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PPAR-alpha agonists: LY518674 shows no advantages compared with Fenofibrate

Researchers at Cleveland Clinic have recently completed a pair of studies to determine the safety and efficacy of a new, potent type of cholesterol treatment known as a peroxisome proliferator-activated receptor alpha ( PPAR-alpha ) agonist. The new drug, LY518674 ( LY5 ) is similar to an existing agent, Fenofibrate ( TriCor ), but is approximately 10,000 times more potent.

Steven Nissen, chairman of Cardiovascular Medicine at Cleveland Clinic and lead investigator of this study reported that despite the potency of this new drug, it showed no advantages compared with Fenofibrate. Moreover, both LY5 and Fenofibrate raised safety concerns.

" Our study found that both LY518674 and Fenofibrate decreased triglycerides and increased HDL-cholesterol for patients with dyslipidemia. However LY5 also increased levels of LDL-cholesterol and both drugs showed evidence of worsening kidney function, " Nissen said. " These results suggest the new PPAR agonists will not likely offer important advantages over existing drugs."

LY5 was intended to be effective in treating atherogenic dyslipidemia, a cholesterol disorder characterized by the elevation of triglycerides and a decrease in 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 cholesterol ), these drugs have limited effects on HDL or triglycerides. Therefore, researchers have explored the use of treatments targeting PPAR-alpha family to reduce triglycerides and raise HDL. This approach has 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, were randomized into six treatment groups and efficacy was measured by change in lipid levels during 12-weeks treatment. Both Fenofibrate and LY5 markedly decreased triglycerides levels and increased levels of HDL. LY5 produced a modest increase with the lowest dose, maximum increases with an intermediate dose and less increase with higher dosages.

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 / Lipitor ). In this population, LY5 lowered triglycerides, raised HDL, and slightly lowered LDL. These effects were similar to results obtained in previous studies using Fenofibrate.

In the dyslipidemia study, both Fenofibrate and LY5 increased levels of creatinine suggesting the potential for an adverse effect on kidney function.

Source: Cleveland Clinic, 2007