Pioglitazone cuts risk of progression to diabetes.

SAN FRANCISCO- 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 a prospective, randomized, double-blind, placebocontrolled study of 602 patients.

One new case of diabetes could be avoided per year for every 3.5 patients treated with pioglitazone for impaired glucose tolerance, Dr. Ralph A. DeFron zo said at the annual scientific sessions of the American Diabetes Association. His report caused a wave of excited murmurs and some uncharacteristic cheers from the packed audience.

The 303 patients on the thiazolidinedione pioglitazone (Actos) also significantly improved on measures of insulin resistance and [beta]-cell function, while there were no significant changes in the 299 patients on placebo, Dr. DeFronzo, professor of medicine and division chief at the University of Texas Health Science Center, San Antonio, said in an interview.

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.

"It's a very impressive study. Those are numbers you don't see very often," Dr. Paul Jellinger commented in a phone interview.

The findings are likely to increase the off-label treatment of prediabetes with thiazolidinediones (TZDs) as monotherapy or in combination with metformin, according to Dr. Jellinger, professor of medicine on the voluntary faculty at the University of Miami and a past president of both the American College of Endocrinology and the American Association of Clinical Endocrinologists.

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--bene fits. Adding metformin may modulate some of the weight gain associated with TZDs, he noted.

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/[m.sup.2] 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 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 con trols, 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, he said. The study had 90% power to detect at least a 50% reduction in progression to diabetes in the treatment group vs. placebo.

Future long-term research should examine whether treating prediabetes with TZDs or metformin delays or actually prevents progression to diabetes, and whether these drugs reduce cardiovascular events in these patients, Dr. Jellinger suggested.

Approximately 21 million people in the United States have impaired glucose tolerance, which puts them at risk for diabetes and for cardiovascular disease, Dr. DeFronzo said. From 3% to 13% of people with impaired glucose tolerance go on to develop diabetes.

Dr. Jellinger is on the speakers bureau of Takeda Pharmaceutical Co., which makes pioglitazone, as well as the speakers' bureaus for Merck, Novo Nordisk, Eli Lilly & Co., Amylin Pharmaceutical, and Glaxo SmithKline.

Dr. DeFronzo is an adviser and speaker for Takeda, which funded the study. He also is a consultant, adviser, or speaker for, or has received research support from Bristol-Myers Squibb Co., Amylin Pharmaceuticals Inc., Eli Lilly & Co., Novartis, Pfizer Inc., Roche Duagnistucs, AstraZenca Pharameceuticals LP,Johnson& Johndon, and Isis Pharamaceuticals Inc.

BY SHERRY BOSCHERT

San Francisco Bureau