Drugs Log

The findings of clinical trials have linked the use of thiazolidinediones, a class of diabetes drugs, with congestive heart failure and possibly heart attacks. Now, new research indicates that these associations, at least with Avandia, also apply to individuals in the community, and not just clinical trials.

Dr. Lorraine L. Lipscombe, from the Institute for Clinical Evaluative Sciences in Toronto, and colleagues analyzed data for 159,026 older adults who were treated with at least one oral diabetes drug between 2002 and 2005 and were entered in an Ontario healthcare database. The subjects were followed through March 2006.

During an average follow-up period of 3.8 years, 7.9 percent of the patients were hospitalized for congestive heart failure, 7.9 percent were hospitalized for a heart attack, and 19 percent died, according to the researchers’ report in Journal of the American Medical Association.

Current thiazolidinediones use increased the risks of heart failure, heart attack and death by 60 percent, 40 percent, and 29 percent, respectively, compared with the use of other types of oral diabetes drugs.

Further analysis revealed that the risks were largely confined to patients who were using Avandia, known generically as rosiglitazone.

“These findings provide evidence from a real-world setting and support data from clinical trials that the harms of thiazolidinediones may outweigh their benefits, even in patients without obvious…cardiovascular disease,” the authors write.

More studies are needed to better define the risk-benefit ratio and the trade-offs associated with thiazolidinedione therapy and to explore if the treatment risks are confined specifically to rosiglitazone.

Avandia risks highlighted

Canadian researchers furnished the strongest evidence to date linking the popular diabetes drug Avandia to an increased risk of heart attack in a scientific study released yesterday.

Compared with other diabetes pills, Avandia’s use was associated with a 60 percent higher risk of heart failure, 40 percent higher risk of heart attack and 30 percent higher risk of death in patients 65 and older, the researchers found.

“The risks associated with these drugs may outweigh the benefits, at least for older populations,” said Dr. Lorraine L. Lipscombe, the lead author of the study and a researcher at a health research agency funded by the Ontario government.

The findings, published in the influential Journal of the American Medical Association, will probably intensify pressure on the government to restrict sales of the oral diabetes medicine.

“It should come off the market,” said Dr. Sidney M. Wolfe, director of health research at Public Citizen, a liberal interest group preparing to petition the Food and Drug Administration to pull the drug.

Sales of Avandia have plummeted since Dr. Steven Nissen, a prominent cardiologist, reported in May that it raised the risk of heart attack. His report prompted congressional hearings and demands to stop sales.

The FDA decided against that last month, instead adding a label warning that urges users to consult a doctor if they have serious heart problems.

The decision divided agency staff. Ultimately, FDA officials decided the scientific evidence wasn’t conclusive, and they asked Avandia’s manufacturer to conduct a long-term study.

In a statement, the FDA said it would review the results from the Canadian study, but it needs more evidence before taking any further action. “This new study we have just seen today does not change FDA’s recommendations,” the agency said.

GlaxoSmithKline, Avandia’s maker, dismissed the Canadians’ findings as limited and misleading because the elderly studied might have been at higher risk of heart problems.

The Philadelphia company, which is conducting a long-term study of Avandia’s side effects, said in a statement that many other studies show Avandia is safe and effective.

The new study is the first to review side effects in real patients, rather than test subjects, according to Lipscombe, a researcher at the Institute for Clinical Evaluative Sciences in Toronto.

Beginning in March, Lipscombe and her colleagues analyzed health care records for all elderly Ontario residents who took an oral diabetes medicine between 2002 and 2006.

Lipscombe said they focused on the elderly because 40 percent of diabetes patients in Ontario are 65 and older, but the elderly tend to be underrepresented in scientific drug studies.

The researchers didn’t find a higher heart risk among users of Actos, an Avandia competitor that belongs to the same class of diabetes drugs, but Lipscombe said there weren’t enough Actos users to draw a firm conclusion.

Older Diabetics Using Avandia Face Increased Death Risk

Older patients using the diabetes drug Avandia faced an increased risk of heart attack, heart failure and even death, new research shows.

According to the Canadian authors of the study, which is published in the Dec. 12 issue of the Journal of the American Medical Association, this is the first population-based look at the class of drugs to which Avandia belongs and the first report to find an increase in mortality rates.

“Our study looked at an older population in the real world who tend to be underrepresented in research trials and are at higher risk,” said study author Dr. Lorraine L. Lipscombe, a researcher with the Institute for Clinical Evaluative Sciences in Toronto. “While the overall risk versus benefit is difficult to interpret in all people, in older people, the risks may outweigh the benefit.”

“This is very striking data,” added Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation. “This and other studies are going to put tremendous pressure on the FDA [U.S. Food and Drug Administration] to act more forcefully with regard to Avandia.”

But the maker of Avandia (rosiglitazone), GlaxoSmithKline, took issue with the findings.

In a prepared statement, the company said the Canadian study “has significant limitations and generates misleading conclusions regarding acute myocardial infarction and death. These conclusions are inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies, including ADOPT and RECORD. These long-term trials in diabetic patients comparing rosiglitazone to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well-known risk of congestive heart failure with thiazolidinedione (TZDs).”

Nissen was the first scientist to publish concerns about Avandia and increased heart risks in a study last May.

After that and other research was released, the FDA added a “black box” warning to all drugs in the class. An FDA advisory panel voted against removing the drug from the market, citing inconclusive evidence.

The Canadian label for Avandia carries a stronger message: The drug is not to be used as the sole medication for type 2 diabetes unless the patient cannot take another drug to lower blood sugar and that the drug should not be used by any patient with heart failure.

People with type 2 diabetes are already at heightened risk for cardiovascular disease.

Thiazolidinediones including Avandia and Actos (pioglitazone) heighten the body’s sensitivity to insulin. Some 3.5 million U.S. patients take Avandia, which has also been linked to bone loss in some patients.

The current study involved an older (66 and over), “real-world” population consisting of more than 159,000 residents of Ontario in this age group who were treated with at least one oral diabetic medication. The patients were followed for about four years.

Compared to individuals taking more than one oral hypoglycemic agent, people using Avandia on its own had a 60 percent increased risk of congestive heart failure, a 40 percent increased risk of heart attack, and a 29 percent increased risk of dying.

The increased risks were associated with Avandia only, but fewer people in the study took Actos, so the results could be skewed, the researchers noted.

“It looks like the results were limited to Avandia, but 50 percent fewer people were on Actos, so you can’t rule out an increased or decreased risk with Actos,” Lipscombe said. “We need more studies.”

“It’s an observational study and, like all observational studies, this has strengths and weaknesses. These studies do not provide the strength of evidence of a prospective, randomized trial,” Nissen pointed out. “But as observational studies go, this one is very helpful, because it is quite large, and it is independent, not sponsored by any company. Remarkably, with Avandia, the increased risk of heart attack is very similar to what we reported in our meta-analysis last May.”

In related research appearing in the same issue of JAMA, a review of 25 studies found that current smokers have a 44 percent increased risk of developing type 2 diabetes compared with nonsmokers.

The degree of risk was linked to the level of smoking — there was a 61 percent increased risk for those smoking 20 or more cigarettes a day and a 29 percent increased risk for those who smoked less, said the Swiss researchers. Former smokers had a 23 percent increased risk.