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Pioglitazone in Prediabetes Curbs Disease Progression

Jul 16, 2008

People with impaired glucose tolerance were 81% less likely to develop type 2 diabetes over a 3-year period if treated with pioglitazone, according to the findings of an industry-sponsored randomized, double-blind, placebo-controlled study of 602 patients.

Dr. Ralph A. DeFronzo stated that, “One new case of diabetes could be avoided per year for every 3.5 patients treated with pioglitazone for impaired glucose tolerance.”


Experts disagree, however, about whether such findings support treating prediabetes with pioglitazone in clinical practice.
The 303 patients on the thiazolidinedione pioglitazone (Actos) also significantly improved on measures of insulin resistance and β-cell function, while there were no significant changes in the 299 patients on placebo.

In the pioglitazone group, 1.5% of patients per year developed diabetes, compared with 6.8% per year on placebo. Impaired glucose tolerance converted back to normal glucose tolerance in 42% of the pioglitazone group by the end of the study, compared with 28% on placebo.

Dr. Paul Jellinger said that the findings are likely to increase the off-label treatment of prediabetes with thiazolidinediones (TZDs) as monotherapy or in combination with metformin. “It’s a very impressive study. Those are numbers you don’t see very often,” said the professor of medicine on the voluntary faculty at the University of Miami.

There are no medications approved for the treatment of prediabetes to prevent progression to diabetes. Metformin probably is the most common off-label treatment used for this purpose, Dr. Jellinger said, because a previous study showed similar—though not as striking—benefits. Adding metformin may modulate some of the weight gain associated with TZDs, stated Dr. Jellinger.

In Dr. DeFronzo’s trial, called the Actos Now for Prevention of Diabetes (ACT NOW) study, patients started with an average body mass index of 34 kg/m2 and gained a mean of 3.5 kg (about 8 pounds) in the pioglitazone group and 0.7 kg (less than 2 pounds) in the placebo group over a mean 2.6-year follow-up.

Patients had a mean age of 52 years and were recruited in eight medical centers over a 2-year period, then followed for at least 2 more years or until a diabetes diagnosis. All had 2-hour glucose values of 140–199 mg/dL on oral glucose tolerance test, a fasting plasma glucose concentration of 95–125 mg/dL, and one or more other high-risk characteristics (at least one component of the metabolic syndrome, a family history of type 2 diabetes, a history of gestational diabetes, the presence of polycystic ovary syndrome, or minority ethnic background).

A combination of impaired glucose tolerance and impaired fasting glucose was present in 68% of patients, and the rest had isolated impaired glucose tolerance. Compared with 102 healthy matched controls, patients in the study showed a 48% reduction in insulin sensitivity and a 78% decrease in the insulin secretion/insulin resistance index.

Patients were randomized to treatment with placebo or 30 mg/day pioglitazone. If the drug was tolerated after 1 month, the dose could be increased up to 45 mg/day.

“What was quite surprising was how quickly pioglitazone dropped the fasting glucose,” Dr. DeFronzo said. “Within the first 3 months of initiating pioglitazone, there was a defined decrease in glucose” separating the two groups that was maintained to the end.

The study had 90% power to detect at least a 50% reduction in progression to diabetes in the treatment group vs. placebo.
About 21 million people in the United States have impaired glucose tolerance, which puts them at risk for diabetes and for heart disease, Dr. DeFronzo said. From 3% to 13% of people with impaired glucose tolerance go on to develop diabetes.
Presented at the ADA Scientific Sessions 2008


“More than two-thirds of Americans are overweight or obese.” If we all lost just nine pounds, like the majority of people in this study did, our nation would see vast decreases in hypertension, high cholesterol, diabetes, heart disease and stroke,” said study co-author Victor Stevens, Ph.D., a Kaiser Permanente researcher. For example, in an earlier study Stevens found that losing as little as five pounds can reduce the risk of developing high blood pressure by 20 percent.


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