For the 200 million diabetics worldwide, the past few years have brought some disturbing findings about risks that may be associated with certain diabetes drugs. Recent concerns that Avandia (rosiglitazone) might cause cardiovascular problems, for example, have led some experts to call for it to be pulled from the market, although it remains available today. And in late June, studies published online by the journal Diabetologia raised questions about a possible link between the diabetes medication Lantus (insulin glargine) and an increased risk of cancer.
The safety worries about these diabetes medications come from scientific studies of varying designs. Some of the research, like that on Lantus and cancer, is based on observational data, which is not always reliable. The concern about Avandia, on the other hand, comes from clinical trials, which are the gold standard of research, and meta-analyses.
The key thing to remember is not to panic when you hear news of safety concerns about a medication you're taking—and definitely don't quit taking a prescribed diabetes drug without asking your doctor first. "Be sure you talk to your healthcare professional before you stop taking any diabetes medication," says Ann Albright, director of the division of diabetes translation at the Centers for Disease Control and Prevention. "You've got to be sure you're keeping your blood sugar and cholesterol" and blood pressure levels under control, she says.
Indeed, the Food and Drug Administration, the American Diabetes Association, and the American Association of Clinical Endocrinologists offered similar advice in response to the recently released studies on Lantus. Here's a look at the concerns raised about cancer risk, as well as four other risks that some experts in the past few years have mentioned about the diabetes drugs Avandia and Actos.
Cancer. The journal Diabetologia recently published four observational studies on its website. Three of those studies suggested a possible increased risk for cancer in those taking Lantus. The studies examined large patient databases, which should add to their reliability. However, inconsistencies among the studies have led experts to doubt whether there truly is an association between Lantus and cancer, the FDA says. The agency is now looking into safety data from these studies and previously completed clinical trials to determine whether such a risk exists. Sanofi-Aventis, the maker of Lantus, says it will continue to monitor the safety of Lantus and will work with the FDA and other regulatory agencies.
"These are provocative studies, but they're really nonconclusive," says Paul Robertson, president for medicine and science at the American Diabetes Association. "It's something that we have to take seriously, but there's just no consensus." Lantus is widely used, he added, and is considered to be a "very useful, very effective drug." Sanofi-Aventis contributes funding for the ADA's professional, patient, and consumer education programs.
Heart problems. The latest trial to investigate Avandia's cardiovascular risk was the RECORD study, which was published in June in the Lancet. In that trial, as in previous research, Avandia seemed to increase the risk of heart failure. The labels for both Avandia and Actos contain warnings that the drugs may cause or exacerbate congestive heart failure in certain patients.
Some studies, but not all, also link Avandia to cardiovascular risks such as heart attack and death. (Avandia's label describes research linking the drug to risk of heart attack.) A 2007 meta-analysis, which was published in the New England Journal of Medicine and prompted the flurry of concern about Avandia, found that people taking Avandia had a higher risk of heart attack and death from cardiovascular causes. But the recently reported RECORD trial, which was sponsored by Avandia manufacturer GlaxoSmithKline, found that taking Avandia did not seem to up the risk of heart attack or death. And another study, published in November in the Archives of Internal Medicine, found that the risk of death and heart failure for older people with diabetes seems to be greater in those taking Avandia than in those taking Actos (pioglitazone), another medication in the same class.
While the findings may be conflicting, the hint of cardiovascular safety issues is enough to worry some. "Any [diabetes] drug that is worth anything needs to decrease the risk of cardiovascular disease," says Sidney Wolfe, editor of worstpills.org and director of the health research group at the consumer advocacy organization Public Citizen. "When a drug increases the risk of cardiovascular disease, it should be off the market," he says. "It's a huge failure that the FDA has not taken it off the market." The FDA says that it is requiring GlaxoSmithKline to conduct a cardiovascular outcome trial on Avandia to provide a definitive answer to whether Avandia poses an unacceptable risk of cardiovascular disease.
