NEJM: Actos prevents diabetes in 72% of pre-diabetics
Compared with placebo, pioglitazone (Actos, Takeda Pharmaceuticals) reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72 percent, but was associated with significant weight gain and edema, according to a study published March 24 in the New England Journal of Medicine.

"This is the largest decrease in the conversion rate of pre-diabetes to diabetes ever demonstrated by any intervention including diet, exercise or medication," co-author Devjit Tripathy, MD, PhD, an endocrinologist at the University of Texas (UT) Health Science Center in San Antonio, told Cardiovascular Business News.

Treatment of 18 participants for one year prevented one case of diabetes, while treatment of eight participants for two years prevented one case of diabetes, Tripathy said.

Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance, the authors noted.

Rosiglitazone (Avandia, GlaxoSmithKline) belongs to the same drug class as pioglitazone, thiazolidinediones. However, controversy has surrounded rosiglitazone for its propensity to cause cardiac events. In fact, the EU has taken the drug off the shelves, while the FDA and the Canadian government have imposed severe restrictions on its use and labeling.

"Although these two drugs belong to the same class, there is a big difference between them," Tripathy said. "The advantages of pioglitazone is that it has a marked effect on lowering triglycerides and increases levels of high-density lipoprotein cholesterol [HDL], which we have not seen in rosiglitazone. Our study did not look at cardiovascular outcomes, but we did show that pioglitazone helped decrease carotid intima-media thickness [CIMT], which is a surrogate for atherosclerosis. We assume that if you reduce the risks for cardiac events, you will reduce the events themselves."

The study, led by Ralph A. DeFronzo, MD, from UT, on behalf of the ACT Now investigators, was a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance.

Researchers randomly assigned 602 patients to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Participants were chosen because of their high risk for diabetes, including obesity, family history and impaired glucose tolerance as demonstrated by a glucose test. Compliance was similar for both groups, around 80 percent.

DeFronzo and colleagues found an annual incidence rate for type 2 diabetes mellitus at 2.1 percent in the pioglitazone group compared with 7.6 percent in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28, a significant difference.

Conversion to normal glucose tolerance occurred in 48 percent of the patients in the pioglitazone group and 28 percent of those in the placebo group. The difference was significant.

Researchers also found that pioglitazone was associated with significantly reduced levels of fasting glucose, two-hour glucose and HbA1c, compared with placebo.

Pioglitazone therapy also was associated with a decrease in diastolic blood pressure, a 31 percent reduced rate of CIMT and a greater increase in the level of HDL.

"The protective effect of pioglitazone was of similar magnitude (with no significant heterogeneity) in subgroups defined by sex, age, weight, race or ethnic group, and fasting glucose level, as well as in patients with both impaired glucose tolerance and impaired fasting glucose and those with isolated impaired glucose tolerance," the authors wrote.

While significant weight gain and edema were associated with the pioglitazone group, it did not appear to be associated with adverse cardiac events, although the study was not powered to measure this effect, Tripathy said

"This drug shifts the fat from the visceral region to the limbs," Tripathy said. "It takes it out of muscle, the liver and beta cells. We know that abdomen fat is worse in terms of cardiovascular risk, which could explain why we didn't see an association between weight gain and cardiovascular events. However, again, the study was not powered to measure these effects."

To mitigate weight gain, it may be possible for some patients to take a smaller dose of the drug, from 45 mg to 30 mg, Tripathy said. "We believe we will see the same effects with the smaller dose."

He also said they did not see other adverse side effects associated with thiazolidinediones such as fractures, but the study was not powered to measure this effect.

"Although they are considered to have pre-diabetes, patients in the upper third of the range for impaired glucose tolerance are at or close to the maximum level of insulin resistance and have lost approximately 80 percent of beta-cell function," researchers wrote.

"Histologic studies suggest that the beta-cell mass in patients with impaired fasting glucose is significantly reduced as compared with persons who have normal fasting glucose, and two thirds of the patients in our study had impaired fasting glucose. ... It is reasonable to consider interventions at this stage to prevent the development of overt diabetes."

Robert Chilton, DO, a cardiologist at UT Health Science Center San Antonio who was not involved with the ACT Now study, said the slowing of CIMT indicated that the participants' glucose was well controlled, preventing blood vessel damage that leads to heart attacks, strokes and peripheral vascular disease.

Individuals who have diabetes have the same high risk of having a first heart attack as do non-diabetic people who already had a heart attack, he noted.

Takeda Pharmaceutical provided funds for the study.