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The New England Journal of Medicine (NEJM) rocked the diabetes world recently when it published a study led by Steven E. Nissen, MD, indicating a 43% higher rate of heart attacks among diabetes patients on the widely prescribed thiazolidinedione (TZD) rosiglitazone (Avandia, GlaxoSmithKline) versus other diabetes drugs.1 A second, marginally significant finding indicates a 64% higher rate of cardiovascular death among patients taking rosiglitazone.
The Food and Drug Administration (FDA) issued a safety alert, then revealed at a June 6 congressional hearing that it has asked GlaxoSmithKline (GSK) and Takeda Pharmaceutical Co. Ltd.—manufacturer of the other FDA-approved TZD, pioglitazone (Actos)—to put "black box" warnings about congestive heart failure risks on both products' labels.2
The agency, however, also states the available rosiglitazone data on ischemic heart disease risk are "contradictory."3 The FDA expects more conclusive data to come from several ongoing, longer-term rosiglitazone trials.3
The American Diabetes Association (ADA), American College of Cardiology, and American Heart Association note in a measured joint statement that the overall heart risk reported in the study is small.4 In a seperate statement, ADA urges patients to consult their providers about the drug's benefits and risks.
"We don't want patients to just stop taking the drug, but they should talk to their health provider about what to do," says Sue Kirkman, MD, ADA's vice president of clinical affairs.
Therein lies the dilemma for physicians: How should they advise the legions of patients calling with rosiglitazone questions? On one end of the spectrum, clinicians are watching and waiting. On the other end, they are taking all their patients off rosiglitazone, sometimes switching them to pioglitazone, and sometimes taking them off all TZDs. Physicians taking a middle-of-the-road position are discontinuing rosiglitazone only in patients with the highest cardiovascular disease (CVD) risk and more closely monitoring those who stay on the drug.
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IMMEDIATE TREATMENT DECISIONS
Physicians find themselves in a tough position, says University of Alabama endocrinologist Fernando Ovalle, MD. Rosiglitazone has become a mainstay of diabetes treatment because of its effectiveness in lowering glycated hemoglobin (A1C), he explains. Authorities such as ADA put TZDs on par with insulin and sulfonylureas as a second-line treatment for type 2 diabetes.5
The recommended first-line treatment is metformin plus lifestyle intervention, but that combination may not drop A1C enough, Ovalle says. Many physicians choose to add TZDs to the regimen, he says, because these drugs tend to help patients hit A1C goals without inducing hypoglycemia.
But with possible increased cardiac risks, what's a physician to do? Here are some reported approaches:
STAY THE COURSE
Ovalle is reviewing the research with patients and recommending they stick with rosiglitazone.
"I explain that Nissen's study is not well designed and advise them to wait," he says. "I don't think we should rush to do anything. Let's wait for the dust to settle and let the organizations that lead clinical practice make recommendations based on the research."
That said, if Ovalle's patients request a switch or do poorly on rosiglitazone, he says he'll switch them to pioglitazone. If they don't want a TZD, he'll prescribe insulin, which he likes less because of adherence and glucose control challenges. Ovalle notes that his own research suggests rosiglitazone helps recovery of pancreatic beta-cell function.6 He also discloses that he has received funding from GSK and its speakers bureau.
Like Ovalle, Barry Goldstein, MD, director of the endocrinology and
metabolism division at Thomas Jefferson University Hospital in Philadelphia,
is advising patients that "a real risk of Avandia hasn't been
proven." Goldstein says many patients do well on the drug and notes
other diabetes drugs pose their own risks. Each patient needs a customized
"cocktail" to reach ADA's 
7% A1C goal, he says.
"Dropping one medication will almost always make the blood sugar go up," says Goldstein, who also discloses that he has received funding from GSK.
LET PATIENTS DECIDE
Jim Applegate, MD, a primary care physician in private practice in Grand Rapids, Mich., is giving patients three options:
Applegate says patients tend to come to him panicked about the study portrayals they've seen in the media. Once he explains the relatively small heart attack risk, they calm down. Still, most of Applegate's patients have asked to discontinue rosiglitazone.
"Most of my patients are already on metformin and sulfonylureas, so I don't expect to see a massive change in blood sugar," he says.