Concern about how Avandia affects the heart led Public Citizen to call for a ban on the drug. The nonprofit watchdog group sent a petition to the FDA in October 2008 but so far has not received a response, Wolfe says. FDA spokesperson Karen Riley says that the agency tries to respond to citizen petitions within a 90-day time frame and that the Public Citizen petition is under active review.
"Patients with diabetes have a two-to-four-times greater risk of heart disease than their nondiabetic counterparts, and none of the currently approved antidiabetic therapies has been convincingly proven to reduce that risk," says Riley. Responding to questions raised about Avandia, the FDA in December 2008 instituted tougher standards for approval of diabetes drugs. It now asks drug companies applying for approval of a new diabetes medication to "provide better evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack," Riley says. A medication called alogliptin, which drugmaker Takeda Pharmaceutical Co. had hoped to win approval for this year, will most likely be delayed until 2012 because the FDA has asked the company to conduct a cardiovascular safety clinical trial. Another new diabetes drug, Victoza (liraglutide), has been approved in Europe but not in the United States.
Public Citizen says that Glucophage (metformin) and Glucotrol (glipizide) are safer diabetes treatment options; it does not recommend Actos because the group believes Actos shares some of Avandia's safety problems, except for risk of heart attack. Robert Spanheimer, vice president of medical and scientific affairs at Takeda—which also makes Actos—says that the company acknowledges the drug's possible link to heart failure. He said that people who develop signs of heart failure should seek prompt treatment. Heart failure "is recognizable, [and] it is treatable," he says. "If patients understand the risk and understand the early symptoms, they can go to their doctor and be treated."
GlaxoSmithKline says it stands behind the safety of Avandia. "We think that it's been shown to be a safe and effective treatment for type 2 diabetes for the appropriate patient," says Mary Anne Rhyne, a GlaxoSmithKline spokesperson. The RECORD study "addresses some of the [previous] concern, and we feel like it reinforces its safety for long-term glucose control for diabetes patients."
Eye risks. People taking medications in a class of drugs called thiazolidinediones, also known as glitazones—comprising Avandia and Actos—appear to be at higher risk for macular edema, according to a study published in April in the American Journal of Ophthalmology. (Macular edema occurs when the macula—the portion of the retina responsible for sharp central vision—swells as a result of leaking fluid.) While the authors said that more research is needed, they noted that eye doctors should consider the role of glitazones when treating patients who have macular edema. The labels for Avandia and Actos warn that anyone taking the medication who experiences vision problems should promptly see an ophthalmologist. (In a bit of good news, a separate study found that Avandia may help to slow certain types of eye disease.)
Fractures. Both Avandia and Actos appear to increase the risk of bone fractures in women—but not in men, according to a meta-analysis published in December 2008 in the Canadian Medical Association Journal. Researchers looked at 10 clinical trials involving more than 13,000 diabetics who were taking Avandia, Actos, or neither medication. The medications seemed to reduce bone density in the hips and spine of the women taking them—which researchers estimated could double the fracture risk in these women.
The research team theorized that the difference between men and women observed in this analysis may exist partially because women have small er , thin ner bones. Also, these medications may interact with estrogen in the body, resulting in weakening bones. The RECORD trial published in June also found an increased risk of fractures among women taking Avandia. The labels for Actos and Avandia both contain warnings about increased fracture risk in women.
Liver problems. Public Citizen says it has identified 14 cases of liver failure induced by Avandia, including 12 deaths, which occurred between 1997 and 2006. The group used the FDA's Adverse Event Reporting System to identify these cases. Many of the patients, according to Public Citizen, had gotten liver-function tests not long after starting Avandia, and the results were ei ther normal or mildly elevated. The people whose cases Public Citizen examined took Avandia for anywhere from half a week to more than four years . Liver toxicity has also been observed in rats, mice, and dogs that were given Avandia, according to Public Citizen's petition to the FDA. The FDA didn't respond to requests for comment about Public Citizen's analysis of liver risks. Rhyne, the GlaxoSmithKline spokesperson, says the company does not believe there is a link between Avandia and liver failure.