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Diabetes Prevention Hopes Revived for Thiazolidinedione

Posted: Friday, June 20, 2008

Pioglitazone (Actos) may prevent or delay progression to diabetes for patients with pre-diabetes by 81%, researchers found. 

At an average 2.6 years of follow-up, the thiazolidinedione extended time to occurrence of diabetes by 81% for patients with impaired glucose tolerance compared with placebo in the large randomized ACT NOW trial.

The number needed to treat to prevent one case of type 2 diabetes was 3.5 for one year, "a pretty favorable number," reported Ralph A. DeFronzo, M.D., of the University of Texas Health Science Center at San Antonio, at the at the American Diabetes Association meeting.

 
If replicated, these findings put pioglitazone in the lead for prevention, commented Saul Genuth, M.D., of Case Western Reserve in Cleveland, who was a chair of the late-breaking clinical trials session at which the results were reported.
The only other agent to show a comparable benefit was the thiazolidinedione rosiglitazone (Avandia) with a 60% reduction in progression to diabetes for high-risk patients in the DREAM trial.  Diet and exercise -- recommended by the ADA as topline diabetes prevention -- similarly reduced progression of impaired glucose tolerance to diabetes by about 58% in the Diabetes Prevention Program study.

The big question, though, is whether pioglitazone or any other agent could truly prevent diabetes, or if the benefits would erode as treatment ended. While unwilling to speculate, Dr. DeFronzo said the answer is coming. The washout phase of the ACT NOW trial will end on Aug. 1, he said.

For now, it appears that pioglitazone would have to be continued indefinitely, Dr. Genuth said, which raises concerns about long-term adverse events.

 
About a third of the U.S. population is estimated to have prediabetes, so even the low risk of heart failure and fracture seen with the drug in other trials could mean a substantial number of affected patients among 100 million potential users, he noted.
In ACT NOW, the risk of fracture, heart failure, and other adverse events was similar except for a higher rate of edema in the pioglitazone group compared with placebo (22% versus 15%). Weight gain was also greater (3.5 versus 0.6 to 0.7 kg).
The prospective, double-blind trial included 602 patients with a fasting plasma glucose in the 95 to 125 mg/dl range, impaired glucose tolerance diagnosed with a single oral glucose tolerance test, and at least one component of the metabolic syndrome or other factor placing them at high risk for diabetes.

The mean Matsuda insulin sensitivity index score was 4.76 in the placebo group and 4.25 in the pioglitazone group. Participants were randomized to placebo or pioglitazone at a starting dose of 30 mg titrated up to 45 mg per day. Pioglitazone improved the rate of progression to diabetes to 1.5% per year compared with 6.8% per year with placebo (hazard ratio 0.19, P<0.00001). Conversion to type 2 diabetes was defined as a fasting plasma glucose of 126 mg/dL or higher during follow-up confirmed with an oral glucose tolerance test.

Prediabetic patients with the lowest beta-cell function and insulin sensitivity at baseline appeared to be at the greatest risk of developing diabetes during follow-up. Patients were also more likely to return to normal glucose tolerance during the trial when treated with pioglitazone (42% versus 28%, P<0.001).

 
These benefits appeared to be due to a greater improvement in beta-cell function as expected for a thiazolidinedione. These findings included significant benefits in:
 
  • Ratio of insulin secretion to insulin resistance index with pioglitazone compared with baseline (P<0.005) but not with placebo.
  • Disposition (AIR X SI) index for pioglitazone (P<0.005) but not placebo.
  • Matsuda index of insulin sensitivity with pioglitazone (P<0.001) but not placebo.
  • Hepatic insulin resistance index with pioglitazone (P<0.002) but not placebo.
This kind of early approach to diabetes makes sense, Dr. DeFronzo said, "because by the time patients become type 2 diabetic, they don't have a whole lot of beta-cells left."
Practice Pearls:
  • Explain to interested patients that the study suggested that pioglitazone could be effective for prevention of delay of diabetes in high-risk patients.
  •  Point out that the drug is not approved for this indication.

Source: Diabetes In Control: ADA meeting: DeFronzo R, et al "ACTos NOW for the prevention of diabetes (ACT NOW) study" ADA meeting 2008. Presented at the ADA’s 68th Annual Scientific Sessions.

 
 
 
 
 
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