A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia

Ronald B. Goldberg, MD; David M. Kendall, MD; Mark A. Deeg, MD, PHD; John B. Buse, MD, PHD; Anthony J. Zagar, MS; Jane A. Pinaire, PHD; Meng H. Tan, MD; Mehmood A. Khan, MD; Alfonso T. Perez, MD; Scott J. Jacober, DO


Diabetes Care. 2005;28(7):1547-1554. 

In This Article

Abstract and Introduction

Objective: Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone.
Research Design and Methods: We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals.
Results: Triglyceride levels were reduced by 51.9 ± 7.8 mg/dl with pioglitazone, but were increased by 13.1 ± 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 ± 0.5 vs. 2.4 ± 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 ± 1.6 vs. 21.3 ± 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005).
Conclusions: Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.

Two core metabolic defects contribute to the development of type 2 diabetes: relative insulin insufficiency and insulin resistance. Approximately 92% of patients with type 2 diabetes demonstrate insulin resistance.[1] Even in the absence of overt hyperglycemia, insulin resistance is associated with a cluster of abnormalities that increase the risk for cardiovascular disease (CVD), including dyslipidemia, increased expression of inflammatory markers, activation of procoagulants, hemodynamic changes, and endothelial dysfunction.[2,3]

The dyslipidemia associated with insulin resistance and type 2 diabetes is characterized by elevated triglycerides and decreased HDL cholesterol.[4,5,6] Although LDL cholesterol may not be elevated in type 2 diabetes, an increase in the proportion of small, dense, and potentially more atherogenic LDL cholesterol particles is observed.[7] In addition to LDL cholesterol, elevated triglyceride levels and reduced HDL cholesterol levels are both risk factors for coronary heart disease (CHD).[8,9,10,11] Compared with nondiabetic individuals, patients with type 2 diabetes have a two- to fourfold higher risk of CVD, and dyslipidemia is an important contributor to the increased risk in this population.[12]

By targeting insulin resistance, the members of the thiazolidinedione class of oral antihyperglycemic medications possess both a glucose-lowering effect and the potential to alter lipid/lipoprotein metabolism. Two members of the thiazolidinedione class are currently available for the treatment of type 2 diabetes: pioglitazone hydrochloride (Actos; Takeda Pharmaceuticals North America, Lincolnshire, IL) and rosiglitazone maleate (Avandia; GlaxoSmithKline, Research Triangle Park, NC).

This study was conceived following the report of a nonrandomized clinical comparison of potential differences in lipid effects among thiazolidinediones.[13] Since that time, multiple reports[14,15,16,17,18,19,20,21,22] have been published suggesting that pioglitazone has differential effects on lipid parameters in patients with type 2 diabetes when compared with rosiglitazone. However, these previous studies were either retrospective chart review studies, clinical trials not rigorously controlled for concomitant glucose-lowering and lipid-lowering therapies, or systematic reviews. With the primary objective to test the hypothesis that pioglitazone has greater triglyceride-lowering effects than rosiglitazone, this study reports results from the first multicenter, prospective, randomized, double-blind, parallel- group comparison of maximally effective monotherapy doses of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia receiving no concomitant glucose-lowering or lipid-lowering therapies.