Letter Urging Rejection of Diabetes Drug Muraglitazar (Pargluva)
November 21, 2005
Andrew Von Eschenbach, M.D.
U.S. Food and Drug Administration
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Von Eschenbach:
We are writing to expand upon our concerns regarding the possible approval of the diabetes drug muraglitazar (Pargluva), a drug with no proven benefit on cardiovascular end points but with a demonstrated unique toxicity profile. Based upon currently available data, muraglitazar should not be approved.
In testimony before the Food and Drug Administration’s (FDA’s) Endocrine and Metabolic Drugs Advisory Committee on September 9, 2005, Public Citizen presented information based on FDA briefing documents relating to the striking increase in deaths due to treatment with muraglitazar (a PPAR alpha/gamma inhibitor). Deaths from any cause were increased by approximately 2.5-fold in muraglitazar treated patients compared to pioglitazone (a PPAR gamma inhibitor); about half of the muraglitazar deaths were due to cardiovascular causes.
The dose-related nature of muraglitazar deaths is of particular note: the relative risk of death from any cause (vs. placebo) increased from 1.7-fold (at 2.5 mg) to 4.6-fold (at 5 mg); the relative risk of death from cardiovascular causes increased from 2.0-fold (at 2.5 mg) to almost 6-fold (at 5 mg). Increases in edema and congestive heart failure (CHF) seen with the 10 and 20 mg doses caused the sponsor to limit the proposed marketing doses to the 2.5 mg and 5 mg, which is not a comforting margin of safety given the great variability in the responses of humans to pharmaceuticals.
At the advisory committee meeting, the sponsor presented evidence of a “dose-dependent increase in heart failure risk with muraglitazar ... with a higher risk for the 10 and 20 mg doses.” Its slide showed the risk continually increasing as the dose increased from 2.5 mg and as time on the drug increased. (slide 63)
Despite this evidence, the advisory committee voted 8-1 to approve muraglitazar as monotherapy and 7-2 to approve it in combination with metformin; only the combination with sulfonylurea was voted down, 2-7. The committee based its positive conclusions on the understanding that the sponsor would, according to the Division Director, “continue formal investigations of muraglitazar, including an eventual morbidity and mortality trial which ... is still in the planning stage and awaits the results of two important landmark studies ... for its final design.” Asking advisory committees to vote based on vague promises from industry to conduct studies with unknown outcomes is inappropriate. The lack of a cardiologist on the advisory committee prevented an area that was key to the evaluation of the drug’s safety from being analyzed adequately.
The FDA itself was apparently not convinced of muraglitazar’s safety, since on October 18, 2005, according to press reports, the FDA issued an approvable letter to the sponsor that the company says asks for information on heart risk that would require 5 years to obtain. The public does not have access to the sponsor’s protocol and few details have been provided. However, the material presented by the company at the advisory committee meeting indicates that it plans a pharmacoepidemiology study based on data from a managed healthcare database. In this type of study, patients may change drugs, stop taking a drug, or move away, weakening any conclusions. The only way to answer the question of whether muraglitazar causes cardiovascular and other deaths is with a randomized, controlled clinical trial and not with this type of epidemiological study.
Two days after the approvable letter was sent, Nissen et al. published a reanalysis of the sponsor’s data, based also on the material posted by the FDA on its website. These researchers limited their analyses to doses of 5 mg or less (the sponsor is seeking approval of 2.5 and 5 mg doses), pooled pioglitazone and placebo patients to compare to muraglitazar, and used as the primary outcome measure a composite end point commonly used in cardiovascular trials: the combined incidence of death, heart attack, or stroke (increased 2.2-fold, p=0.03). They also looked at five other composite end points and six individual end points. All twelve end points showed increases in relative risk of more than 2-fold with the relative risk of all-cause mortality plus nonfatal heart attack, stroke, CHF or transient ischemic attack increasing 2.6-fold (p=0.004) and adjudicated CHF increasing over 7-fold (p=0.053). The authors concluded that “The consistency in magnitude and direction of the adverse effects across multiple cardiovascular end points reduce[s] the likelihood that these findings result from chance alone.” They further concluded that muraglitazar “should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.”
