Causal Association Between Cholesterol-Lowering Drugs and Diabetic Microvascular Complications: A Drug-Target Mendelian Randomization Study.

Background: It remains unclear whether cholesterol-lowering therapy can reduce the incidence of microvascular complications in patients with diabetes. We aim to explore the potential causal relationship between three common types of cholesterol-lowering drugs and diabetic microvascular complications through drug-target Mendelian randomization (MR) study, laying the groundwork for the development of new medications. Methods: In this study, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) inhibitors, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, and NPC1L1 (Niemann-Pick C1-Like 1) inhibitors from published genome-wide association study statistics. Subsequently, drug-target MR analyses were performed to investigate the effects of these inhibitors on low-density lipoprotein cholesterol (LDL-C) level-mediated microvascular complications in diabetes mellitus. Coronary atherosclerosis as a positive control. Primary outcomes included diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy from the FinnGen Consortium. Results: The MR analysis revealed significant associations between HMGCR inhibition and increased risks of diabetic nephropathy (OR [95%confidence interval (CI)] = 1.88 [1.50, 2.36], p = 5.55 × 10^-8), retinopathy (OR [95%CI] = 1.86 [1.54, 2.24], p = 6.28 × 10^-11), and neuropathy (OR [95%CI] = 2.63 [1.84, 3.75], p = 1.14 × 10^-7) using the inverse variance weighted method. PCSK9 inhibitors have been associated with an increased risk of diabetic nephropathy (OR [95%CI] = 1.30 [1.07, 1.58], p = 0.009) and diabetic neuropathy (OR [95%CI] = 1.40 [1.15, 1.72], p = 0.001); NPC1L1 inhibitors significantly reduce the incidence of diabetic retinopathy (OR [95%CI] = 0.48 [0.28, 0.85], p = 0.01). The coronary heart disease as positive control. Conclusions: The findings show that HMGCR inhibitors and PCSK9 inhibitors may significantly increase the risk of diabetic microvascular complications. However, NPC1L1 inhibitors may provide protection against diabetic retinopathy.