals, Richmond, VA); apolipoprotein B by immunoassay (Beckman IMMAGE Immunochemistry System, Beckman Instruments, Brea, CA); A1C by chromatography (Bio-Rad, Hercules, CA); total insulin by immunoassay (Abbott IMX Microparticle EIA, Abbott Laboratories, Abbott Park, IL); C-peptide by radioimmunoassay (Adaltis Italia, Rome, Italy); highly sensitive C-reactive protein by immunonephelometry (Dade Behring, Newark, DE); and plasminogen activator inhibitor-1 (PAI-1) by immunoassay (Asserachrom PAI-1 Antigen EIA, Diagnostica Stago, France). LDL particle size and concentration were measured using proton nuclear magnetic resonance spectroscopy at LipoScience (Raleigh, NC). Surrogates of insulin resistance and β-cell function were estimated by homeostasis model assessments. Safety assessments included adverse events, blood pressure and heart rate, hemoglobin and hematocrit, liver function, pedal edema, body weight, and hypoglycemic episodes.
Data are presented as means ± SE (or SD where indicated). Differences between treatments in demographics and baseline levels (visit 3) for patients entering active drug therapy were evaluated using a χ2 test for categorical variables or an independent-groups t test for continuous variables. Efficacy analyses were conducted on subjects providing a baseline measurement and at least one postbaseline measurement. The last-observation-carried- forward (LOCF) change from baseline level and LOCF actual value were analyzed using a fixed-effects ANCOVA. The ANCOVA model was composed of terms for strata, geographic region in which the investigative site was located (five regions: Mexico/Puerto-Rico/Colombia, Mid-Atlantic/Eastern, West/Midwest/Texas, South/Southeast, and West Coast/Hawaii), treatment, and baseline value. The change from baseline to the last observed value was of primary interest, and the triglycerides change was the primary efficacy variable. The visit-wise changes from baseline were also analyzed using LOCF. LOCF percent change from baseline was also analyzed for the lipid variables. Treatments were compared using least-square means.[26,27]
A mixed-model repeated-measures analysis was used to confirm the LOCF triglyceride results. The model used was comprised of terms for strata, geographic region, treatment, visit, treatment × visit interaction, baseline value, and visit × baseline level interaction. The covariance structure was modeled using an unstructured covariance matrix within each treatment. The Kenward-Roger degrees of freedom were used for the tests. Additionally, the change from baseline triglycerides was analyzed for the subset of patients who completed the study. SAS version 8.2 (SAS Institute, Cary, NC) was used for all analyses. All tests were two sided, and results were considered statistically significant at P ≤ 0.05.
Diabetes Care. 2005;28(7):1547-1554. © 2005 American Diabetes Association, Inc.
Cite this: A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia - Medscape - Jul 01, 2005.