Abstract 18285: ARI-3037MO, a Novel Niacin Analog, Significantly Improves Plasma Lipid Levels in the Hyperlipidemic Golden Syrian Hamster

Abstract

Introduction: ARI-3037MO is a once-a-day structural analog of niacin currently in Phase I clinical trials for treatment of dyslipidemia. In preclinical studies in multiple species, ARI-3037MO did not induce cutaneous flushing, an adverse event that is commonplace with existing niacin preparations. Hypotheses: We hypothesized that ARI-3037MO would significantly improve the lipoprotein profile of hamsters with diet-induced hyperlipidemia. Methods: Golden Syrian hamsters (n=30, 111-120 g, 56-61 days old) were fed a diet consisting of 11.5% corn oil, 11.5% coconut oil, 0.5% cholesterol, and 0.25% deoxycholate and were provided water containing 10% fructose for 20 days. Animals remained on the atherogenic diet and were dosed P.O. with either vehicle (n=12), 1200 mg/kg/day (9.8 mmol/kg/day) niacin (n=9), or 1400 mg/kg/day (5.8 mmol/kg/day) ARI-3037MO (n=9) for 18 days. At the end of the dosing period, hamsters were sacrificed via CO2 asphyxiation, blood was collected via cardiac puncture, and tissues were harvested. Results: Compared to vehicle, ARI-3037MO significantly reduced plasma levels of TC (mean±SEM; 857±122 vs. 343±66 mg/dL, -60%, p<0.01), LDL-C (253±24 vs. 114±30 mg/dL, -55%, p<0.001), TG (1065±140 vs. 138±28 mg/dL, -87%, p<0.001), and free fatty acids (FFA) (1.96±0.16 vs. 0.75±0.05 mmol/L, -62%, p<0.001). Niacin, administered at a higher molar dose than ARI-3037MO, showed a less pronounced lipid modulating effect (TC, -39%, p=0.05; LDL-C, -33%, p<0.05; no significant changes in TG or FFA). Compared to vehicle, the increase in plasma HDL-C with ARI-3037MO was borderline significant (139±9 vs. 186±25 mg/dL, +33%, p=0.06); however, fast pressure liquid chromatography analysis of pooled plasma indicated an increase in the HDL-C fraction of the ARI-3037MO treated animals. Also, relative to vehicle, ARI-3037MO significantly increased liver Apo-A1 and ATP-Binding Cassette Transporter (ABC) A1 mRNA levels (+66%, p<0.001 and +55%, p<0.01, respectively). Conclusions: Relative to vehicle, ARI-3037MO was more effective than niacin at significantly reducing pro-atherogenic lipoproteins in the hyperlipidemic hamster. In addition, ARI-3037MO increased the proportion of HDL-C, possibly through liver apoAI- and ABCA1-mediated mechanisms.