Association of lipid-lowering drugs with the risk of type 2 diabetes and its complications: a mendelian randomized study.

Background: The pathogenesis of type 2 diabetes mellitus is somewhat associated with lipid metabolism. We aim to assess the impact of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) on type 2 diabetes mellitus and its complications through a two-sample Mendelian randomization (MR) study.

Method: We identified suitable genetic instruments from the GWAS database that represent the expression levels of three genes, interpreting reduced genetically proxied gene expression as indicative of lipid-lowering drug use. We evaluated the causal relationships among these variables employing a two-sample Mendelian randomization approach, with the Inverse Variance Weighted (IVW) analysis serving as the primary method. Coronary artery disease was utilized as a positive control to validate the reliability of the selected genetic instruments.

Result: Increased genetically proxied HMGCR expression is significantly associated with a reduced risk of type 2 diabetes mellitus (OR = 0.64, 95%CI = 0.55-0.74), which was replicated in the FinnGen study with consistent results (OR = 0.65, 95%CI = 0.53-0.80). Increased genetically proxied HMGCR expression is associated with a reduced risk of diabetic retinopathy (OR = 0.23, 95%CI = 0.12-0.44) and diabetic nephropathy (OR = 0.35, 95%CI = 0.17-0.71). In contrast, increased genetically proxied PCSK9 expression is associated with a decreased risk of diabetic coma (OR = 0.70, 95%CI = 0.50-0.98), diabetic neuropathy (OR = 0.24, 95%CI = 0.14-0.42), diabetic retinopathy (OR = 0.67, 95%CI = 0.48-0.96), diabetic cardiovascular diseases (OR = 0.62, 95%CI = 0.38-0.99), and diabetic nephropathy (OR = 0.62, 95%CI = 0.41-0.95).

Conclusions: This Mendelian randomization study suggests an association between HMGCR and the pathogenesis of type 2 diabetes mellitus, with increased genetically proxied HMGCR expression reducing the risk of type 2 diabetes mellitus, while PCSK9 and NPC1L1 show no significant association with type 2 diabetes mellitus. These findings may offer more reasonable lipid-lowering drug options for patients with dyslipidemia.