Possible heart-failure risks hit diabetes medication sales

WASHINGTON —The diabetes drugs Avandia and Actos will be receiving new labels with severe warnings about a risk of heart failure to some patients.

The makers of the drugs, GlaxoSmithKline and Takeda Pharmaceutical, have agreed to add the black-box warnings, the Food and Drug Administration stated. The warnings, the most severe that prescription drugs can bear, stress the medicines may cause or worsen heart failure and that patients should be monitored closely.

The warnings also apply to combination drugs that include the active ingredients in Avandia and Actos. Drugs containing Avandia are: Avandaryl, a combination with glimepiride or amaryl, and Avandamet, which combines metformin and Avandia. Actos also is available as a combination drug, known as ActoplusMet, with the medication metformin. The drugs help patients with type 2 diabetes control their blood-sugar levels.

Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. According to the Centers for Disease Control, while an estimated 14.6 million have been diagnosed with diabetes, another 6.2 million people (nearly one-third) are unaware that they have the disease.

The warnings, which the FDA said in June that it would seek, are separate from concerns that Avandia also raises the risk of heart attack. FDA advisers said a few months ago that the risk appeared real, but that the evidence wasn’t conclusive enough to pull Avandia from the market. The agency did recommend Avandia’s label be updated to include information on that risk. The FDA said it was continuing its review of the issue.

Separately, an FDA review of reports of side effects in patients taking either Avandia or Actos found cases of significant weight gain and build up of fluids, both of which are warning signs of heart failure, the agency said.

In a statement, the FDA released this message about diabetic medications, “Diabetes is a progressive disease, and for the majority of patients, multiple drug therapy will be the rule, not the exception. The ‘new’ drugs are those that have been approved within the past 10 years. For close to 70 years before that, the choices were limited to two oral agents and insulin, and metformin was only available in the early 1990s. Not everyone can tolerate or will be adequately controlled with these ‘older’ agents. So having many different therapies targeting different defects in diabetes is important. That said, all drugs have their own inherent risks, old or new.”

“The breadth and depth of Actos data—encompassing more than 16,000 patients over the past 10 years—is consistent: Short- and long-term studies, both prospective and observational, studies in both humans and animals, all have shown no evidence that Actos is associated with an increased risk of heart attack or stroke,” said Mehmood Khan, Takeda group and research development president. “Critical in this body of data is the PROactive [PROspective PioglitAzone Clinical Trial In MacroVascular Events] study, since the only scientific way to determine a medication’s safety is a prospective, long-term trial.”

The numbers though are revealing when looking at what the FDA warnings have done to sales of Avandia and Actos. Since 2002, both drugs had seen an increase in total prescriptions dispensed as compared with the year before. That changed though in the first half of 2007.

According to IMS Health, the class of drugs containing the two medications decreased in total prescriptions dispensed by 8 percent compared with the first half of 2006. Actos actually increased in script growth by 6 percent, while Avandia decreased by 22 percent.

Meanwhile, newer diabetic medications have seen growth in the market. The new DPP-4 inhibitor Januvia and the incretin mimetics drug Byetta have jumped onto the market and are doing well in terms of sales and prescriptions dispensed. Januvia only entered the market toward the end of 2006, so the numbers do not tell as much as with Byetta, which saw a 55 percent increase in prescriptions dispensed between the first half of 2006 and that of 2007. Also, the total amount of sales for Byetta has increased by 72 percent compared with the same period last year, according to IMS Health.

Avandia has seen the most damage as a result of an article published in the New England Journal of Medicine, which although it did not have enough statistical evidence to pull the drug off the market, did prove the drug may increase the risk of heart failure.

In a statement, the American Diabetes Association said, “As a result of all of this information, the American Diabetes Association strongly encourages patients taking this medication to consult with their physicians as to its benefits and risks.”

In response to another article, published by the Journal of the American Medical Association, GSK pointed out that Avandia was 32 percent more effective than metformin over a five-year period in controlling blood sugar.