Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus.
The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.
Terra
Steven G
SG
Pfizer Global Research and Development, Groton, Connecticut, USA. steven.g.terra@pfizer.com
Francone
Omar L
OL
Contant
Charles F
CF
Gao
Xiang
X
Lewin
Andrew J
AJ
Nguyen
Tu T
TT
D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000187:drug effects; D053299:Apolipoprotein B-100 / Q000187:drug effects; D002097:C-Reactive Protein / Q000187:drug effects; D008076:Cholesterol, HDL / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D011345:Fenofibrate / Q000009:adverse effects / Q000627:therapeutic use*; D015248:Gemfibrozil / Q000009:adverse effects / Q000627:therapeutic use*; D006710:Homocysteine / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists*
D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D006710:Homocysteine; D002097:C-Reactive Protein; D015248:Gemfibrozil; D011345:Fenofibrate