A few patients have stayed with rosiglitazone, and a few with particular glucose-control difficulties have traded it in for insulin, sitagliptin (Januvia, Merck), or exenatide (Byetta, Amylin/Lilly), Applegate says.
Another primary care physician, Andrew Carroll, MD, recommends pioglitazone to patients worried about staying on roziglitazone. If, after he explains the research to them, they opt to stay on roziglitazone, he keeps prescribing it. But, either way, the patients must decide, says the private practitioner in Chandler, Ariz. Why? To avoid legal fallout, he says.
"There's been enough legal precedent for situations like this that end up with litigation," says Carroll.
SWITCH THE RISKIEST
James Chamberlain, MD, a diabetologist at Utah Diabetes Center in Salt Lake City, believes TZDs' drawbacks outweigh the benefits. He is putting his rosiglitazone patients with known CVD risks on different drugs. He'll use more insulin, but his favorite alternative is exenatide, which he says helps with weight loss.
And while he doesn't think it's fair to lump all TZDs together, Chamberlain is concerned about pioglitazone. "I have very few patients on TZDs in the first place," he says. "I've always thought weight gain can't be the right way to treat diabetes."
INTENSIFY PATIENT MONITORING
Chamberlain plans to step up stress echocardiography and myocardial perfusion stress testing for signs of coronary artery disease (CAD) in patients who stay on rosiglitazone.
By comparison, he does not advocate stress EKG testing in these patients. "It's not sensitive enough for diabetics. There are too many false negatives—it misses too many people who truly have CAD."
Chamberlain also will use coronary artery calcium scoring, which he considers sensitive and cost-effective.7
SWITCH ALL PATIENTS
Curt D. Furberg, MD, PhD, a public health sciences professor at Wake Forest University School of Medicine in Winston-Salem, N.C., plans to switch all his patients who are taking TZDs to different drugs. Given the ischemic risk, discontinuing rosiglitazone is the best choice, says Furberg, who co-authored a NEJM editorial criticizing the FDA's handling of the drug.8 Furberg says in-press research he's conducted indicates pioglitazone also poses heart failure risks, in line with the updated boxed labeling requested by the FDA.
"If my wife were on a TZD, I'd switch her," Furberg says. "You don't gamble when treating patients. You play it safe."
Others appear to share Furberg's view: Avandia's stock tumbled, and prescriptions for the drug dropped markedly in the weeks following publication of Nissen's study.
Yet more questions than answers remain. Only time—and more
research—will tip that balance. 
References
2. Food and Drug Administration: FDA issues safety alert on Avandia (press release). May 21, 2007. Available online at http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html. Accessed June 4, 2007.
3. Food and Drug Administration/Center for Drug Evaluation and Research: Information for healthcare professionals: Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) (FDA alert). May 2007. Available online at http://www.fda.gov/cder/drug/InfoSheets/HCP/rosiglitazoneHCP.htm. Accessed June 4, 2007.
4. American Diabetes Association: Statement from the American College of Cardiology, American Diabetes Association, and American Heart Association related to NEJM article, "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes." Available online at http://diabetes.org/diabetesnewsarticle.jsp?storyId=15115339&filename=20070521/comtex20070521pr00004113diabetesavandiariskEDIT.xml. Accessed June 4, 2007.
5. American Diabetes Association: Standards of medical care—2007. Diabetes Care 30 (Suppl. 1):S1 –S41, 2007.
6. Ovalle F, Bell DS: Effect of rosiglitazone versus insulin on the
pancreatic beta-cell function of subjects with type 2 diabetes.
Diabetes Care 27:2585–2589, 2004.
7. Anand DV, Lim E, Hopkins D, et al.: Risk stratification in
uncomplicated type 2 diabetes: Prospective evaluation of the combined use of
coronary artery calcium imaging and selective myocardial perfusion
scintigraphy. Eur Heart J 27:713–721, 2006.
8. Psaty BM, Furberg CD: Rosiglitazone and cardiovascular risk (editorial). N Engl J Med [Epub ahead of print May 21] 2007. Available online at http://content.nejm.org/cgi/content/extract/NEJMe078099v1. Accessed June 4, 2007.
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