AHA: Factors Found to Explain Atherosclerosis Benefit with Pioglitazone (Actos)

ORLANDO, Nov. 11 -- Peering into the innards of a study that found pioglitazone (Actos) slowed progression of atherosclerosis compared with glimepiride (Amaryl), researchers think they have figured out the dynamics of why.
Compared with all other potential predictors of carotid intima-media thickness change, only HDL and insulin parameters significantly changed to account for the treatment effect seen with pioglitazone, said Michael H. Davidson, M.D., of Rush Presbyterian-St. Lukes Medical Center in Chicago, in an oral presentation at the American Heart Association meeting here.
That observation emerged from a post hoc analysis of data from the CHICAGO trial, which found that pioglitazone treatment was associated with a significant slowing of progression of plaque, as measured by carotid intima-media thickness compared with glimepiride treatment.
The CHICAGO findings, which were reported at the 2006 AHA meeting, were published in the Journal of the American Medical Association. (See: AHA: Actos (pioglitazone) May Slow Progression of Atherosclerosis)
The CHICAGO trial enrolled 462 men and women ages 45 to 85 with type 2 diabetes. They were randomized to pioglitazone 15 to 45 mg daily or glimepiride at 1 to 4 mg.
After 72 weeks of treatment, carotid intima-media thickness -- a marker of atherosclerosis -- was narrowed by 0.001 mm in the pioglitazone arm versus an increase of 0.012 mm in the control arm. This was an absolute difference of 0.013 mm, which was significant (P=0.02).
Dr. Davidson and colleagues adjusted for a variety of predictors of change in carotid intima-media thickness by adding them one at a time to the initial model to determine if any one of those predictions could undermine the observed significant treatment effect.
They considered baseline and six-month changes in blood pressure, standard lipids, free-fatty acids, ApoB, ApoA1, A1c, fasting plasma glucose, insulin, pro-insulin, weight, BMI, waist/hip ratio, C-reactive protein, duration of diabetes, number of metabolic syndrome components, statin use, baseline age, and smoking status.
The inclusion of baseline values did not affect the significance of pioglitazone treatment.
By six months, pioglitazone treatment was associated with significant increase in HDL (6.3 mg/dL) and significant decreases in triglycerides (-22.6 mg/dL), hemoglobin A1c (0.3%), fasting glucose (15 mg/dL), insulin (48.3 pmol/L) pro-insulin (23.3 pmol/L), and CRP (0.6 mg/L) compared with baseline (P0.01 for all).
But when Dr. Davidson and colleagues tested each of these parameters in their model, only changes in HDL and insulin resulted in a loss of significant treatment effect.
"Adjustment for the change in HDL resulted in a 30% decrease in the regression coefficient and changed the P-value from 0.02 to 0.12 for the effect of pioglitazone on carotid intima-media thickness. The adjustment for the insulin levels decreased the regression coefficient by 19.8% and changed the P-value to 0.08," he said.
The CHICAGO study was funded by Takeda Pharmaceuticals, which markets pioglitazone. Dr. Davidson disclosed grant, research, and honoraria from Abbott Laboratories, AstraZeneca Pharmaceuticals, Kos Pharmaceuticals, Merck, Merck/Schering-Plough, Pfizer Inc., Reliant Pharmaceuticals, Inc., Sankyo Pharma, Sumitomo Pharmaceuticals, and Takeda Pharmaceuticals.Primary source: American Heart AssociationSource reference: Davidson MH, et al "Increases in HDL-C in the CHICAGO Study Explain the Benefits of Pioglitazone in Reducing CIMT Progression in Patients With Type 2 Diabetes" AHA Meeting 2007; Abstract 3632