An additional analysis critical of muraglitazar appeared in the same issue of JAMA. In an accompanying editorial, James Brophy pointed out that the sponsor had diluted out the muraglitazar adverse events by including in the denominator patients taking less than the proposed marketed doses, a group of patients who had no cardiovascular events. He also pointed out that there were only 25 patients with mild CHF symptoms, an unacceptably small number given the population that is likely to take this drug. He worried that the increases in body weight, edema, and CHF (13 adjudicated cases of CHF in muraglitazar-treated patients compared with only one in the placebo group) posed serious concerns for the health of patients. His analysis, like Nissen’s, used the proposed marketed doses, but he adjusted for patient-years of exposure to obtain a 1.35-fold increase in CHF for muraglitazar-treated patients compared to placebo and a 1.9-fold increase in CHF when compared to a combined placebo/pioglitazone control group.
Thus, four analyses of cardiac adverse events have now been done: that of the sponsor, the FDA, Nissen et al. and Brophy (Public Citizen presented data from the FDA analysis at the advisory committee but did not perform any new analyses). The latter two independent groups did their own analyses using slightly different methods, but all came to the same basic conclusion: muraglitazar causes an increase in heart failure.
The risk of cancer is another reason for unease. As calculated by Brophy, the incidence of cancer in the muraglitazar-treated group of patients was more than 3-fold higher than that seen in placebo patients. He concluded that, “this is a worrisome observation that requires immediate further study as a very large increase in cancer risk cannot be excluded with the limited available data.” Although microscopic hematuria may be the earliest sign of bladder cancer, and the sponsor monitored patients for this, they never did a statistical analysis of the incidence of this condition, nor did they provide specific information on microscopic hematuria from the long-term phases of their studies. There were four cases of bladder cancer in their trials, two with muraglitazar and two with pioglitazone.
The FDA’s pharm/tox reviewer stated in her testimony before the advisory committee that, because of multiple tumor findings in both mice and rats of both sexes, the Environmental Protection Agency and the International Agency for Research on Cancer, would classify the PPAR gamma and dual agonists as “probable human carcinogens.” Furthermore, she stated that “The sites of tumor development with PPARs are consistent with the distribution of the receptors”: bladder, adipose tissue, and gallbladder. Although the bladder tumors occurred at more than 8 times the expected clinical exposure, this level has clinical relevance when a large, variable human population is exposed. It also does not allow for the possibility that humans may have increased susceptibility to the carcinogenic properties of muraglitazar.
Public Citizen, along with the undersigned, urges the FDA not to approve muraglitazar before a careful examination of data from a 5-year randomized controlled trial. However, we question why a drug that an FDA medical officer has concluded causes dose-related edema, weight gain, and congestive heart failure needs to be approved for diabetic patients who are already at increased risk for cardiovascular adverse effects and who already have multiple drugs available to treat their conditions.
Elizabeth Barbehenn, Ph.D.
Peter Lurie, M.D., M.P.H.
Sidney M. Wolfe, M.D.
Public Citizen's Health Research Group
Curt Furberg, M.D., Ph.D.
Professor of Public Health Sciences
Wake Forest University School of Medicine
James M. Brophy, M.D., FRCPC, Ph.D.
Department of Medicine
 Saul S. Article says diabetes pill would increase coronary risks. The New York Times, October 21, 2005.
 Martinez B. Bristol may end the development of diabetes drug. The Wall Street Journal; October 28, 2005.
 Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294. Published online: October 20, JAMA.(doi:10.1001/jama.294.20.joc50147). Accessed November 3, 2005.
 Brophy JM. Selling safety- lessons from muraglitazar. JAMA 2005;294. Published online: October 20, 2005. Available at (doi:10.1001/jama.294.20.jed50074). Accessed November 3, 2005.
 The Merck Manual of Diagnosis and Therapy. 17th edition; chapter 233, section 17.