Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of
lipid and
glucose metabolism.
PPARgamma agonists improve
insulin sensitivity and
hyperglycemia and are effective in treating
type 2 diabetes mellitus (T2DM), whereas
PPARalpha agonists are used to treat
dyslipidemia and
atherosclerosis. The goal here was to examine the efficacy of a selective
PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-
piperidine-1-
carboxylic acid 4-trifluoromethyl-benzyl
ester;
CP-900691} on
lipid, glycemic, and
inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily
insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or
CP-900691 (3 mg/kg, n = 7) daily for 6 weeks.
CP-900691 treatment increased plasma
high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and
apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma
triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and
apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the
lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased
body weight (p < 0.01) and
C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased
adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline.
CP-900691 treatment reduced exogenous
insulin requirements by approximately 25% (p < 0.04) while lowering plasma
fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved
glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high
triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in
glycemic control,
body weight, and CRP, suggest that
CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.