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Diabetes: Pargluva increases the risk for morbidity and mortality

Peroxisome proliferator–activated receptors ( PPARs ) are ligand-activated nuclear transcription factors that modulate expression of a large number of genes.

In the United States, therapeutic agents that target two distinct families of PPARs ( alpha and gamma ) have been introduced.

Examples of PPAR-alpha agents include the fibric acid derivatives Fenofibrate and Gemfibrozil.
These agents modulate lipid metabolism primarily by lowering serum triglyceride levels and modestly increasing levels of high-density lipoprotein ( HDL ) cholesterol.
In several clinical trials, these PPAR- agents have reduced cardiovascular events or demonstrated slowing of atherosclerosis progression.

The PPAR-gamma agonists increase insulin sensitivity and are widely used as antidiabetic agents.
Two drugs are currently available, Pioglitazone ( Actos ) and Rosiglitazone ( Avandia ).

The first dual-PPAR agonist to reach the US Food and Drug Administration ( FDA ) for consideration of approval is Muraglitazar ( Pargluva ), a strong PPAR-gamma agonist with moderate PPAR-alpha effects.

An Advisory Committee for the FDA Endocrinology and Metabolic Drugs Division reviewed Muraglitazar’s clinical trials and recommended approval of the drug as monotherapy for treatment of 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 ).

Researchers at the Cleveland Clinic Foundation reviewed the FDA briefing documents available via the FDA Web site.
They found two major documents, an analysis of data in the Muraglitazar clinical development program provided by FDA staff and a separate document prepared by the developers of the drug ( Bristol-Myers Squibb and Merck ).
These documents provide data for five clinical trials that assessed safety and efficacy in diabetic patients.
Two different comparators were studied in these five trials: placebo and the approved PPAR-gamma agonist Pioglitazone.

A high rate of edema and congestive heart failure ( CHF ) with high doses of Muraglitazar was observed early in the development program and the sponsor ceased development of daily dosages higher than 5 mg, only requesting regulatory approval for dosages of 5 mg/d or less.

Researchers have restricted their analysis to treatment groups using Muraglitazar doses of 5 mg/d or less.
This analysis yielded 2374 patients exposed to Muraglitazar and 1351 patients exposed to comparator agents, of which 823 received Pioglitazone and 528 placebo.

The studies varied in duration from 24 to 104 weeks and included patients who received Muraglitazar monotherapy or Muraglitazar in combination with two other diabetes treatments, either Metformin or Glyburide.
Several features were common to all five trials.
Patients were aged 18 to 70 years, had a body mass index less than 41, triglycerides lower than 600 mg/dL ( 6.8 mmol/L ), and hemoglobin A1c levels between 7% and 10%.

Patients with class III or IV CHF were excluded. Also excluded were patients with a history of myocardial infarction, unstable angina, stroke, TIA ( transient ischemic attack ), angioplasty, or coronary artery bypass graft surgery within 6 months prior to enrollment.

Researchers have observed a numerical excess of adverse cardiovascular events for patients treated with Muraglitazar compared with controls ( patients treated with either placebo or Pioglitazone ).
For the most widely accepted composite end point of death, myocardial infarction, and stroke, the RR ( relative risk ) for Muraglitazar was 2.23.
Other end points using narrower definitions ( including only cardiovascular death ) or broader composites ( including CHF and TIA events ) showed similar risks.
The most inclusive composite end point that included all-cause mortality, nonfatal myocardial infarction, stroke, TIA, and CHF showed a highly significant increase in RR for Muraglitazar-treated patients ( 2.62; P = .004 ).

According to authors, Muraglitazar, is associated with an excess incidence of the composite end point of death, major adverse cardiovascular events ( myocardial infarction, stroke, TIA ), and congestive heart failure, compared with placebo or Pioglitazone.

Source: American Medical Association, 2005