PROactive Substudy: Significant reductions in MI and ACS in high-risk diabetic patients

November 16, 2005—Pioglitazone, compared to placebo, on top of optimal medical therapy for all other risk factors, provided a clear benefit in patients with diabetes and a prior MI. This pre-specified subgroup was presented by Dr. Erland Erdmann, University of Koeln Germany, at the 2005 Scientific Sessions of the American Heart Association, held in Dallas, Texas from November 13-16.

Pioglitazone is the first drug to show a beneficial effect on cardiovascular events in diabetes, based on the data from the main PROactive study. Pioglitazone is an insulin-sensitizing agent, and reduces triglycerides, HbA1c, inflammatory markers such as CRP, blood pressure, and increases HDL cholesterol.

At 321 medical centers in 19 countries in Europe, 2445 patients who were in the main PROactive trial were randomized to either pioglitazone (n=1230) or placebo (n=1215). Study treatment was on topof optimal medical treatment for diabetes, coronary disease, hypertension, and hyperlipidemia, and physicians were reminded and encouraged throughout the study to maintain optimal medical therapy. Follow-up was a minimum of 2.5 years and the mean was 2.85 years.

The patients were 61 years old on average, 73% male, and 98% Caucasian. The median duration of diabetes was 8 years. Mean BMI was 30. Mean SBP was 141 mmHg and mean DBP was 82 mmHg. Seven percent of patients had a prior stroke (≥ 6 months), 43% had a prior PCI or CABG (≥ 6 months), 13% had a prior ACS, and 7% had symptomatic peripheral arterial obstructive disease. Fewer adverse events were found with pioglitazone (47% vs 51% with placebo).

For the 3 pre-specified analyses, pioglitazone, compared to placebo, resulted in:

• 28% significant reduction in recurrent fatal and non-fatal MI (excluding silent MI; p=0.045; NNT =22 for 3 years).
• 37% significant reduction in ACS (p=0.035).
• 19% significant reduction in the composite endpoint.
• Significantly improved HbA1c, triglycerides, and HDL.
• No difference in all-cause death in heart failure patients (1.8% Pio, 1.7%).

ACS was defined as treatment in a hospital setting as a consequence of 1 or more episodes of ischemic discomfort at rest and characterized by ECG changes and/or and elevation of a cardiac marker to an extent to not indicate MI.

Notably, although there were more reports of heart failure with pioglitazone (7.5% vs 5.2% with placebo), all-cause mortality was similar in both groups. Thus, it is believed that physicians are misdiagnosing edema as heart failure. These data are reassuring, because of the concern that this class of drugs increases heart failure.
Improvements in cholesterol are thought to be specific to pioglitazone, not the class of agents, because no other drug in the class has shown this improvement.

Reductions in HbA1c and lipids with pioglitazone and placebo from baseline were:

Erdmann noted that the reductions in this PROactive analysis are additive to the 17% reduction seen in the Heart Protection Study at 3 years.