Another Novel HDL-Raising Therapy, Another Negative Trial

A novel, potent, selective peroxisome proliferator-activated receptor-α (PPAR-α) agonist, LY518674, has been touted for its potential to improve lipid profiles. To study its safety and efficacy, researchers conducted two manufacturer-funded, multicenter, randomized, controlled trials.

One trial focused on raising HDL-cholesterol levels. A total of 309 patients with atherogenic dyslipidemia followed guideline-recommended lifestyle changes for a 4-week placebo run-in period. Then they were randomized to receive daily LY518674 (10, 25, 50, or 100 μg), the weaker PPAR-α agonist fenofibrate (200 mg), or placebo for 12 weeks. Clinically indicated statin use was permitted, but statin dose adjustments were not. For both raising HDL levels and lowering triglyceride levels, LY518674 and fenofibrate each outperformed placebo, with no significant differences between the two PPAR-α agonists. LY518674 also raised LDL levels in a dose-dependent fashion — and much more than fenofibrate did.

The other trial focused on lowering LDL-cholesterol levels. A total of 304 statin-naive patients (baseline LDL levels, 100–160 mg/dL) had a 4- to 6-week washout and then were randomized to receive daily atorvastatin (10 or 40 mg) or placebo for 4 weeks. Patients in both groups were then randomized to receive adjunctive daily LY518674 (10 or 50 μg) or placebo for 12 weeks. LY518674 and atorvastatin each significantly reduced triglyceride and LDL levels, and increased HDL levels. In atorvastatin recipients, the addition of LY518674 further increased HDL levels (by 1% to 12%) and further reduced triglyceride levels, but it changed LDL levels little.

In both trials, LY518674 showed evidence of increasing serum creatinine levels, sometimes substantially. Fenofibrate also increased creatinine levels in the first trial.