Statin Use and Neuropathic Pain: Evidence from NHANES and Mendelian Randomization Analyses

Neuropathic pain (NP) is a type of pain resulting from damage or dysfunction of the somatosensory system. Emerging evidence suggests that lipid-lowering drugs may influence the development or progression of NP. This study's objectives are to examine the association between statin use and diabetic peripheral neuropathy (DPN) using NHANES cross-sectional data, and to evaluate whether genetically proxied inhibition of HMGCR, PCSK9, and NPC1L1 is associated with DPN, trigeminal neuralgia (TN), and postherpetic neuralgia (PHN). In the NHANES component, we conducted a cross-sectional analysis of adults with diabetes and dyslipidemia from NHANES 1999-2004 to examine the association between statin use and DPN. In the primary analysis, dyslipidemia was defined using nonfasting/full-sample indicators, and an additional fasting-weight sensitivity analysis was performed using a broader fasting lipid definition. MR analyses were then performed to evaluate the associations of genetically proxied HMGCR, PCSK9, and NPC1L1 inhibition with DPN, TN, and PHN. In NHANES, statin use was not significantly associated with DPN in the primary analysis across progressively adjusted models, and the fasting-weight sensitivity analysis showed directionally similar but still non-significant results. By contrast, MR analyses suggested that genetically proxied HMGCR inhibition was associated with increased odds of DPN (OR = 4.20, 95% CI [2.42, 7.30]) and TN (OR = 1.52, 95% CI [1.14, 2.04]), PCSK9 inhibition with increased odds of DPN (OR = 4.85, 95% CI [2.64, 8.91]), and NPC1L1 inhibition with increased odds of TN (OR = 3.05, 95% CI [1.58, 5.91]). Evidence for PHN was inconsistent across analyses. The NHANES analyses did not identify a statistically significant association between statin use and DPN. By contrast, MR analyses suggested that genetically proxied HMGCR and PCSK9 inhibition may be associated with increased DPN risk, whereas HMGCR and NPC1L1 inhibition may be associated with TN. These associations warrant validation in independent populations and in studies with more precise neuropathic pain phenotyping.