FDA Recommends Approval of Muraglitazar, But May Need To Reconsider

Pharmacology Watch

In September of 2005, an FDA advisory committee recommended approval of muraglitazar for the treatment of type 2 diabetes. However new review of the data presented to the FDA challenges the safety of the drug, and suggests that compared with placebo or standard treatment, muraglitazar is associated with excess mortality.

The drug is a peroxisome proliferator-activated receptor (PPAR) that has both alpha receptor activity (similar to fenofibrate and gemfibrozil) and gamma receptor activity (similar to pioglitazone and rosiglitazone). Muraglitazar has been widely anticipated because of its dual effect of improving lipid profiles and increasing insulin sensitivity in patients with type 2 diabetes.

In the new study, researchers from the Cleveland clinic reviewed the data submitted to the FDA from phase 2 and 3 clinical trials. The combined studies included 3725 patients who were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo in combination with metformin or glyburide in trials ranging from 24 to 104 weeks. The primary end points were death, nonfatal MI, or nonfatal stroke and a more comprehensive composite outcome, which included those 3 outcomes plus incidence of CHF or TIA. The primary outcome (death, MI, or stroke) occurred in 35 of 2374 (1.47%) of muraglitazar treated patients and in 9 of 1351 (0.67%) of patients in the combined placebo and pioglitazone treatment groups (RR 2.23; 95% CI, 1.07-4.66; P. = .03). The more comprehensive outcome occurred in 2.11% of muraglitazar treated patients and 0.81% of control patients (RR, 2.62; 95%CI, 1.36-5.05; P = .004). Incidence of CHF was 0.55% muraglitazar and 0.07% controls (P = .053).

The authors conclude that compared with placebo or pioglitazone, muraglitazar was associated with increased risk of death, major adverse cardiovascular events, and CHF. They also recommend the FDA not approve the drug until safety can be documented (Nissen SE, et al. Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus. JAMA. 2005;294:2581-2586).

In a related, provocative editorial, James Brophy MD from McGill University suggests tactics that pharmaceutical companies use to "foster an allusion of safety" when presenting data as part of a FDA application including selecting study populations unlikely to have adverse outcomes, conducting under powered studies that are unable to detect meaningful safety differences, reporting individual rather than composite safety outcomes, and others. He poses the question "which safety message will the FDA buy?" (Brophy JM. Selling Safety—Lessons From Muraglitazar. JAMA. 2005;294:2633-2635).

Which Antipsychotics Are More Dangerous?

Newer atypical antipsychotic drugs have been associated with higher death rates in elderly patients. Now, a new study shows that conventional antipsychotics are at least as dangerous as the newer drugs. In a retrospective cohort study, nearly 23,000 patients age 65 and older who had received conventional or atypical antipsychotic medications between 1994 and 2003 were studied. Conventional antipsychotic medications were associated with a significantly higher adjusted death rate then atypical antipsychotic medications for all time intervals studied up to 180 days (relative risk 1.37; 95% CI, 1.27-1.49). The relative risk was also higher for less than 40 days (RR, 1.56), 40-79 days (RR, 1.37), and 80-180 days (RR, 1.27). The greatest risks were for death occurring within the first few weeks after initiation of medication especially higher doses of conventional antipsychotics drugs.

The authors conclude that conventional antipsychotic medications are least as likely as atypical agents to increase the risk of death among elderly patients, and that conventional drugs should not be used to replace atypical agents if they were discontinued because of recent FDA warnings (Wang PS, et al. Risk of Death in Elderly Users of Conventional Vs. Atypical Antipsychotic Medications. N Engl J Med. 2005;353:2335-2341).

Should CPOE Undergo Evaluation?

Physicians who use computerized physician order entry (CPOE) systems often report that it is not a panacea for saving time and preventing medication errors. A new study raises concerns about an increase in adverse outcomes associated with CPOE. Researchers from Children's Hospital of Pittsburgh reviewed demographic, clinical, and mortality data before and after implementation of a commercially sold CPOE. Mortality rates were significant higher after implementation (75 deaths among 1942 children, 3.86% after implementation vs 39 of 1394, 2.80% prior to implementation, odds ratio: 3.28; 95% CI; 1.94-5.55). The authors suggest that while CPOE may hold great promise, "Institutions should continue to evaluate mortality effects, in addition to medication air rates. . ." They also suggest that CPOE should undergo rigorous review and evaluation, similar to drugs, to assess safety prior to implementation (Han YY, et al. Unexpected Increased Mortality After Implementation of a Commercially Sold Computerized Physician Order Entry System. Pediatrics. 2005;116:1506-1512).

New Treatment for Tennis Elbow

Botulinum toxin may be effective for treating tennis elbow, according to new study. Sixty patients with lateral epicondylitis were randomized to injections of 6 units of botulinum toxin type A or normal saline placebo injections. Subjective pain was significantly reduced in the botulinum group at 4 weeks (visual analog scale 25.3 mm botulinum vs 50.5 mm placebo [P < 0.001]) and was sustained at 12 weeks. Grip strength was not statistically different between the 2 groups, although mild paresis of the fingers occurred in 4 patients in the botulinum group at 4 weeks, but none of the patients in the placebo group. In only one patient did the symptoms persist until week 12. More patients in the botulinum group experience weak finger extension at 4 weeks as well (10 patients botulinum vs 6 patients placebo).

The authors conclude that botulinum toxin may be effective in treating pain over 3-month periods in patients with lateral epicondylitis, but the injections may be assisted with digit paresis and weakness of finger extension (Wong SM, et al. Treatment of Lateral Epicondylitis with Botulinum Toxin: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Int Med. 2005;143:793-797).

FDA Actions

Moxifloxacin (Avelox-Bayer) has been approved for the treatment of complicated intra-abdominal infections including polymicrobial infections. The approval was based on a study which showed that intravenous or oral moxifloxacin was as effective as IV therapies such as piperacillin/tazobactam (Zosyn) followed by oral amoxicillin/clavulanic acid (Augmentin). In a separate study, moxifloxacin was found to be equivalent to ceftriaxone plus metronidazole followed by oral amoxicillin/clavulanic acid for treating complicated intraabdominal infections. Moxifloxacin is also approved for treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, and skin and skin structure infections caused by susceptible organisms.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: leslie.hamlin@thomson.com.