News Release

New cholesterol-modifying agent tested to regulate tryglyceride and HDL levels

Peer-Reviewed Publication

American College of Cardiology

NEW ORLEANS, La. (March 24, 2007) — Today researchers at the American College of Cardiology's 56th Annual Scientific Session reported results for a pair of studies designed to determine the safety and efficacy of a new, potent type of cholesterol treatment known as a peroxisome proliferator-activated receptor alpha (PPAR-Α) agonist.

The new drug, LY518674 (LY5) is similar to an existing agent, fenofibrate, but is approximately 10,000 times more potent. The study will be simultaneously published in the Journal of the American Medical Association (JAMA) and will appear in the March 28 print issue. ACC.07 is the premier cardiovascular medical meeting, bringing together cardiologists and cardiovascular specialists to further breakthroughs in cardiovascular medicine. Despite the potency of this new drug, researchers found it showed no advantages compared with fenofibrate. Moreover, both LY5 and fenofibrate raised safety concerns, according to the studies. It was hoped that LY5 would be particularly effective in treating atherogenic dyslipidemia, a cholesterol disorder characterized by the elevation of triglycerides (TRIGS) and a decrease in "good" high-density lipoprotein (HDL) levels in the blood. This lipid disorder is associated with an increased risk of developing cardiovascular disease.

Although statins represent the primary treatment of patients with abnormal cholesterol levels (by lowering LDL or "bad cholesterol"), these drugs have limited effects on HDL or TRIGS. Therefore, researchers have explored the use of treatments targeting the PPAR-Α family to manage atherogenic dyslipidemia. PPAR-Αmedications reduce TRIGS and raise HDL, and have shown benefits in reducing adverse outcomes in some, but not all, studies of cardiovascular disease. In one of the two studies, 309 atherogenic dyslipidemia patients, defined as HDL ≤45 mg/dL (men) or 50 mg/dL (women), TRIGS of 150-600 mg/dL and LDL ≤160 mg/dL were randomized into six treatment groups: LY5 at doses of 10 µg, 25 µg, 50 µg or 100 µg, fenofibrate 200 mg, or placebo. Efficacy was measured by change in lipid levels (LDL, HDL and TRIGS) during 12-weeks treatment. Both fenofibrate and LY5 markedly decreased triglycerides levels (32.8 vs. 24.8-39.9%, respectively). The reduction from LY5 was not statistically different from the effect produced by fenofibrate.

Both fenofibrate and LY5 increased levels of LDL, with an increase of 2.3 percent for fenofibrate and a significantly greater increase for the 50 and 100 µg LY5 groups (18.3 and 19.5%, respectively). Fenofibrate increased HDL levels by 14.4 percent. LY5 showed an unusual dose response pattern, with the lowest dose (10 µg) producing a modest increase (9.6%) in HDL levels, a maximum increase occurring at the 25 µg dose (15.8%) and lesser increases with higher dosages. The 100µg LY5 dose produced only a 2.1 percent increase in levels of HDL, which was not significantly different from the effect produced by placebo and smaller when compared with fenofibrate. In the dyslipidemia study, both fenofibrate and LY5 increased levels of creatinine suggesting the potential for an adverse effect on kidney function.

In the second of the two studies, LY5 was studied in patients with elevated levels of LDL cholesterol with or without treatment using a statin (atorvastatin). In this population, LY5 lowered triglycerides, raised HDL and slightly lowered LDL. These effects were similar to results obtained in previous studies using fenofibrate.

"Our study found that in patients with dyslipidemia, LY518674 and fenofibrate decreased triglycerides and increased HDL-C, but also increased LDL and showed evidence of worsening kidney function. These results demonstrate the challenges in developing new PPAR agonists as therapeutic agents," said Steven E. Nissen, M.D., of the Cleveland Clinic and lead investigator of this study. "It is vitally important that we continue to study combinations of therapies that not only reduce 'bad' cholesterol, but also improve 'good' cholesterol to manage patients' cardiovascular risks. Such studies advance the understanding of risks and benefits of new approaches and enable subsequent development programs to refine future study designs."

Dr. Nissen will present this study, "Efficacy and Safety of a Potent New PPAR-Alpha Agonist as Monotherapy or in Combination With Statins in Subjects With Dyslipidemia," on Sunday, March 25, at 1:30 p.m. in room Hall A.

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The American College of Cardiology (www.acc.org) represents the majority of board certified cardiovascular physicians in the United States. Its mission is to advocate for quality cardiovascular care through education, research, promotion, development and application of standards and guidelines- and to influence health care policy. ACC.07 and the i2 Summit is the largest cardiovascular meeting, bringing together cardiologists and cardiovascular specialists to share the newest discoveries in the treatment and prevention, while helping the ACC achieve its mission to address and improve issues in cardiovascular medicine.


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