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

Disclosures

Diabetes Care. 2005;28(7):1547-1554. 

In This Article

Conclusions

This prospective, randomized, multicenter, double-blind clinical trial demonstrates that pioglitazone and rosiglitazone exert different effects on plasma lipids. Pioglitazone is associated with significant improvements versus rosiglitazone in triglyceride, HDL cholesterol, non-HDL cholesterol, and LDL particle concentrations and LDL particle size, despite similar effects on glycemic control and surrogate measures of insulin resistance.

The different lipid responses to maximal monotherapy doses of pioglitazone and rosiglitazone observed in this study are consistent with results from prior, less well-controlled comparison studies and the large, randomized, multicenter placebo-controlled trials for pioglitazone.[23,28,29] Additionally, a meta-analysis of these studies[18] demonstrates results very similar to those of our study. The mechanism(s) by which these agents exert differential effects on the lipid profile are not clearly understood, and studies are underway to elucidate these mechanisms.

The effects of lipids on cardiovascular disease are well known. At increased concentrations, LDL cholesterol, total cholesterol, and triglycerides, and HDL cholesterol at decreased concentrations, are known to be risk factors for CVD in the general population[8,9,10,11] and in subjects with type 2 diabetes.[34] Although lowering LDL cholesterol is the primary target according to both the National Cholesterol Education Program Adult Treatment Panel III[35,36] and American Diabetes Association guidelines,[12] raising HDL cholesterol is a secondary target, the benefit of which was demonstrated by the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) study,[37] in which increasing HDL cholesterol and lowering triglycerides with the fibrate gemfibrozil decreased cardiovascular events by 24%. In subjects with hypertriglyceridemia (>200 mg/dl), lowering non-HDL cholesterol to levels <130 mg/dl is recommended for high-risk subjects by the National Cholesterol Education Program Adult Treatment Panel III.[36] In our study, rosiglitazone raised non-HDL cholesterol levels and pioglitazone did not.

The dyslipidemia of diabetes is usually characterized by a combination of increased triglyceride and decreased HDL cholesterol levels and, most often, near-normal LDL cholesterol concentrations.[38] However, insulin resistance with or without hyperglycemia is associated with qualitative changes in the composition of LDL particles shown to be associated with greater risk for atherosclerosis and cardiovascular disease.[39] These changes in the LDL particles include a decrease in particle size and a greater density of each particle concomitant with a relative decrease in the cholesterol content of each particle.[40] It is generally accepted that the increase in triglyceride levels in type 2 diabetes is in part responsible for these atherogenic changes in the LDL profile.[5,7,11,41,42]

In the current study, pioglitazone and rosiglitazone differed significantly with opposing effects on triglycerides. Although both agents increased HDL cholesterol, pioglitazone increased HDL cholesterol more. Furthermore, pioglitazone caused a shift from small, dense LDL particles to larger, more buoyant LDL particles. This change in the size of the particles was accompanied by a decrease in particle concentration (particle number), an effect not observed with rosiglitazone. Rosiglitazone was associated with an increase in LDL particle size as well as an increase in triglyceride levels and LDL particle numbers. These observed differences in the lipid effects between pioglitazone and rosiglitazone raise several mechanistic questions. First, the shift toward larger LDL particles observed with rosiglitazone therapy cannot be due to effects on triglyceride levels. Secondly, the increase in LDL by pioglitazone can only be explained by increases in particle size, as the measured number of LDL particles was slightly reduced. The greater increase in LDL observed with rosiglitazone is the result of both increases in particle size and particle number. These observations suggest that previous speculation[43,44] that differences in lipid effects between pioglitazone and rosiglitazone might be due to differential effects on particle size are no longer tenable.

Finally, in light of the recent guidelines, subjects with diabetes often are prescribed lipid-lowering medication, most frequently a statin. However, subjects in this study were not treated with such therapy. This study was purposely designed to eliminate the confounding influence of concomitant glucose-lowering and lipid-lowering medications to allow for a clear assessment of the glycemic and lipid effects of the two thiazolidinediones. Simvastatin, when added to either pioglitazone or rosiglitazone, produced similar mean lipid changes from baseline with both these thiazolidinediones, suggesting that differences between these agents would be preserved with concomitant statin therapy.[45] A current, ongoing study named COMPLEMENT has been designed to assess these parameters in subjects with diabetes who are simultaneously taking a statin.[46]

In summary, the current study demonstrates that pioglitazone and rosiglitazone differ in their effects on triglyceride, HDL cholesterol, non-HDL cholesterol, and LDL cholesterol particle concentrations and particle size. These differences were observed despite the finding that these agents produced similar improvements in many of the nonlipid CHD/CVD risk factors associated with insulin resistance and type 2 diabetes (A1C, fasting plasma glucose, fasting insulin levels, homeostasis model assessment of insulin resistance, PAI-1, and C-reactive protein). Whether these differences in lipid effects translate into differences for the risk of CVD is not clear. Although no trials directly comparing the effects of pioglitazone and rosiglitazone on CVD outcomes are underway, multiple ongoing trials are evaluating CVD event reduction with either pioglitazone or rosiglitazone (Prospective Pioglitazone Clinical Trial in Macrovascular Events [PROactive],[47] Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes [RECORD],[48] and the Rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D] trial[49]). These studies should provide insight into the cardiovascular benefits of the two drugs.

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