DIABETES

Effects of 1 Year of Treatment with Pioglitazone or Rosiglitazone Added to Glimepiride on Lipoprotein (a) and Homocysteine Concentations in Patients with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Multicenter, Randomized, Double-Blind, Controlled Clinical Trial

Giuseppe Derosa, MD, PhD; Arrigo F.G. Cicero, MD; Angela D’Angelo, BD, PhD; Antonio Gaddi, MD; Leonardina Ciccarelli, MD; Mario N. Piccinni, MD; Sibilla A.T. Salvadeo, MD; Fabio Pricolo, MD; Ilaria Ferrari, MD; Alessia Gravina, MD; and Pietro D. Ragonesi, MD

Commentary by Philip D. Walson, MD
Editor-in-Chief
University of Cincinnati and Children’s Hospital Medical Center
Office of Clinical Trials

It is unfortunate that many study guidelines request washout periods because they can decrease subject enrollment as well as clinical applicability of the observations. There are also ethical concerns associated with removing effective therapy, even briefly. In addition, it is at least theoretically possible that results are altered by rebound effects or that compliance is altered by these off-treatment holiday periods.

However, a recent study of lipid-lowering drugs did not require any washout between prior and experimental treatment. In the paper "Effects of 1 Year of Treatment with Pioglitazone or Rosiglitazone Added to Glimepiride on Lipoprotein (a) and Homocysteine Concentrations in Patients with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Multicenter, Randomized, Double-Blind, Controlled, Clinical Trial" (Clin Ther. 2006;28:679–688), Derosa et al compared the effects of 1-year treatment with 2 thiazolidinediones (pioglitazone 15 mg/d or rosiglitazone 4 mg/d), each combined with an oral hypoglycemic agent (glimepiride 2 mg BID). The study population consisted of Italian patients with type 2 diabetes mellitus, the metabolic syndrome, and uncontrolled glycemia with diet and maximum tolerated doses of oral hypoglycemic agents (glycosylated hemoglobin, >7.0%). The results in this selected population over a 1-year duration imply significant differences in the effects of these 2 thiazolidinediones on the concentrations of cholesterol (TC, HDL-C, and LDL-C), triglycerides, as well as lipoprotein (a) (Lp[a]). The subjects who received pioglitazone had statistically significant improvements (decreased TC, LDL-C, and triglycerides, with increased HDL-C), whereas those who received rosiglitazone had significantly increased concentrations of TC, LDL-C, and triglycerides, as well as no decrease in Lp(a). There were similar decreases in glycosylated hemoglobin, glucose, insulin, and homocysteine levels, and both groups had similar increases in body mass index (BMI). Longer-term, larger studies are needed to determine whether and how common serious liver toxicity seen with earlier agents in this class might occur.

There are some concerns about the ability to generalize the results, however. The inclusion criteria excluded many subjects who might otherwise be candidates for similar combination therapy. In addition, the subjects had rather low BMIs (mean, 24.3–24.4 kg/m2) and body weights (mean, 67.8–68.9 kg), and therapeutic doses may be quite different in larger patients. Unfortunately, the doses used (4 and 15 mg/d) are not those maximally recommended for either drug, no ranges of weights or doses were provided, and the effects were not correlated with the doses administered. Studies with maximally tolerated amounts of both agents with analysis of the dose effect are needed to determine whether this comparison is valid.

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