New Orleans, LA - Results of a head-to-head comparison of two insulin-sensitizing agents, pioglitazone (Actos^®, Takeda/Lilly) and rosiglitazone (Avandia^®, GlaxoSmithKline), show that although both are equally effective in achieving glycemic control in patients with type 2 diabetes mellitus and dyslipidemia, they appear to have differential effects on lipids. Relative to rosiglitazone, pioglitazone improved triglycerides, HDL-C, non-HDL-C, and LDL particle concentration and size, although both agents increased LDL levels.

Dr Ronald B Goldberg

"Whether these differences in lipid effects translate into differences in the risk of cardiovascular disease has yet to be determined," lead author Dr Ronald B Goldberg (University of Miami School of Medicine, FL) concluded.

The results were presented here at the American Heart Association's Scientific Sessions 2004.

Diabetic dyslipidemia, characterized by low HDL-C, high triglycerides, and a predominance of small, dense LDL, is a common cardiovascular risk factor in patients with type 2 diabetes, Goldberg said. The insulin-sensitizing drugs rosiglitazone and pioglitazone affect lipid metabolism in addition to their effects on glycemia in type 2 diabetes, which has raised interest in their effects on plasma lipids and lipoproteins, he said. Previous published reports have suggested these drugs have different effects on lipid parameters but were based on retrospective chart reviews or clinical trials that didn't control for concomitant glucose and lipid-lowering therapies.

In this randomized, prospective, multicenter, double-blind study, the effects of pioglitazone and rosiglitazone were compared in patients with type 2 diabetes and dyslipidemia, defined as fasting triglyceride (TG) levels >150 and <600 mg/dL and fasting LDL levels <130 mg/dL. Patients discontinued any prior monotherapy, followed by four weeks of placebo, and then were randomized to 24 weeks of treatment with either pioglitazone or rosiglitazone monotherapy. Treatment was begun with 30 mg daily pioglitazone or 4 mg daily rosiglitazone. At 12 weeks, they were uptitrated to 45 mg in the morning and placebo in the evening of pioglitazone and 4 mg bid of rosiglitazone. No other glucose or lipid-lowering therapies were allowed.

Of 4410 subjects screened, 802 were eventually randomized, 369 in the pioglitazone group and 366 in the rosiglitazone group. About 80% of patients in each group completed 24 weeks of therapy.

The effect on hemoglobin A1c (HbA1c) was similar at 24 weeks in both groups, with a reduction of 0.7% seen with pioglitazone and a rise of 0.6% with rosiglitazone. The primary end point was the effect on fasting triglyceride values. By week four there was a significant reduction in TG values in the pioglitazone group, but a significant increase in TG in the rosiglitazone group. The values gradually decreased over the remainder of the study but remained significantly lower with pioglitazone at each visit, Goldberg said.

HDL cholesterol tended to increase in both groups, but pioglitazone values were significantly higher than those seen with rosiglitazone. Non-HDL cholesterol was stable with pioglitazone but increased with rosiglitazone. LDL cholesterol increased gradually with both treatments over 24 weeks, but starting at week 8, pioglitazone group values were significantly less than those with rosiglitazone. LDL particle size increased in both groups, considered a lower risk feature than smaller particles, but particle size was increased significantly more with pioglitazone. LDL particle concentration was reduced by pioglitazone but increased with rosiglitazone. There was no significant change in apolipoprotein B with pioglitazone, but a significant increase with rosiglitazone.

There was no significant difference between agents in the change from baseline to end point in measures of free fatty acids, fasting insulin, PAI-1, and hs-CRP values, he added, although the values decreased significantly from baseline in each group. ApoC-3 levels increased with rosiglitazone and decreased with pioglitazone, a highly significant difference, he added.

What the effect of concomitant statin therapy would be in concert with these insulin-sensitizing drugs is not clear at this point, Goldberg noted, and clinical outcomes trials are now under way. "These two are going to be used together, clearly, and the anticipation is that their effects will be additive," he told heartwire. "Certainly, one could see how the two complement each other, statins focused mostly on LDL, and the [peroxisome proliferator-activated receptor] PPAR agonists focused more on the dyslipidemia side of the story."

One such outcomes trial, called COMPLEMENT, is comparing the two drugs with statins as background therapy, and results are expected to be reported "in the near future," said Dr Mehmood Kahn (Takeda Pharmaceuticals, Lincolnshire, IL). Together there are three such trials under way and they are "quite far along," he said.

Discussant for the trial was Dr Robert M Califf (Duke University Medical Center, Durham, NC). Califf said that it was a "significant step forward" that this study was done, calling it "extremely well conducted" and well presented, with appropriate caveats.

He expressed some concern about the number of patients who were not available for analysis in the trial and the lack of participation of African Americans, what he called a common feature of drug-company-sponsored trials. He suggested it was also somewhat "puristic," enrolling patients ideal for looking at biochemical parameters rather than those that might be seen by clinicians in practice.

"Nevertheless, what we see from this study is a clear indication of a difference in the biochemical profiles that emerges when the two drugs are compared, at doses that are standardly given, and that is an important thing for us to know."

He took the opportunity, however, to discuss some general issues that arise with head-to-head drug comparisons, particularly those that are industry sponsored. First, he said, it is "remarkable" that these drugs are used so commonly in patients with cardiovascular disease yet are so little studied with regard to outcomes.

"While this is a valuable study, I would put forward to you the possibility that the companies who make these drugs might have invested more money sooner in getting the answer as to which was better in the things that patients care about, such as how long they live or whether they're likely to have a heart attack or a stroke, which may be affected by the factors studied in this trial but may not be," Califf said. "They have said, I know, that outcome trials are under way, but I would also point out that at least one outcome trial that I know of with this class of drugs has been completed for a year and still not been published."

Although there have been some notable exceptions recently in cardiology, he noted, a system in which head-to-head comparisons are funded by one or the other of the competing companies introduces the question of whether the experiment was fair, since generally the sponsoring company comes out ahead.

However, the current study does provide valuable insight into possible differential effects with these drugs. "Indeed, if these kinds of changes really do have an impact on clinical outcomes to the same degree as we see differing between these two drugs in terms of their biochemical profile, the investigators would have done us a real service by doing this study, but even a better service by forcing the issue of a true outcome-based head-to-head trial in people who have cardiovascular disease, where there's so much at stake," Califf concluded.