Abstract 1278: Aleglitazar, a Balanced Peroxisome Proliferator-activated Receptor (PPAR)α/γ Agonist, Exerts Potent Lipid-modifying Effects in a Primate Model of Metabolic Syndrome and Type 2 Diabetes
Aleglitazar is a balanced dual PPAR agonist with high potency and affinity for both PPARα and PPARγ. As such, aleglitazar is designed to optimize glycemic and lipid benefits, and minimize the risk of weight gain and edema. The aim of this study was to evaluate the effects of aleglitazar on lipid homeostasis in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys. Following a 28-day baseline phase, 6 rhesus monkeys received aleglitazar 0.03 mg/kg orally once daily for 6 weeks. Plasma lipid levels and particle size (assessed by nuclear magnetic resonance [NMR]), as well as body weight, were measured at baseline and at the end of the dosing period. Aleglitazar treatment was associated with robust changes in fasting lipid levels, including significant reductions in LDL-cholesterol, VLDL-cholesterol, and apolipoprotein B, and a significant increase in HDL-cholesterol (Table⇓). NMR analysis revealed decreases in LDL2 particles (−80%; p=0.013). Trends towards a decrease in small dense LDL (LDL1), an increase in large LDL (LDL3), and decreases in all VLDL particle fractions were also observed. Insulin-sensitizing and glucose-lowering effects were also observed with aleglitazar treatment. Glucose infusion rate (under maximal insulin-stimulating conditions) increased by 60% from 7.8 to 12.5 mg/fat free mass/min (p=0.001) and fasting plasma glucose was reduced by 17% from 86.3 to 71.8 mg/dL (p=0.119). Interestingly, body weight was reduced from 20.5 to 19.5 kg (mean weight loss 4.8%; p=0.040). In this animal model of metabolic syndrome and T2D that mirrors the features of human obesity-associated T2D, aleglitazar modified lipid metabolism, producing a shift to an anti-atherogenic profile. This suggests that aleglitazar may have a therapeutic role in the reduction of cardiovascular risk factors in the human diabetic state.