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Is Pioglitazone the Answer in Pre-diabetes?

Posted: Tuesday, April 05, 2011

A pill taken once a day in the morning prevented Type 2 diabetes in more than 70 percent of individuals whose obesity, ethnicity and other markers put them at highest risk for the disease.

Pioglitazone also led to adverse effects including weight gain and edema, according to a published study.

Senior author Ralph DeFronzo, M.D., professor in the School of Medicine and chief of the diabetes division at the UT Health Science Center San Antonio, led the trial of pioglitazone, which is marketed as Actos® by Takeda Pharmaceutical Co. Ltd. The Japanese company provided an independent investigator grant to Dr. DeFronzo to conduct the ACT Now study. Some patients were followed for as long as four years; the average follow-up was 2.4 years.

Type 2 diabetes goes through a natural progression, beginning with genetic predisposition in some individuals and progressing to normal glucose tolerance with insulin resistance. Individuals may then go on to develop impaired glucose tolerance and finally Type 2 diabetes and beta-cell failure.

Hyperglycemia contributes to microvascular and macrovascular complications of diabetes, suggesting that preventing or delaying hyperglycemia could lead to reductions in long-term complications. Previous studies showed that conversion of impaired glucose tolerance to Type 2 diabetes can be reduced through lifestyle modification; bariatric surgery; or the use of metformin, thiazolidinediones or acarbose.

Pioglitazone is a thiazolidinedione (TZD) used to treat Type 2 diabetes by increasing sensitivity to insulin. To investigate whether it could reduce the risk for Type 2 diabetes in patients with impaired glucose tolerance, the researchers conducted a randomized, double-blind, placebo-controlled study in 602 adults who received pioglitazone or placebo. Median follow-up was 2.4 years. The researchers measured fasting glucose levels 4 times a year and oral glucose tolerance yearly. Diagnosis of diabetes was based on repeat testing.

Of these patients, 2.1% of those receiving pioglitazone converted to Type 2 diabetes, compared with 7.6% of the placebo group (72% reduction; hazard ratio for conversion to Type 2 diabetes in pioglitazone group, 0.28 [95% confidence interval, 0.16 to 0.49; P < .001]). In addition, 48% of patients receiving pioglitazone converted to normal glucose levels, compared with 28% in the placebo group (P < .001). Pioglitazone treatment was also associated with reduced levels of fasting glucose compared with placebo (a decrease of 11.7 mg/L vs. 8.1 mg/dL; P < .001), as well as 2-hour glucose (a decrease of 30.5 mg/dL vs. 15.6 mg/dL; P < .001), and hemoglobin A1c (a decrease of 0.04% vs. an increase of 0.20%; P < .001).

Patients receiving pioglitazone also had a decrease in diastolic blood pressure (-2.0 mm Hg vs. 0.0 mm Hg; P = .03), a reduction in carotid intima-media thickening (31.5%; P = .047), and a bigger increase in the level of high-density lipoprotein cholesterol (7.35 mg/dL vs. 4.5 mg/dL; P = .008).

Those receiving pioglitazone gained more weight than the placebo group (3.9 kg vs. 0.77 kg; P < .001) and had higher rates of edema (12.9% vs. 6.4%; P = .007).

"It's a blockbuster study," said Dr. DeFronzo. "The 72 percent reduction is the largest decrease in the conversion rate of pre-diabetes to diabetes that has ever been demonstrated by any intervention, be it diet, exercise or medication."

Timothy S. Harlan, MD, medical director at Tulane University Medical Group, New Orleans, stated that, "We know these medications control H1 quite well, but the problem is that they often do so at the expense of weight gain and edema."

Dr. Harlan said that the data from the study suggest that pioglitazone is safer than other drugs in the class, but he isn't entirely convinced yet. "I have prescribed [pioglitazone] and I do it very carefully, as a third-line therapy. At this stage, I don't think I would prescribe this to prevent diabetes in my patients. I'd like to see a lot more data before I widely prescribe it."

Instead, he favors more emphasis on diet and exercise. "Insurance companies will willingly reimburse for medicines like this, yet we will not invest that same level in helping people do what works better, and that's lifestyle changes."

Pioglitazone was well tolerated by participants, with weight gain and fluid retention observed at the dose used in the study. Dr. DeFronzo said those side effects can be mitigated by using a lower dose that works equally well. Pioglitazone stimulates appetite while at the same time shifting fat around in the body, taking it out of muscle, the liver and beta cells and putting it in subcutaneous fat depots under the skin where it is inert and not harmful, he said.

"No drug is perfect," Dr. DeFronzo said. "This particular medication does two things -- improves insulin resistance and improves beta cell function, which are the two core defects of diabetes."

Source:, N Engl J Med. 2011;12:1104-1115.

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