Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis

Abstract

Background: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.

Methods: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.

Results: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10^{- 5}) and slower walking pace (OR = 0.918, P = 6.06 × 10^{- 9}). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10^{- 3}), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10^{- 3}) and decelerate walking pace (OR = 0.932, P = 1.43 × 10^{- 6}), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10^{- 6}). Meta-analysis further supported the robustness of these causal associations.

Conclusions: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Keywords: HMGCR; Low-density lipoprotein cholesterol; Mendelian randomization; NPC1L1; PCSK9; Sarcopenia.

Fig. 1

Study design overview. HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1-like 1; Chr, chromosome; LD, linkage disequilibrium; MAF, minor allele frequency; LDL-C, low-density lipoprotein cholesterol; GLGC, Global Lipids Genetics Consortium; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier

Fig. 2

Forest plots illustrate the causal estimates from the MR investigation employing LDL-C decrease as a proxy for lipid-lowering drug effects. The findings indicate that genetically proxied inhibitions of HMGCR, PCSK9, and NPC1L1 may not causally influence low hand grip strength based on LDL-C datasets from Sakaue et al. (a), as well as GLGC (b). Genetically proxied inhibition of HMGCR correlates with an increase in appendicular lean mass, while inhibition of PCSK9 associates with a decrease in appendicular lean mass, according to LDL-C datasets from Sakaue et al. (c), and GLGC (d). Additionally, genetically proxied inhibition of HMGCR is linked to decelerating walking pace based on LDL-C datasets from Sakaue et al. (e), and GLGC (f). Genetically proxied inhibition of NPC1L1 has no causal impact on sarcopenia-related traits. P-values in bold and red to indicate the results with statistical significance. MR, Mendelian randomization; OR, odds ratio; CI, confidence interval; IVW, inverse variance weighted; FE, fixed effects; MRE, multiplicative random effects; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1-like 1; LDL-C, low-density lipoprotein cholesterol; GLGC, Global Lipids Genetics Consortium

Fig. 3

Scatter plots depict the SNP effect of genetically proxied LDL-C decrease (x-axis) on the risk of sarcopenia related-traits (y-axis), which indicate that inhibition of HMGCR is related to an increase in appendicular lean mass using LDL-C datasets from Sakaue et al. (a) and GLGC (b). In contrast, inhibition of PCSK9 is significantly associated with a decrease in appendicular lean mass using LDL-C datasets from Sakaue et al. (c) and GLGC (d). Inhibition of HMGCR is associated with a decelerated walking pace using LDL-C datasets from Sakaue et al. (e) and GLGC (f). MR, Mendelian randomization; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1-like 1; LDL-C, low-density lipoprotein cholesterol; GLGC, Global Lipids Genetics Consortium

Fig. 4

A meta-analysis was conducted by merging the inverse-variance weighted causal estimates obtained from MR analysis using LDL-C datasets from Sakaue et al., as well as GLGC. The plots illustrate the combined estimates for inhibitions of HMGCR, PCSK9, and NPC1L on sarcopenia-related traits. Genetically proxied inhibitions of HMGCR, PCSK9, and NPC1L1 have no causal impact on risk of low hand grip strength (a). Genetically predicted inhibition of HMGCR is related to an increase in appendicular lean mass, while inhibition of PCSK9 is associated with a decrease in appendicular lean mass (b). Genetically proxied inhibition of HMGCR is also associated with a decelerated walking pace (c). P-values in bold and red to indicate the results with statistical significance. OR, odds ratio; CI, confidence interval; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1-like 1; LDL-C, low-density lipoprotein cholesterol; GLGC; Global Lipids Genetics Consortium