Effects of fenofibrate on lipid parameters in obese rhesus monkeys.
Fenofibrate is a member of the fibrate class of hypolipidemic agents used clinically to treat hypertriglyceridemia and mixed hyperlipidemia. The fibrates were developed primarily on the basis of their cholesterol and triglyceride lowering in rodents. Fibrates have historically been ineffective at lowering triglycerides in experimentally-induced dyslipidemia in nonhuman primate models. The spontaneously obese rhesus monkey is a well-recognized animal model for the study of human obesity and type 2 diabetes, and many of these monkeys exhibit naturally occurring lipid abnormalities, including elevated triglycerides and low HDL cholesterol (HDL-C), similar to patients with type 2 diabetes. To explore whether the obese rhesus model was predictive of the lipid lowering effects of fibrates, we evaluated fenofibrate in six hypertriglyceridemic, hyperinsulinemic, nondiabetic animals in a 20-week, dose-escalating study. The study consisted of a 4-week baseline period, two treatment periods of 10 mg/kg twice daily (b.i.d) for 4 weeks and 30 mg/kg b.i.d. for 8 weeks, and a 4-week washout period. Fenofibrate (30 mg/kg b.i.d) decreased serum triglycerides 55% and LDL-C 27%, whereas HDL-C increased 35%. Apolipoproteins B-100 and C-III levels were also reduced 70% and 29%, respectively. Food intake, body weight, and plasma glucose were not affected throughout the study. Interestingly, plasma insulin levels decreased 40% during the 30 mg/kg treatment period, suggesting improvement in insulin sensitivity. These results support the use of obese rhesus monkey as an excellent animal model for studying the effects of novel hypolipidemic agents, particularly agents that impact serum triglycerides and HDL-C.
Winegar
D A
DA
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA. daw17189@gsk.com
Brown
P J
PJ
Wilkison
W O
WO
Lewis
M C
MC
Ott
R J
RJ
Tong
W Q
WQ
Brown
H R
HR
Lehmann
J M
JM
Kliewer
S A
SA
Plunket
K D
KD
Way
J M
JM
Bodkin
N L
NL
Hansen
B C
BC
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000097:blood; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008253:Macaca mulatta / Q000097:blood / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001053:Apolipoproteins; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D007328:Insulin; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D011345:Fenofibrate