Abstract 545: Evolocumab Alters LDL-cholesterol Levels but Not Glycemic Profile and Liver Lipids in Chow Fed and High fat/Cholesterol/Fructose Fed Golden Syrian Hamsters

Abstract

Background: Beside its effect on LDL-cholesterol levels, proprotein convertase subtilisin/kexin9 (PCSK9) could also be linked to glucose metabolism and non-alcoholic fatty liver diseases. Here we evaluated whether Evolocumab (EVO), a monoclonal antibody targeting PCSK9, may alter glycemic profile and liver lipids in hamsters. Methods: Hamsters were maintained on either a control chow (CC) or high fat/cholesterol/fructose (HFCF) diet for 5 weeks. After 2 weeks of diet, hamsters were randomized into 2 groups, control or EVO at 30mg/kg s.c. once weekly for 3 weeks, to evaluate the effects on lipoprotein/glycemic profiles, and liver lipids. Results: When compared with CC diet, HFCF diet significantly increased total cholesterol and LDL-cholesterol levels by 87% and 102%. Hamsters fed the HFCF diet also showed higher HOMA-IR index of insulin resistance, higher blood glucose area under the curve (AUC) during an oral glucose tolerance test (OGTT), and higher liver lipids (triglycerides: +197%, total cholesterol: +421%, both p<0.001 vs. CC). However, plasma PCSK9 levels were markedly reduced by 47% in HFCF fed hamsters (p<0.001 vs. CC). As expected, treatment with EVO significantly increased hepatic LDL-receptor protein levels by 1.74-fold and reduced plasma LDL-cholesterol by up to 28% in CC fed hamsters (p<0.01 vs. CC control). The LDL-cholesterol reduction was also observed in HFCF fed hamsters treated with EVO, but to a lesser extent (up to 16%). In both CC and HFCF fed hamsters, EVO did not alter fasting glycemia and plasma insulin levels. IN CC fed hamsters, EVO transiently reduced blood glucose levels by 15% at time 15 minutes (p<0.01 vs. CC control) after an oral glucose load. However, EVO did not change blood glucose levels AUC or plasma insulin levels during the OGTT, in neither CC nor HFCF fed hamsters. As well, no change in liver lipids levels was observed in CC or HFCF fed hamsters treated with EVO. Conclusion: Our data indicate that diet-induced insulin resistance and liver steatosis in hamsters are not associated with elevated plasma PCSK9 levels, and are not altered by Evolocumab. Whether these results are specific to our hamster model and can translate to humans remains to be further investigated.