Experts ponder rosiglitazone use.
The 2-hour session featured presentations from Dr. Steven E. Nissen and Dr. Philip D. Home, along with panelists Dr. David M. Nathan, Dr. Barry J. Goldstein, and Dr. John B. Buse.
Dr. Nissen, of the Cleveland Clinic, reviewed the results of his meta-analysis of 42 trials that revealed a significant increase in the risk of MI with rosiglitazone (N. Engl. J. Med. 2007;356:2457-71).
Dr. Home, of Newcastle University, Newcastle upon Tyne, England, then summarized the inconclusive findings of the 3.75-year analysis of data from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, designed as a 6-year trial to assess the safety of rosiglitazone (INTERNAL MEDICINE NEWS, June 15, 2007, p. 18). The unplanned interim analysis had been published rapidly in response to the media attention (N. Engl. J. Med. 2007 June 5 [Epub doi:10.1056/NEJMoa073394]) and congressional scrutiny garnered by Dr. Nissen's report.
During the animated debate that followed, some audience members criticized Dr. Nissen for publishing his analysis before the RECORD study was completed, noting that the publicity led patients to drop out of the trial.
But Dr. Nissen defended his efforts to bring the attention of the medical community to the elevated risk, stating: "We didn't call for withdrawal of the drug. We didn't call for regulatory action. We simply said we want you and others who treat these patients [to be aware] of the findings.... The alternative would be to keep the scientific community in the dark."
Dr. Nathan, who is chief of the Diabetes Center at Massachusetts General Hospital, Boston, and who authored editorials for both Dr. Nissen's and Dr. Home's articles, remarked, "There are insufficient data to come to any conclusions that would convince us all. That has given rise to this enormous controversy, as well as the obvious impact on patients and the economic impact on the company."
Dr. Buse, who had testified before Congress on June 6 about his efforts to bring attention to rosiglitazone's safety issues as far back as 1999 (INTERNAL MEDICINE NEWS, June 15, 2007, p. 18), said that a joint meeting of the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, scheduled for July 30, is likely to bring forth all available data.
In the meantime, Dr. Buse--along with Dr. Goldstein and Dr. Nathan--offered advice about how they would approach three clinical scenarios presented by ADA chief scientific officer Richard Kahn, Ph.D., who moderated the panel:
* A patient with diabetes in poor control who is not currently taking rosiglitazone. Dr. Buse and Dr. Nathan agreed that they would not start a patient on rosiglitazone (Avandia) at this point, at least until more data become available.
Dr. Nathan pointed out that the well-known adverse lipid profile of rosiglitazone, compared with pioglitazone, already made it a less attractive option. Indeed, he said, the data on fluid retention and heart failure--combined with the newer data on fractures and decreased bone density--render the whole thiazolidinedione (TZD) class less attractive than other agents.
But Dr. Goldstein suggested that rosiglitazone in low doses might still play a role in combination therapy in patients with insulin resistance. He advised following the ADA's 2006 treatment algorithm, which recommends metformin as first-line therapy with the TZDs as a possible add-on in patients who don't achieve glycemic goals (Diabetes Care 2006;29:1963-72).
"At a lower dose, they can be used in combination," said Dr. Goldstein, director of endocrinology, diabetes, and metabolic disease at Jefferson Medical College, Philadelphia.
* A patient with diabetes who is in good control on a regimen that includes rosiglitazone. All three panelists felt that they wouldn't rock the boat in this situation. "There would be more risk to switching someone ... over the next 1.5-2 months ... until we know everything we're going to know for the next 2 years," when the RECORD results are available, Dr. Buse said.
Dr. Goldstein said that such a patient "should certainly stay on either [TZD] until we learn more." And, said Dr. Nathan, "I would think twice about changing someone who's achieving all the other goals."
* A patient with diabetes who is taking rosiglitazone but is not in good control. All three felt that consideration should be given to stopping rosiglitazone in this situation. Dr. Buse remarked, "If you're going to have to rethink the regimen, I think it's appropriate to rethink the Avandia as well."
Dr. Goldstein noted that such patients are often taking several oral glucose lowering agents, most commonly metformin and a sulfonylurea in combination with a TZD, and that insulin is generally considered to be the next step. Given that it's rare for patients to be on insulin combined with three oral agents, and that the weight gain and fluid retention problems associated with TZDs are often exacerbated by insulin, "the TZD is often the one that's dropped when insulin is added."
Dr. Nathan was more direct: "If the patient is not achieving goals, I would stop Avandia and change the regimen."
Dr. Buse disclosed no financial ties with either GlaxoSmithKline Inc., maker of rosiglitazone, or Takeda Pharmaceutical Co., maker of pioglitazone. Dr. Goldstein has ties to both, whereas Dr. Nathan has received research support from GSK. All three have relationships with makers of other diabetes drugs.
BY MIRIAM E. TUCKER
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|Author:||Tucker, Miriam E.|
|Publication:||Internal Medicine News|
|Date:||Jul 15, 2007|
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