Effects of a potent and selective PPAR-alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials.
BACKGROUND
Fibrates are weak agonists of peroxisome proliferator-activated receptor alpha (PPAR-alpha). No trials have reported effects of more potent and selective agents.


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


METHODS
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.


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


METHODS
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 mug) and fenofibrate increased HDL-C by 5.9 and 5.5 mg/dL (15.8% and 14.4%) (both P< or =.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-mug dose vs 0.3 mg/dL (2.3%) for fenofibrate (P< or =.01). Fenofibrate and LY518674 (50 microg and 100 microg) increased serum creatinine (P< or =.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 mug or 50 microg) decreased LDL-C by 21.4 to 26.0 mg/dL (13.2%-15.8%) and triglycerides approximately 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.


BACKGROUND
clinicaltrials.gov Identifiers: NCT00133380 and NCT00116519
Nissen
Steven E
SE
Department of Cardiovascular Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio 44195, USA. nissens@ccf.org
Nicholls
Stephen J
SJ
Wolski
Kathy
K
Howey
Daniel C
DC
McErlean
Ellen
E
Wang
Ming-Dauh
MD
Gomez
Elisa V
EV
Russo
John M
JM
D000069059:Atorvastatin; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists*; D011422:Propionates / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; C479889:LY 518674; D008055:Lipids; D047493:PPAR alpha; D011422:Propionates; D011758:Pyrroles; D014230:Triazoles; D000069059:Atorvastatin; D011345:Fenofibrate