A new systematic review calls into the question the health benefits versus risks of an oral medicine widely prescribed for diabetes throughout the United States, Canada, Europe and Asia.
The drug -- called pioglitazone -- is marketed in the United States by Takeda Pharmaceuticals North America, Inc., and Eli Lilly and Co. under the trade name Actos.
"Our results showed that published scientific studies of at least 24 weeks of pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects and health-related quality of life are positively influenced by this drug," said lead author Bernd Richter, M.D.
"Until new evidence becomes available, the benefit-risk ratio of pioglitazone therapy in type 2 diabetes mellitus remains unclear," added Richter, assistant professor in the department of endocrinology, diabetes and rheumatology at Heinrich-Heine University in Dόsseldorf, Germany.
According to Richter, not only did the review demonstrate no clear-cut benefit to using pioglitazone, but it also showed an increased occurrence of edema and heart failure -- including heart failure requiring hospital admission -- among patients taking the drug.
The review appears in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
For the review, the authors analyzed the results of 22 randomized clinical trials involving 6,200 patients with type II diabetes receiving pioglitazone treatment. The longest duration of pioglitazone therapy received by any patient was 34.5 months.
Pioglitazone is one drug in a class of medicines called "thiazolidinediones," which are said to increase the body's sensitivity to insulin produced naturally by the body, thereby allowing better uptake of glucose into the cells of the body and lowering blood glucose levels.
Physicians in the U.S. prescribe drugs such as Actos to patients with type II diabetes, whose bodies either do not produce enough natural insulin or don't use the insulin as effectively as those not affected by diabetes.
HbA1c, or hemoglobin A1c, is a blood test that assesses a patient's blood glucose levels over time. The HbA1c number correlates with average blood glucose levels during the preceding 120 days, and most tellingly, during the previous eight to 12 weeks.
The review found that pioglitazone lowers HbA1c, but when compared to other active glucose-lowering drugs, similar reductions of HbA1c were achieved, so that "no apparent advantage of pioglitazone treatment could be demonstrated," said Richter. "Probably, the best comparison would be with metformin, where pioglitazone lowered HbA1c between 1.3 percent and 1.4 percent and metformin by 1.5 percent."
Pioglitazone has many possible side effects, including fluid retention, weight gain, and leg and ankle "edema" or swelling. In isolated cases it may lead to, or worsen, heart failure.
In the review studies, 15 percent of participants receiving pioglitazone therapy reported edema compared with 7 percent of participants in control groups.
The 15 studies that looked at body weight reported an increase of up to 8.6 pounds in those patients receiving pioglitazone treatment.
In one major study in the review, significantly more patients developed edema and heart failure, including heart failure needing hospital admission, following administration of pioglitazone -- 6 percent versus 4 percent on placebo. Heart failure was reported in 11 percent of patients on pioglitazone therapy versus 8 percent on placebo.
The drug may also cause dangerous drops in blood glucose in people taking the drug in combination with insulin or another class of diabetes drugs called "sulfonylureas," which are marketed in the United States under the generic names glipizide, glyburide, glimepiride and chlorpropamide.
"The kernel from this review is that pioglitazone is effective in glucose-lowering, has some other beneficial and potentially harmful associated features and just has not been evaluated in the right way to prove that it will help people lead longer and more productive lives," said John Buse, M.D., director of the Diabetes Care Center at the University of North Carolina School of Medicine. "This is true for essentially every drug available for the treatment of diabetes."
"I am fairly certain that we are better off with pioglitazone than without it," Buse added. "We do not have proof but a great deal of signal that the benefits outweigh the risks. There are more data to come. The authors of the review are not incorrect in their assessments, but there is just not enough long-term data available in the literature to be certain of the benefits whereas the risks are much easier to assess."
"Pioglitazone treatment should be restricted to patients demonstrating real benefit of this therapy," Richter said. "Benefit should not be postulated on the basis of improvement of metabolic parameters like HbA1c reduction alone but should refer to patient-oriented outcomes such as fewer diabetic complications or better health-related quality of life."
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