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.