ACC: Pioglitazone (ACTOS) Slows Atherosclerosis Progression

The diabetes drug pioglitazone (Actos) led to a significant slowing of atherosclerosis, albeit small, as measured by intravascular ultrasound (IVUS), compared with glimepiride, according to the results of a new study. Mean percent atheroma volume increased to 0.73% (95% CI 0.33% to 1.12%) with glimepiride versus a 0.16% decrease with pioglitazone (95% CI -0.57% to 0.25%) (P=0.002), reported Steven E. Nissen, M.D., of the Cleveland Clinic, at a late-breaking trials session at the American College of Cardiology meeting.

Dr. Nissen said,  "This marks the first time that a non-statin drug has demonstrated the ability to slow the progression of atherosclerosis,"  and that reducing cardiovascular risks in diabetics is not just a matter of "how much you can lower glucose, but how you lower it."

PERISCOPE, a double-blind trial conducted at 97 centers in North and South America, randomized 543 patients with coronary artery disease and type 2 diabetes to glimepiride at 1 to 4 mg or pioglitazone at 15 to 45 mg for 18 months.
Patients were titrated to the maximum tolerated dose. All patients had IVUS before randomization and 360 patients had a repeat IVUS at 18 months.  The mean HbA1c was 7.4% in both groups and declined by an average of 0.55% in the pioglitazone group versus 0.36% in the glimepiride group (P=0.03).

Dr. Nissen said there were three possible explanations for the findings: glimepiride could have a proatherogenic effect, pioglitazone could have an antiatherosclerotic effect, or both.

His inclination was toward an antiatherosclerotic effect for pioglitazone, and, although the exact mechanism remains unknown, he said it was likely that the drug’s "potent effects on metabolism, a 16% increase in HDL, 15% reduction in triglycerides, and 45% reduction in C-reactive protein levels, are the key."

In the pioglitazone arm, HDL increased by an average of 5.7 mg/dL versus 0.9 mg/dL in glimepiride patients and triglycerides decreased by 16.3 mg/dL versus an increase of 3.3 mg/dL in the glimepiride group (P0.001 for both).
Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P0.001).

Dr. Nissen cautioned against interpreting the finding as a class effect. The other drug in the class, rosiglitazone (Avandia), has been linked to an increased risk of acute cardiovascular events in a number of studies.

On the basis of this study, Dr. Nissen said it was time to do "comparative studies of all diabetes drugs."

Asked whether so small a difference in a surrogate measure — less than 1% change — could translate into a clinical benefit, Dr. Nissen said that based on his previous IVUS studies he was confident it would.

In an editorial that accompanied the JAMA publication Philippe Gabriel Steg, M.D., of Centre Hospitalier Bihat-Claude Bernard in Paris, and Michel Marre, M.D., of the University of Paris, urged caution in interpreting the findings, noting that more than a third of the patients did not have a second IVUS.

"Although the authors used a sophisticated imputation algorithm to reanalyze their results and found essentially consistent outcomes, the high rate of noncompletion raises caution against over interpreting the results," they wrote.

They also commented that "there is a distinct difference between slowing or preventing progression of mild coronary stenoses and improving cardiovascular outcomes. As the authors carefully point out, ‘clinical outcomes trials, not surrogate end point studies, are the preferred approach to the determination of the benefits of any therapeutic intervention.’"

Given the current concern about cardiovascular risk in patients with diabetes, the editorialists concluded that "regardless of the mechanisms involved, PERISCOPE provides a reassuring perspective for patients with type 2 diabetes and high cardiovascular risk."

Journal of the American Medical Association, Nissen, SE "Comparison of Pioglitazone vs. Glimepiride on Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes The PERISCOPE Randomized Controlled Trial"JAMA 2008; 299: 1561-1573.

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DID YOU KNOW:
Sharp rise in Asia Pacific diabetes: There’s been a big increase in people suffering diabetes, with the rise most marked in India and China. The number diabetics in the world is expected to grow more than 50 per cent by 2025. And rapid modernization in Asia means about two-thirds of all cases worldwide are found in the Asia-Pacific region.