Is Diabetic Drug Effective?

At least 20 million Americans suffer from diabetes, a devastating disease that contributes to more than 200,000 deaths a year. Many of them have used Actos over the past seven years, since the type 2 diabetes treatment was approved. But a new report now questions the advantages of taking the popular prescription drug.

In the review, which appears in the current issue of The Cochrane Library (a quarterly publication of medicine reviews from the nonprofit Cochrane Collaboration), researchers say they found no clear long-term benefit to taking Takeda Pharmaceutical's pioglitazone (sold as Actos), which racked up nearly $1.8 billion in sales last year. They also noted an increased occurrence of edema, or excessive swelling, and heart failure among patients.

The examination of data from 22 clinical trials of Actos involving 6,200 patients, revives questions about the long-term effectiveness and risks of the class of medicines called thiazolidinediones (TZDs) to which Actos—as well as a popular drug made by GlaxoSmithKline, rosiglitazone (sold as Avandia)—belong. "After all these studies, we do not have convincing evidence that pioglitazone works with regards to patient-oriented outcomes like mortality, morbidity, diabetic complications, health-related quality of life [and] adverse effects," says lead author Dr. Bernd Richter, an assistant professor in the department of endocrinology, diabetes and rheumatology at Heinrich-Heine University in Duesseldorf, Germany. "What we know from all the trials is a definite increase in various side effects."

Concerns have been raised before about these drugs. In 2002, following the release of findings from three clinical trials of the medications, the Food and Drug Administration issued a warning that both drugs could cause fluid retention that could lead to, or worsen, congestive heart failure in patients, and cautioned practitioners to discontinue use in patients who exhibited heart problems after taking the medication. "[The swelling and heart failure] has come up in all the studies," says Dr. Richard Jackson, senior investigator of the Joslin Diabetes Center, an institution affiliated with Harvard University.

He and other doctors note that most of the trials examined for this review were short (between 24 weeks and 34.5 months)—long enough for swelling and heart failure to show up but not long enough to see whether the drug helps, or harms, the heart in other ways. And the new report does not include new data about Actos and the heart that will be presented at an American Heart Association meeting Nov. 13. "What is promising about Actos is it improves the [good] HDL cholesterol and lowers triglycerides. That's an element you can't get from other diabetes medications," says Dr. Michael Davidson, director of preventive cardiology at Rush University Medical Center in Chicago. "It helps improve the hardening of the arteries that leads to heart disease."

Though they caution that patients should be closely monitored for signs of edema or heart failure, doctors note that Actos and Avandia are effective in many patients in helping to lower their blood-sugar levels. Despite the FDA warning, the drugs remain extremely popular. Dr. Robert Spanheimer, senior medical director for diabetes and metabolism at Takeda Pharmaceuticals, notes that 7 million patients have taken Actos in the past seven years. "This is not news, it's information we had before. Physicians weigh the benefits and the risks," he says.

And many physicians believe the benefits outweigh the risks, says John Buse, director of the Diabetes Care Center at the University of North Carolina and president-elect of the American Diabetes Association. "This fluid retention can be monitored," he explains, "and the vast majority of people don't get it."

Still, diabetics are getting more options from which to choose, should they have concerns about a particular drug. On Tuesday, Merck received FDA approval for Januvia, a once-a-day pill that stimulates insulin only when it's needed. And the FDA is considering approval of Sanofi-Aventis's rimonabant pill, which lowers blood-sugar and triglyceride levels, raises good HDL cholesterol levels and causes weight loss. "We have choices, and we can tailor therapy to help prevent complications," says endocrinologist Larry Deeb, president of medicine and science at the American Diabetes Association.

TZDs like Actos and Avandia (often called insulin sensitizers) help to lower the body's blood-glucose levels by increasing the ability of the skeletal muscle to take up glucose and improving the sensitivity of the patient's insulin receptors. They are often used in conjunction with other drugs. "For most people with type 2 diabetes, you need two or three pills," says Dr. David Baldwin, director of endocrinology at Rush University Medical Center in Chicago. "They each have different mechanisms of action."

Sulfonylureas (like Glucotrol), for example, increase the release of insulin from the pancreas, and metformin (like Glucophage) reduces glucose production by the liver. Byetta, a twice-a-day injectable from Amylin Pharmaceuticals and Eli Lilly, lowers blood-sugar levels, reduces appetite, augments insulin secretion from the pancreas and causes weight loss. (It seems to make people feel full faster.)

Unless obesity rates drop, expect pharmaceutical companies to continue to develop new and better drugs. Type 2 diabetes patients—who comprise more than 90 percent of diabetics in the United States—are mostly overweight adults. If current trends continue, the World Health Organization predicts that by 2025, more than 300 million people worldwide will suffer from diabetes. "We're all looking for legitimate things that will help us," says Marc Onigman, 56, a type 2 diabetic who founded Diabetes Alerts, which gives news and information about treatments.

His sister-in-law, Mary Beth Finnerty, 57, also a type 2 diabetic, is on the same page. She tried Actos for a few months and didn't like the swelling or the five-pound weight gain. "I just really didn't feel good," she says. "It was not the dream medicine." Instead, she takes Glucophage and Amaryl (a sulfonylurea) and plans to ask about Januvia and other new medications as they get approved by the FDA. "Anybody that has type 2 diabetes and understands the long-term effects of it is looking forward to having more options," she says.