Preliminary research suggests that use of a novel, potent drug to treat cholesterol disorders decreases triglycerides and increases HDL-C, the "good" cholesterol, but also raises some safety concerns, according to a study in the March 28 issue of JAMA. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.
Several different classes of drugs are used to treat lipid disorders. Fibrates reduce the liver's production of a triglyceride-carrying particle and speed up removal of triglycerides from the blood. Statins reduce cholesterol levels by inhibiting an enzyme that produces cholesterol in the liver. New, more potent and selective medications are being developed to treat lipid disorders within the class of drugs known as peroxisome proliferator-activated receptor (PPAR)-alpha agonists - drugs that turn on one of several cellular switches, according to background information in the article. None of the new PPAR-alpha agonists has achieved regulatory approval.
Steven E. Nissen, M.D., of the Cleveland Clinic Lerner School of Medicine, Cleveland, and colleagues conducted two multi-center, randomized trials to examine the safety and efficacy of a PPAR-alpha agonist known as LY518674. In one study, 309 patients with atherogenic dyslipidemia (elevated triglycerides and low HDL-C) received LY518674 (in one of 4 doses, 10, 25, 50 or 100 micrograms), placebo, or the fibrate drug fenofibrate. In the other study, 304 patients with hypercholesterolemia (elevated LDL-C, the "bad" cholesterol) received placebo or the statin drug atorvastatin for four weeks, then placebo or LY518674 (in one of 2 doses, 10 or 50 micrograms) for 12 more weeks. The patients were randomized between August 2005 and August 2006.
"Efficacy in an atherogenic dyslipidemia population was generally similar to that of fenofibrate, producing a 35 percent to 42 percent decrease in triglyceride levels and a two percent to 16 percent increase in HDL-C levels," the authors report.
"In those with hypercholesterolemia, LY518674 reduced triglycerides and increased HDL-C, but did not further reduce LDL-C in combination with atorvastatin," they continue.
In general, both LY518674 and fenofibrate were well tolerated, but the authors report both drugs raised some safety concerns. LY518674 and fenofibrate increased serum creatinine levels among patients with dyslipidemia. In some patients, serum creatinine increased above the upper limit of normal. (Abnormally high levels of creatinine may signal impaired function or failure of the kidneys). Also, LY518674 increased LDL-C in patients with dyslipidemia.
"These drugs modulate activity of a large number of genes, some of which produce unknown effects," the authors write. "Accordingly, the beneficial effects of PPAR activation appear to be associated with a variety of untoward effects, which may include oncogenesis [the progression of genetic and cellular changes that culminate in a malignant tumor], renal [kidney] dysfunction, rhabdomyolysis [a condition in which skeletal muscle cells break down] and cardiovascular toxicity."
The authors believe their findings underscore the importance of prompt and thorough reporting of clinical trials of new pharmaceutical agents.
"Such studies advance the understanding of risks and benefits of new approaches and enable subsequent development programs to refine future study designs. Prompt publication also allows better protection of patient safety by providing study sponsors, investigators, and data and safety monitoring committees with a better appreciation of any potential risks that may require close monitoring," they conclude.
(JAMA. 2007;297:1362-1373. Available pre-embargo to the media at www.jamamedia.org.)
Editor's Note: This study was funded by Eli Lilly and Co. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
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