Switch Pitch? Think Beyond TZD Ads When Taking Patients Off Rosiglitazone

Shelley Wood

February 23, 2011

February 23, 2011 (New Haven, Connecticut) — One day after last year's FDA joint advisory committee delivered its mixed message on the cardiovascular safety of rosiglitazone (Avandia, GlaxoSmithKline), the company making the only other drug in the same class unleashed a major direct-to-consumer advertising campaign stressing the safety of its drug, including full-page ads in the New York Times.

Now, authors of a comment published online in the Journal of the American Medical Association (JAMA) today are urging physicians to consider a wider range of options for diabetic patients needing to switch off rosiglitazone, rather than defaulting to pioglitazone (Actos, Takeda), the only other drug in the thiazolidinedione (TZD) class [1].

"With the mounting data suggesting risk with rosiglitazone, many physicians have been dealing with the fact that they have been advising patients to switch from rosiglitazone to another medication," first author on the comment, Dr Kasia J Lipska (Yale University, New Haven, CT), told heartwire . "And what we wanted to bring to light is that the decision making with the patient about which medications should be used should consider all available options and not automatically involve switching from rosiglitazone to pioglitazone, as the ads suggest."

"Think Outside the Class"

Lipska and coauthor Dr Joseph S Ross (Yale University) point out that there is little in the way of comparative effectiveness studies for diabetes drugs, particularly concerning long-term cardiovascular outcomes, but that physicians don't necessarily "think outside the class" when it comes to substituting one drug for another, even when cheaper and safer drugs are available.

One reason is the way prescription plans are "tiered," Lipska explains. For example, she says, "we switch from one proton-pump inhibitor to another because the insurance company pays for one and not the other. We're familiar with that, so we assume, sometimes erroneously, that drugs in the same class are similar, and oftentimes they are. Now with rosiglitazone and pioglitazone, obviously they're not, but the assumption is, well we've used one drug in a class and now we want to switch to one that's very similar without the apparent increased risk for CV events, so wouldn't that be the easy [answer]?"

While the increased risk of MI and stroke with rosiglitazone has dominated headlines in recent years, pioglitazone has its own share of significant cardiovascular side effects, chief among them heart failure--a risk it shares with rosiglitazone. As Lipska and Ross point out, neither TZD "matches the safety, tolerability, and low cost of metformin," although Lipska stressed that she's suggesting not that there is just "one right choice" but that decisions need to be tailored to individual patients.

"The first question is, how well is the patient doing currently on their regimen? Is there even a need to substitute the medication? Could exercise, diet, and lifestyle modification be substituted, and has that been tried? The second question is, if another drug is needed, would the patient qualify for metformin, which is the recommended first-line therapy?"

If not, she continues, then the discussion between physicians and patients should be about all the other diabetes drugs, including sulfonylureas and insulin, as well as pioglitazone.

Most Patients Will Need Drugs

Commenting on Lipska and Ross's article, Dr Stephen J Nicholls (Cleveland Clinic, OH) agreed that the question of just how to manage patients deemed inappropriate for rosiglitazone has dogged physicians ever since the first questions were raised about the drug safety, and he echoes their lament about the lack of comparative data. But he resists the notion that pioglitazone is not a reasonable choice for some patients, pointing to a range of potential benefits of the drug on HDL, triglycerides, inflammation, and coronary plaque progression, suggested in the PERISCOPE and PROactive studies.

"We just have no evidence from big trials, but I think to say that the step . . . of swapping your patient from rosiglitazone to pioglitazone is harmful or is continuing along a harmful path is probably a little premature."

Given that the contraindications for rosiglitazone are in many cases similar to those for pioglitazone, Nicholls believes physicians would have had reservations about an in-class switch even before the FDA issued its most recent warnings, although in some cases, it's not a bad choice.

"In our institution, there have been patients who have been swapped to pioglitazone and there have been patients swapped to other oral glycemic therapies, and that has largely been tailored on the basis of the clinical context--what the lipid [profile] looks like, who the patient is in general. But the most critical thing is that the overwhelming majority are ultimately transitioned to other therapies."

Most patients, he notes, would have been put on rosiglitazone after failing conservative management (with diet and lifestyle), so a nondrug strategy is unlikely to control their disease. Moreover, he points out, "If a doc took the decision to put someone on rosiglitazone as opposed to metformin in the first place, why did they do that? And if they can't treat their patient with rosiglitazone, do they go back to the drug that they didn't want to use in the first place? Or do they use pioglitazone, which has potential beneficial effects, albeit balanced against the side effects?"

Specific Professional Advice Lacking

From the start, physicians have had mixed feelings about just how they should respond to the mostly negative conclusions of the FDA's advisory meeting. Meanwhile, as Lipska pointed out to heartwire , professional advice from the American Diabetes Association and the European Association for the Study of Diabetes following regulatory decisions about rosiglitazone has emphasized the need for patients to remain on their medication until they could discuss options with their doctors, but neither organization provided any specific decision-making process or algorithm.

The Takeda pioglitazone ad campaign was first reported by Medical Marketing and Media last year; this week's JAMA paper is published just weeks after the FDA announced the details of rosiglitazone's beefed-up warning label. In Europe and other parts of the world, rosiglitazone was removed from the market altogether, after authorities determined that its cardiovascular risks outweighed any benefits of the drug.

Lipska and Ross reported having no conflicts of interest. Nicholls disclosed receiving consulting fees and research support from Takeda and receiving consulting fees from Roche and serving on its steering committee for Roche's a leglitazar study