#3336 EFFECTS OF LIPID-LOWERING DRUGS ON IMPROVING KIDNEY FUNCTION: A DRUG TARGET MENDELIAN RANDOMIZATION STUDY
Authors: Bennett Schyler , Walker Venexia , Zheng Jie , Brumpton Ben , Hveem Kristian , Köttgen Anna , Åsvald Bjørn , Gaunt Tom , Rasheed Humaira 
Published: June 2023

Abstract

Background and Aims
Chronic kidney disease (CKD) affects one in ten adults worldwide. CKD frequently co-occurs with cardiovascular diseases, hypertension, and diabetes. Despite this high prevalence, few specific therapies exist. Thus, using drug-target Mendelian randomization (MR), we investigated the existing treatments for cardiovascular diseases, hypertension, and diabetes as potential treatment options for improving kidney function.

Methods
We identified SNPs as genetic proxies for the effects of targets of statins, ezetimibe, and alirocumab/evolocumab (as hypercholesterolemia drugs); angiotensin-converting enzyme (ACE) inhibitors, β-blockers (BB), and calcium channel blockers (CCB: as antihypertensive drugs); and metformin (as antidiabetic drug) on kidney function. Effects of these SNPs on exposures, including low-density lipoprotein cholesterol (LDL-C) for hypercholesterolemia drugs, systolic blood pressure (SBP) for antihypertensive drugs, and HbA1c for antidiabetic drug, were obtained from published genome wide association studies (GWASs) summary statistics. Similarly, SNP-outcome data for kidney related markers, including serum creatinine and serum cystatin C based estimated glomerular filtration rate (eGFRcrea and eGFRcys, respectively) and blood urea nitrogen (BUN), were obtained using the largest GWAS for these phenotypes. Two-sample MR analysis using the inverse variance weighted (IVW) method and additional sensitivity analyses including weighted median, weighted mode, and MR-Egger methods were carried out in R (version 4.2.1). The results are presented as standard deviation (SD) change in outcome per 1 SD change in exposure caused by the drug.

Results
Each 1 SD lowering in LDL-C caused by HMGCR variants, proxying the effect of statins, was associated with higher serum creatinine and cystatin-C based eGFR of approximately 0.01 SD (eGFRcrea β = 0.012, 95% CI = 0.007-0.018, p = 0.00032; eGFRcys β = 0.012, 95% CI = 0.002-0.022, p = 0.017), and lower BUN of 0.010 SD (β = -0.010, 95% CI = -0.020-0.000020, p = 0.050) (Figure 1), with consistent findings from sensitivity methods and no bias due to pleiotropy (PEgger = 0.22-0.70). Findings for other lipid-lowering drugs including NPC1L1 (target of ezetimibe) and PCSK9 (target of alirocumab/evolocumab) remained inconclusive. Similarly, we found limited evidence for the causal role of genetically proxied antihypertensive or antidiabetic drugs in improving kidney function, though beta values were close to null (Figure 1).

Conclusion
The genetically proxied LDL-C lowering effect of HMGCR is associated with improved kidney function, which is consistent with the reported causal association of LDL-C with kidney function in a previous trans-ethnic MR study (1). Limited evidence was found for antihypertensive and antidiabetic drugs. These results provide insights into potential drug target candidates for future trials to address the treatment of CKD and comorbidities.