Associations of Lipid-Lowering Drugs With Blood Pressure and Fasting Glucose: A Mendelian Randomization Study.

BACKGROUND

Observational studies have linked LDL-C (low-density lipoprotein-cholesterol)-lowering drugs with lower blood pressure (BP) and higher fasting glucose, but the causality remains unclear. We conducted a drug target Mendelian randomization study to assess the causal associations of genetically proxied inhibition of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), PCSK9 (proprotein convertase subtilisin/kexin type 9), and NPC1L1 (Niemann-Pick C1-Like 1) with BP and fasting glucose.

METHODS

Single-nucleotide polymorphisms in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study meta-analysis from the Global Lipid Genetics Consortium (173 082 European individuals) were used to proxy LDL-C-lowering drug targets. BP and fasting glucose data were obtained from genome-wide association studies conducted by the International Consortium of Blood Pressure (757 601 European participants) and the Glucose and Insulin-related Traits Consortium (58 074 European participants). We used the inverse-variance weighted method and a series of sensitivity analyses for assessment.

RESULTS

Genetically proxied inhibition of HMGCR was negatively associated with systolic BP (β, -0.81 [95% CI, -1.26 to -0.37 mm Hg]; P=3.72×10-4) and diastolic BP (β, -1.58 [95% CI, -2.24 to -0.91 mm Hg]; P=3.23×10-6). Conversely, we observed a positive association between genetically proxied inhibition of HMGCR and high fasting glucose (β, 0.13 [95% CI, 0.08-0.17 mmol/L]; P=4.25×10-8). However, there was no association of PCSK9 and NPC1L1 inhibition with BP or fasting glucose.

CONCLUSIONS

Genetically proxied inhibition of HMGCR was significantly associated with low BP and high fasting glucose, while there was no effect of PCSK9 and NPC1L1 inhibition on BP or fasting glucose.