Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats.

Abstract

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). Despite the entry of sodium glucose cotransporter 2 (SGLT2) inhibitors, CKD persists as a medical challenge. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces low-density lipoprotein (LDL)-cholesterol, a major risk factor of CVD. Interestingly, studies indicate that PCSK9 inhibition decreases proteinuria in kidney disease, complementing the reduced CVD risk. This study aimed to validate obese ZSF1 rats as a model for the renoprotective effects of PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin for 15 weeks. Obese rats revealed a significant reduction in measured glomerular filtration rate (mGFR) and increased urine albumin/creatinine ratio (UACR) during follow-up compared to lean controls. Alirocumab treatment resulted in a decline in mGFR and increased UACR compared to vehicle-treated obese rats. Immunohistochemistry showed increased fibrosis and inflammation in kidney tissue from obese rats treated with empagliflozin or alirocumab, whereas hepatic cholesterol and triglyceride levels were lowered compared to vehicle-treated obese rats. While alirocumab lowered circulating free cholesterol levels throughout the treatment period, certain cholesteryl esters were increased at the end of the study, resulting in no overall difference in total cholesterol levels in the alirocumab group. Correspondingly, only a trend toward increased hepatic LDL-receptor levels was observed. In conclusion, these findings suggest that alirocumab treatment aggravates kidney dysfunction in obese ZSF1 rats. Moreover, in contrast to the renoprotective properties of empagliflozin observed in CKD patients, empagliflozin did not ameliorate kidney disease progression in the obese ZSF1 rat.