Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.
By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.
"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA1c improvement to the end of the 2 years."
Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.
There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.
Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.
A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.
In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.
But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."
Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."
Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.
"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."
The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.
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