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.