Patients with diabetes have alternatives to rosiglitazone, experts say

July 22, 2010

Alexandria, VA - Clinicians do not lack for alternative therapies if patients with type 2 diabetes ask to be switched from rosiglitazone (Avandia, GlaxoSmithKline) to another glucose-lowering medication, according to the American Diabetes Association (ADA) and two other expert groups.

Rosiglitazone, one of two FDA-approved medications in the thiazolidinedione (TZD) class—the other is pioglitazone (Actos, Takeda Pharmaceuticals)—is again under increased scrutiny over possible cardiovascular risks.

Last week at a joint session of two of the agency's advisory panels, 12 of 33 voting members of the combined panel voted against keeping rosiglitazone on the US market, as reported by heartwire . The remaining 20 votes were divided among several options for retaining the drug with varying degrees of warnings or restrictions. In a separate vote, a majority of the combined panel contended that rosiglitazone isn't as safe as pioglitazone.

The FDA itself has yet to decide on the drug's fate.

"I don't think any physician or patient should worry that they don't have a good option if they're uncomfortable with Avandia," Dr Richard Bergenstal (Park Nicollet Health Services, St Louis Park, MN), ADA president of medicine and science, told heart wire .

He said published clinical algorithms can guide physicians in selecting the right drug or combination of drugs. Such algorithms take into account factors such as efficacy, the risk for hypoglycemia, weight gain, and other adverse effects, as well as cost.

In their joint statement released July 12, 2010 the ADA, the Endocrine Society (ES), and the American Association of Clinical Endocrinologists (AACE) urged patients now receiving rosiglitazone to continue taking it unless they receive instructions from their healthcare provider to the contrary.

"Until further clarification is provided by the FDA, the decision whether or not to use any medication must remain that of the treating provider in direct discussion with the individual patient," the groups said.

Physicians now are waiting for the FDA to decide whether the drug will remain available. The agency has promised to evaluate the advisory committee proceedings and reach a decision as quickly as possible.

Regardless of the FDA's verdict, physicians and patients alike should know that there are multiple classes of drugs that can be used to maintain glucose control in patients with type 2 diabetes, according to the statement from the ADA, ES, and AACE. Those classes include, besides the TZDs, the sulfonylureas, meglitinides, biguanides, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors. The ADA lists these classes on its website.

Consensus statement goes against rosiglitazone use

In June, the ADA announced on its website that it does not have an official position favoring or recommending against FDA-approved medications to lower glucose. Such positions, however, do appear in a consensus statement of the ADA and the European Association for the Study of Diabetes (EASD) that was published in Diabetes Care in January 2009[1]. (The ADA notes that this consensus statement "does not reflect the official position of the ADA but rather the expert opinion of the authors.")

For most patients with type 2 diabetes, the consensus statement recommended as a "well-validated core therapy" a combination of lifestyle changes—namely, weight loss and increased physical activity—and metformin, which belongs to the biguanide class. If this first-tier therapy fails to achieve or maintain glycemic goals, clinicians can prescribe either insulin or a sulfonylurea (except for chlorpropamide or glibenclamide) in addition to metformin.

The consensus group unanimously advised against prescribing rosiglitazone, although it noted that the evidence on the drug's cardiovascular risk is "not conclusive." However, the group found a second-tier use for the other TZD, pioglitazone: clinicians can consider it when "hypoglycemia is particularly undesirable (eg, in patients who have hazardous jobs)."

There is no dearth of algorithms for the role of medications in glycemic control. The AACE and the American College of Endocrinology (ACE) published one last year that lays out a path from monotherapy to triple therapy[2]. The algorithm prioritizes choices of medication based on "safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and the cost of medications." The guidelines from AACE and ACE do not contain a blanket statement against prescribing rosiglitazone.

Bergenstal's center has developed its own algorithm. Similar to the consensus statement of the ADA and EASD, it recommends pioglitazone, but not rosiglitazone, as part of dual or triple drug therapy when clinicians are targeting insulin resistance.

Switching to a new diabetes drug could pose greater risks

The joint statement from the ADA, AACE, and ES informs clinicians and patients that they have alternatives to rosiglitazone but does not advise physicians to automatically switch patients from this drug to something else. That advice echoes that of AACE president Dr Daniel Einhorn (Scripps Whittier Diabetes Institute, La Jolla, CA).

If patients tell him that they are worried about continuing with rosiglitazone, Einhorn said, he will discuss other drug therapies. However, he has not asked patients to stop using rosiglitazone, at least not yet.

"So far, there is no FDA signal to discontinue the drug," he said. "All we can say is that serious safety questions have been raised. If you've done well on Avandia for years, why switch to another drug that may come with more risks for you?"

At the same time, Einhorn said he is no longer writing new prescriptions for rosiglitazone while the drug is under FDA review, and he doubts that any other physicians are writing them. He acknowledged that the status of the drug is confusing for clinicians, but then, so are the safety data that the FDA advisory committee heard.

"If the data were clear," Einhorn said, "we wouldn't be having this discussion."


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