"Approvable" Diabetes Drug May Be Harmful

Laurie Barclay, MD

Oct. 21, 2005 — Although muraglitazar (Pargluva; Bristol-Myers Squibb/Merck) has been recommended for approval by the U.S. Food and Drug Administration (FDA) in patients with type 2 diabetes mellitus, a current analysis published online in the Oct. 20 issue of JAMA suggests that the drug may be harmful, with increased risk of death and major adverse cardiovascular events.

"Peroxisome proliferator–activated receptors (PPARs) are nuclear transcription factors that modulate gene expression," write Steven E. Nissen, MD, from the Cleveland Clinic Foundation in Ohio, and colleagues. "Therapeutic agents targeting two distinct families of PPARs (alpha and gamma) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by an FDA advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes."

To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with control subjects, the investigators reviewed phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting.

These trials were prospective, randomized, double-blind, multicenter studies enrolling a total of 3,725 patients with type 2 diabetes and hemoglobin A1c levels between 7% and 10%. In trials ranging from 24 to 104 weeks, patients were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide. The main end point was the incidence of death, nonfatal MI, or nonfatal stroke, and a more comprehensive composite end point included these events plus the incidence of CHF and TIA.

Death, MI, or stroke occurred in 35 (1.47%) of 2,374 patients treated with muraglitazar, and in nine (0.67%) of 1,351 patients in the combined placebo and pioglitazone treatment groups (controls; relative risk [RR], 2.23; 95% confidence interval [CI], 1.07 - 4.66; P = .03).

The more comprehensive end point that included TIA and CHF occurred in 50 (2.11%) of 2,374 patients treated with muraglitazar and in 11 (0.81%) of 1,351 controls (RR, 2.62; 95% CI, 1.36 - 5.05; P = .004). For each of the individual components of the composite end point, relative risks exceeded 2.1, but these were not statistically significant. Adjudicated CHF occurred in 13 (0.55%) of 2,374 muraglitazar-treated patients and in one (0.07%) of 1,351 controls (RR, 7.43; 95% CI, 0.97 - 56.8; P = .053).

"Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF," the authors write. "This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial."

The authors state that an advisory committee for the FDA's Endocrinology and Metabolic Drugs Division reviewed the trials incorporated in this analysis at an open public hearing on Sept. 9, 2005, and recommended approval of the drug as monotherapy for type 2 diabetes (by an 8:1 vote) and as combination therapy in patients with blood glucose not adequately controlled with metformin (by a 7:2 vote).

"With any new class of pharmaceutical agents, unexpected toxicity may emerge during the development program," the authors note. "However, in some cases, pharmaceutical sponsors defer or withhold publication of phase 2 and 3 clinical trial data until after drug approval. Accordingly, documents submitted to the FDA for consideration of approval may constitute the only publicly available source of objective information for newly approved pharmaceutical agents."

Compounding the concerns regarding the clinical risk associated with muraglitazar are the relatively short duration of exposure in the reviewed trials, the likely enrollment of the lowest-risk strata of patients, and possibility of an interaction between muraglitazar and other antidiabetes therapies. Furthermore, the efficacy for muraglitazar consisted of laboratory end points, namely a lowering of blood glucose, reduction in triglycerides, and increase in high-density lipoprotein cholesterol, as achieved by demonstrably safer drugs, but not lowering of low-density lipoprotein levels.

"Taken as a whole, these data demonstrate that it is likely that muraglitazar, if approved by the FDA, would constitute an unacceptable patient hazard," the authors conclude. "It is particularly important to weigh the efficacy results against the safety concerns.... Our findings emphasize the need for robust safety data for this class of drugs prior to regulatory approval."

Limitations of this analysis include lack of access to the original trial databases; lack of availability of the exact definitions for MI, stroke, and other events; adverse events other than CHF not centrally adjudicated; small number of analyzed events; inability to use time-to-event analysis; and the number of events too few to perform formal testing for heterogeneity.

Dr. Nissen reports various financial arrangements with AstraZeneca, Abbott, Atherogenics, Bayer, Lipid Sciences, Wyeth, Novartis, Pfizer, Sankyo, Haptogard, Hoffman-LaRoche, Kemia, Takeda, Kowa, Sanofi-Aventis, Protevia, Novo-Nordisk, Eli Lilly, Kos Pharmaceuticals, GlaxoSmithKline, Forbes Medi-tech, Vasgenix, Vascular Biogenics, Isis Pharmaceuticals, Viron Therapeutics, Roche, and Merck–Schering Plough. The authors did not receive any financial support for this analysis.

In an accompanying editorial, James M. Brophy, MD, FRCPC, PhD, from McGill University in Montréal, Quebec, Canada, states that lessons learned from this experience should be more universally applied. Despite potential limitations of this analysis, the authors felt confident in recommending that approval of muraglitazar be delayed pending a dedicated cardiovascular trial. However, the sponsor's presentation to the FDA advisory committee concluded that there was no significant excess risk of deaths or cardiovascular events with muraglitazar treatment.

Dr. Brophy cites specific methodological decisions in the sponsor's FDA application that may have overestimated the safety profile:


Selecting a study population at low risk for adverse outcomes but nonrepresentative of potential future users, such as exclusion of elderly patients;

Conducting studies underpowered to detect meaningful safety differences, and maximizing rather than minimizing type II errors;

In contrast to efficacy determinations, reporting individual rather than composite safety outcomes to decrease the likelihood of statistically significant findings;

Limiting preapproval peer-review publication to minimize scrutiny of both methods and results (for example, of all submitted data, only one study of 340 patients has been published);

Using surrogate measures to evoke biological implausibility of safety concerns (for example, showing that treatment reduces C-reactive protein [CRP] to imply safety, even though there is no proof that CRP reduction is clinically correlated with improved safety);

Recording outcomes only in patients who comply fully with prescribed treatment, because this self-selected group is likely to have fewer adverse events (for example, unknown effect of the failure to analyze the 15% of cases who discontinued treatment);

Excluding consideration of confirmatory safety signals seen in studies of similar molecules (for example, CHF and bladder cancer outcomes with pioglitazone);

Diverting attention to unproven but potential benefits by focusing on reductions in surrogate laboratory values, such as hemoglobin A1C, rather than in meaningful patient health outcomes.

"Risk-benefit assessment is a dynamic process with few absolutes," Dr. Brophy writes. "A new drug for a uniformly fatal disease with no other treatment options is likely, even in the presence of some treatment risks, to be approved by regulators and accepted by patients. Conversely for muraglitazar, for which no meaningful outcome benefits have been demonstrated and other
treatments exist, the safety standards should be proportionally higher and importantly less uncertainty should be tolerated about suspected risks."

To address these safety concerns, the sponsor has proposed an observational pharmacovigilance study of muraglitazar compared with conventional type 2 diabetes treatments in 15,000 patients, using annual questionnaires during five-year follow-up. However, Dr. Brophy notes residual concerns due to possible selection or channeling biases, and he favors a large premarketing safety trial to provide more secure evidence and to limit risk only to study participants.

"Although muraglitazar may yet prove to be a valuable addition to the clinical armamentarium, the meticulous examination of the current evidence by Nissen and colleagues should focus serious attention on the potential cardiovascular risks of this drug," Dr. Brophy concludes. "Residual safety concerns surrounding carcinogenicity also have not been completely resolved. The question now is which safety message will the FDA buy?"

Dr. Brophy has no financial conflicts of interest to disclose.

JAMA. Published online Oct. 20, 2005.

Reviewed by Gary D. Vogin, MD

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