Estimating the effect of lipid‐lowering agents on novel subtypes of adult‐onset diabetes

Abstract Aims The aims of the present study were to assess the effects of lipid‐lowering drugs [HMG‐CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann–Pick C1‐Like 1 (NPC1L1) inhibitors] on novel subtypes of adult‐onset diabetes through a Mendelian randomisation study. Materials and Methods We first inferred causal associations between lipid‐related traits [including high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG), apolipoproteins A‐I, and apolipoproteins B] and novel subtypes of adult‐onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid‐lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL‐C, were then utilised as proxies for the exposure of lipid‐lowering drugs. Mendelian randomisation analysis was performed using summary data from genome‐wide association studies of LDL‐C, severe autoimmune diabetes, severe insulin‐deficient diabetes (SIDD), severe insulin‐resistant diabetes (SIRD), mild obesity‐related diabetes (MOD), and mild age‐related diabetes. Results There was an association between HMGCR‐mediated LDL‐C and the risk of SIRD [odds ratio (OR) = 0.305, 95% confidence interval (CI) = 0.129–0.723; p = 0.007], and there was an association of PCSK9‐mediated LDL‐C with the risk of SIDD (OR = 0.253, 95% CI = 0.120–0.532; p < 0.001) and MOD (OR = 0.345, 95% CI = 0.171–0.696; p = 0.003). Moreover, NPC1L1‐mediated LDL‐C (OR = 0.109, 95% CI = 0.019–0.613; p = 0.012) and the increased expression of NPC1L1 gene in blood (OR = 0.727, 95% CI = 0.541–0.977; p = 0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses. Conclusions In summary, the different lipid‐lowering medications have a specific effect on the increased risk of different novel subtypes of adult‐onset diabetes.