Pioglitazone Reduces Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

Jacquelyn K Beals, PhD

June 10, 2008

June 10, 2008 (San Francisco) — A new study demonstrates that early intervention with pioglitazone in patients with impaired glucose tolerance (IGT) can significantly reduce the number of those patients who subsequently develop type 2 diabetes.

The results of this study were presented here at the American Diabetes Association 68th Scientific Sessions by Ralph A. DeFronzo, MD, professor of medicine and chief of the Diabetes Division at the University of Texas Health Science Center and the Audie L. Murphy Memorial Veterans Affairs Hospital in San Antonio, Texas.

IGT is a condition in which blood glucose levels are higher than normal but are not as high as in diabetes. IGT includes both impaired insulin secretion and insulin resistance and is associated with a high risk of developing type 2 diabetes. Although not classified as diabetic, patients with IGT may show symptoms of peripheral neuropathy or diabetic retinopathy.

Pioglitazone, a drug of the thiazolidinedione (TZD) class, is "a great insulin sensitizer in type 2 diabetics," Dr. DeFronzo explained to Medscape Diabetes & Endocrinology. "It gives you durability of control and improves beta cell function, and those are the 2 core defects that are present in type 2 diabetics." These defects are also present in IGT.

The goal of the randomized, placebo-controlled, double-blind study was to determine whether the development of diabetes could be delayed or prevented by treating IGT patients with pioglitazone.

The 4-year study enrolled 602 participants with IGT for a period of 2 years and followed their progress for 2 more years (or until they developed diabetes). Their average fasting plasma glucose (FPG) was 105 mg% (FPG ≥ 95 mg% was required to qualify for the study), and average HbA1c was 5.5%.

Control patients (n = 102) with normal glucose tolerance were matched for age, sex, and body mass index. At the time subjects entered the study, the insulin sensitivity among patients with IGT was 48% less than that of control patients (P < .0001), and the "insulin secretion/insulin resistance (disposition) index" was 78% lower in patients with IGT than in control patients (P < .0001).

Patients with IGT were randomly assigned to receive 45 mg/day of pioglitazone or a placebo. The participants were assessed every 3 months for FPG and HbA1c and also received an annual oral glucose tolerance test. Diabetes was diagnosed if a patient showed FPG of 126 or more or had a 2-hour plasma glucose level of 200 mg/dL or more.

Asked about patients' weight gain, Dr. DeFronzo noted that the starting body mass index was about 34.3 kg/m2 in both groups. "There was a weight gain of 3.9 kg in the pioglitazone group vs about 0.8 kg in the placebo group," he reported. Weight gain is commonly associated with the use of TZDs.

The study determined that insulin sensitivity and the insulin secretion/insulin resistance index improved significantly in patients receiving pioglitazone (P < .0005 in both cases). Most striking, only 10 individuals in the pioglitazone group compared with 45 patients in the placebo group developed diabetes. This is a conversion rate of 6.8% compared with 1.5% per year and constitutes a significant decrease in the frequency of IGT conversion to type 2 diabetes (P < .000001).

Dr. DeFronzo summarized his results: "Over a mean follow-up of 2.6 years, pioglitazone markedly decreased, by 81%, the conversion rate of IGT to type 2 diabetes. IGT individuals who had the worst level of beta cell function and who were the most insulin resistant were the individuals who were most likely to develop type 2 diabetes, whether they were in the pioglitazone group...or the placebo group. Pioglitazone was quite safe and quite efficacious."

In addition, "if you'd like to know...the number of patients...that you have to treat, you need to treat 3.5 people with IGT for 1 year to prevent the development of 1 added case of type 2 diabetes. I think this is a pretty favorable number," said Dr. DeFronzo.

Medscape Diabetes & Endocrinology also talked via email with Anne L. Peters, MD, CDE, who chaired the Late Breaking Clinical Study session. Dr. Peters is director of the Clinical Diabetes Programs at the University of Southern California and professor of clinical medicine at the university's Keck School of Medicine. Dr. Peters commented that "Dr. DeFronzo's Act Now study adds to the existing body of evidence that TZDs reduce the progression of prediabetes to diabetes."

She continued, "The impressive risk reduction he achieved with pioglitazone further validates the benefit of this drug in terms of disease prevention and stabilization of beta-cell function. Early use of treatment that provides maximal physiologic benefit makes sense in the management of diabetes."

Dr. DeFronzo reported receiving research support, serving as a consultant, a member of the speakers' bureau, or on the advisory panel of Amylin Pharmaceuticals, Inc; Eli Lilly and Company; Takeda Pharmaceuticals North America, Inc; Merck & Co; Novartis Pharmaceuticals Corporation; Pfizer, Inc; and Roche Diagnostics Corporation. Dr. Peters reported that she has received research support from Abbott Laboratories.

American Diabetes Association 68th Scientific Sessions: Late Breaking Clinical Studies. Presented June 9, 2008.

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