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Effects of a Potent and Selective PPAR- Agonist in Patients With Atherogenic Dyslipidemia or Hypercholesterolemia

Two Randomized Controlled Trials

Steven E. Nissen, MD; Stephen J. Nicholls, MBBS, PhD; Kathy Wolski, MPH; Daniel C. Howey, MD; Ellen McErlean, RN, MSN; Ming-Dauh Wang, PhD; Elisa V. Gomez, MS; John M. Russo, MD

JAMA. 2007;297:1362-1373. Published online March 25, 2007 (doi:10.1001/jama.297.12.1362).

Context  Fibrates are weak agonists of peroxisome proliferator–activated receptor (PPAR-). No trials have reported effects of more potent and selective agents.

Objectives  To examine the safety and efficacy of LY518674, a PPAR- agonist.

Design, Setting, and Participants  Two multicenter, randomized, double-blind, placebo-controlled trials: 1 in patients with elevated triglycerides and low HDL-C (atherogenic dyslipidemia), the other in patients with elevated LDL-C (hypercholesterolemia). Between August 2005 and August 2006, the dyslipidemia study randomized 309 patients at US centers; the hypercholesterolemia study, 304 patients.

Interventions  Dyslipidemia study: placebo, fenofibrate (200 mg), or LY518674 (10, 25, 50, or 100 µg) for 12 weeks. Hypercholesterolemia study: placebo or atorvastatin (10 or 40 mg) for 4 weeks, then placebo or LY518674 (10 or 50 µg) for 12 more weeks.

Main Outcome Measures  Dyslipidemia study: percentage change in levels of HDL-C and triglycerides. Hypercholesterolemia study: percentage change in levels of LDL-C.

Results  Dyslipidemia study: LY518674 (25 µg) and fenofibrate increased HDL-C by 5.9 and 5.5 mg/dL (15.8% and 14.4%) (both P.001 vs placebo, P = .79 between treatments). Higher LY518674 doses yielded smaller increases. LY518674 decreased triglycerides by 97.3 to 114.5 mg/dL (34.9% to 41.7%) but was similar to fenofibrate. LY518674 produced a dose-dependent increase in LDL-C, reaching 20.4 mg/dL (19.5%) for the 100-µg dose vs 0.3 mg/dL (2.3%) for fenofibrate (P.01). Fenofibrate and LY518674 (50 µg and 100 µg) increased serum creatinine (P.001 vs placebo), with 38% and 37.3% of patients exceeding the normal range. Fenofibrate, but not LY518674, increased creatine phosphokinase (P = .004 vs placebo). Hypercholesterolemia study: LY518674 (10 µg or 50 µg) decreased LDL-C by 21.4 to 26.0 mg/dL (13.2%-15.8%) and triglycerides 37% for both doses, and increased HDL-C by 6.3 to 6.7 mg/dL (12.5%-15.0%). When added to atorvastatin, LY518674 changed HDL-C by –0.7 to 6.2 mg/dL (–0.6% to 11.9%) and significantly decreased triglycerides but had no additional effect on LDL-C.

Conclusions  In patients with dyslipidemia, LY518674 and fenofibrate decreased triglycerides and increased HDL-C but also increased serum creatinine. LY518674, but not fenofibrate, increased LDL-C. In those with hypercholesterolemia, LY518674 reduced triglycerides and increased HDL-C, but did not further reduce LDL-C in combination with atorvastatin. Fenofibrate and LY518674 both raised safety concerns.

Trial Registration  clinicaltrials.gov Identifiers: NCT00133380 and NCT00116519

Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio (Drs Nissen and Nicholls and Mss Wolski and McErlean); Eli Lilly and Company, Indianapolis, Ind (Drs Howey and Wang and Ms Gomez); and Guilford Medical Associates and Moses Cone Health System, Greensboro, NC (Dr Russo).

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