Pioglitazone Slows CAD Progression by Improving HDL, Triglycerides in Analysis

January 10, 2011

January 7, 2011 (Washington, DC)— The insulin sensitizer pioglitazone(Actos, Takeda Pharmaceuticals) may not be "the next" statin, but--based on a post hoc analysis [1] of the small 2008 trial PERISCOPE--it could also be viewed as a lipid-lowering agent with broad-based metabolic benefits, at least in patients with diabetes.

In that randomized comparison of the thiazolidinedione (TZD) vs glimepiride(Amaryl, Sanofi-Aventis) in patients with diabetes [2], those taking the TZD saw significantly less coronary disease progression as assessed with intravascular ultrasound (IVUS) over 18 months compared with those taking the other drug, a sulfonylurea. They also benefited with steeper declines in fasting insulin and blood glucose levels, glycated hemoglobin (HbA1C), C-reactive protein (CRP), and triglycerides as well as improved HDL-cholesterol levels. A total of 543 patients had been randomized, but follow-up IVUS was available in only 360; they averaged 60 years in age and were predominantly male.

In the post hoc analysis, which was published online January 3, 2011 in the Journal of the American College of Cardiology, the reduced progression of coronary disease among pioglitazone recipients was independently associated with improvements in the ratio of triglycerides to HDL, but not other risk markers, including those related to glucose. No such associations were observed in the glimepiride group.

The observations, according the authors, led by Dr Stephen J Nicholls (Cleveland Clinic, OH), "support the hypothesis that pioglitazone halted disease progression predominantly because of its properties beyond glycemic control. These findings are also consistent with clinical-outcome data indicating the importance of atherogenic dyslipidemia as a target for therapeutic manipulation in patients with diabetes mellitus to achieve more effective prevention of cardiovascular disease."

According to Nicholls, "We've really yet to see any real robust evidence in a big trial that a therapy that lowers glucose has a [cardiovascular] benefit. What we see here is that an antidiabetic therapy does have a cardiovascular benefit [in terms of slowed IVUS progression], but interestingly, it wasn't a therapy that just lowers glucose."

Pioglitazone, he observed for heartwire , has numerous effects that are likely beneficial for reducing cardiovascular risk, such as improvement of lipids, blood pressure, and inflammatory markers. "So it was interesting to see what appeared to be predictors of benefit. It had nothing to do with lowering glucose. It was all about the effects on lipids."

In the current analysis, changes in percent atheroma volume by IVUS in the pioglitazone group were correlated with triglycerides (p=0.04), triglyceride/HDL ratio (p=0.02), and HbA1C (p=0.03). Among those taking glimepiride, changes in percent atheroma volume correlated with LDL-cholesterol (p=0.04), apolipoprotein B (p=0.04), and apolipoprotein A-1 (apoA-1) (p=0.01).

But in multivariate analysis (with adjustment for sex, history of hypertension, history of PCI, hypercholesterolemia, metformin use, baseline HbA1C, and baseline apoA-1), the baseline atheroma burden by IVUS and change in the triglyceride/HDL ratio were the only significant predictors (p<0.001 and p=0.02, respectively) of total atheroma volume in the pioglitazone group. The triglyceride/HDL ratio also predicted percent atheroma volume. No predictors of IVUS-based progression emerged as independent in the glimepiride group.

Nicholls pointed out that the post hoc analysis "ties nicely" with the 2006 CHICAGOstudy, in which elevations in HDL were the most important predictor of reduced progression of carotid intima-media thickness. That trial had randomized 462 diabetic patients to receive either pioglitazone or glimepiride and had followed them for 72 weeks.

The studies, according to Nicholls, "suggest to us that, while lowering LDL is important in diabetes, and for most patients that means statins, it's likely that they'll need something else above and beyond that if we want to truly arrest the growth of plaque in the vessel wall."

Although he cautions that pioglitazone also "comes with challenges," such as a risk of bone fracture and fluid retention, the current analysis suggests that the drug's beneficial effects on markers of atherogenic dyslipidemia are behind its benefits in coronary disease. "So we think those features provide additional targets for modification above and beyond the use of statins and LDL lowering."

Both the PERISCOPE study and the CHICAGO study were sponsored by Takeda Pharmaceuticals. Nicholls reports receiving honoraria and consulting fees from AstraZeneca, Takeda, Pfizer, Merck Schering-Plough, and Roche and research support from Novartis, AstraZeneca, Eli Lilly, and Resverlogix. Disclosures for the PERISCOPE coauthors are listed in the paper.