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Glitazone Prevents Diabetes: Beta Cell Function Preserved with Glitazone Rx
  MedPage Today
Published: May 14, 2010
Action Points
* Explain to interested patients that, according to this study, pioglitazone may slow or stop progression of insulin resistance to full-blown diabetes.
* Explain that neither pioglitazone nor any other drug is FDA approved for this purpose, and that this agent can have adverse side effects.
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
PRAGUE -- In patients with insulin resistance but near-normal glycated hemoglobin levels, pioglitazone (Actos) treatment cut the rate of progression to full-blown type 2 diabetes by 70% relative to placebo, according to updated results from the ACT NOW study reported here.
The annual rate of progression to diabetes in the 602-patient trial was 1.8% with pioglitazone versus 6.0% in the placebo group, said Ralph DeFronzo, MD, of the University of Texas Health Science Center in San Antonio.
The difference translated to a hazard ratio of 0.30 (95% CI 0.17 to 0.54), he told attendees here at the World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension.
"This is a pretty robust effect," he said, adding that it essentially proved the drug helps preserve beta cell function.
DeFronzo had reported initial results from ACT NOW in 2008, but they remain unpublished. He said the journal to which they were submitted has demanded four rounds of revisions and it was unclear when or where a paper would finally appear.
In the 2008 presentation, at the American Diabetes Association's annual meeting, he reported that treating 3.5 patients with pioglitazone for one year would prevent one case of progression to type 2 diabetes.
Here, however, DeFronzo said the number needed to treat was 23. He told MedPage Today that the 3.5 figure was a mistake.
The randomized, double-blind trial assigned patients to a minimum of two years of treatment with placebo or pioglitazone. Patients in the latter group started at 30 mg/day for the first month, with the dose then increased to 45 mg/day.
The primary outcome was progression to type 2 diabetes, defined as fasting plasma glucose of more than 125 mg/dL at any follow-up visit or a two-hour plasma glucose level of at least 200 mg/dL at the annual visit. The diagnosis had to be confirmed with an oral glucose tolerance test.
DeFronzo said that, in his opinion, 30 mg would probably have been adequate to achieve the benefits seen in the study and may have reduced some of the side effects.
Reporting other data not included in the 2008 presentation, DeFronzo said that insulin sensitivity increased significantly with pioglitazone relative to baseline.
From an initial Matsuda index score of 4.25, patients receiving the drug showed an increase to 5.0 (P<0.005), whereas there was no change in the placebo group.
He also noted that fasting plasma glucose levels fell much faster initially with pioglitazone relative to placebo, showing a significant 20-mg/dL difference (P<0.005) within the first two months.
Initial fasting glucose levels were only mildly elevated, with one-third of patients in the normal range and a mean overall of 105 mg/dL.
Mean glycated hemoglobin (HbA1c) level at baseline was 5.5%.
In an interview and in a separate platform presentation here, DeFronzo argued in favor of thiazolidinedione therapy for patients with impaired glucose tolerance who fail to meet formal criteria for type 2 diabetes, despite the weight gain associated with these drugs.
He told MedPage Today that the weight gain in this population is "mischaracterized as an adverse effect." He said it was primarily a cosmetic problem and was actually an indicator "that the drug is working."
"It is not a metabolic problem," he declared, contending that the treatment actually moves fat out of the liver, muscle, and other tissues, accumulating instead under the skin where it is largely innocuous.
DeFronzo also argued that data from multiple studies indicate that the weight gain correlates with the drug's antidiabetic effects including lowered HbA1c and improved insulin sensitivity.
But Jaakko Tuomilehto, MD, of the University of Helsinki in Finland, noted that drug therapy for patients merely at risk for diabetes has a number of drawbacks.
These include cost, adverse effects (which, he insisted, include weight gain), lack of efficacy associated with nonadherence, or genetic factors.
He pointed to data from Finland and from the U.S.-based Diabetes Prevention Program (DPP) showing that aggressive lifestyle interventions can reduce the progression rate from insulin resistance to diabetes by close to 60% relative to standard care.
But DeFronzo countered that the interventions used in these studies are impractical in the real world.
"Nonpharmacologic therapy does not work over the long term," he asserted.
In the DPP and other studies showing durable benefits, participants received months of one-on-one counseling and even longer periods of group sessions to maintain adherence.
DeFronzo said it would be impossible to duplicate that model broadly, at least in the U.S.
On the other hand, Tuomilehto cited a European study suggesting that effective lifestyle interventions cost about $3,000 per quality-adjusted life-year saved, versus $33,000 for rosiglitazone (Avandia).
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