Effects of ACLY Inhibition on Body Weight Distribution: A Drug Target Mendelian Randomization Study

<b>Background:</b> Adenosine triphosphate-citrate lyase (ACLY) inhibition has proven clinically efficacious for low-density lipoprotein cholesterol (LDL-c) lowering and cardiovascular disease (CVD) risk reduction. Clinical and genetic evidence suggests that some LDL-c lowering strategies, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition with statin therapy increase body weight and the risk of developing type 2 diabetes mellitus (T2DM). However, whether ACLY inhibition affects metabolic risk factors is currently unknown. We aimed to investigate the effects of ACLY inhibition on glycaemic and anthropometric traits using Mendelian randomization (MR). <b>Methods:</b> As genetic instruments for ACLY inhibition, we selected weakly correlated single-nucleotide polymorphisms at the <i>ACLY</i> gene associated with lower <i>ACLY</i> gene expression in the eQTLGen study (N = 31,684) and lower LDL-c levels in the Global Lipid Genetic Consortium study (N = 1.65 million). Two-sample Mendelian randomization was employed to investigate the effects of ACLY inhibition on T2DM risk, and glycaemic and anthropometric traits using summary data from large consortia, with sample sizes ranging from 151,013 to 806,834 individuals. Findings for genetically predicted ACLY inhibition were compared to those obtained for genetically predicted HMGCR inhibition using the same instrument selection strategy and outcome data. <b>Results:</b> Primary MR analyses showed that genetically predicted ACLY inhibition was associated with lower waist-to-hip ratio (β per 1 standard deviation lower LDL-c: -1.17; 95% confidence interval (CI): -1.61 to -0.73; <i>p</i> < 0.001) but not with risk of T2DM (odds ratio (OR) per standard deviation lower LDL-c: 0.74, 95% CI = 0.25 to 2.19, <i>p</i> = 0.59). In contrast, genetically predicted HMGCR inhibition was associated with higher waist-to-hip ratio (β = 0.15; 95%CI = 0.04 to 0.26; <i>p</i> = 0.008) and T2DM risk (OR = 1.73, 95% CI = 1.27 to 2.36, <i>p</i> < 0.001). The MR analyses considering secondary outcomes showed that genetically predicted ACLY inhibition was associated with a lower waist-to-hip ratio adjusted for body mass index (BMI) (β = -1.41; 95%CI = -1.81 to -1.02; <i>p</i> < 0.001). In contrast, genetically predicted HMGCR inhibition was associated with higher HbA1c (β = 0.19; 95%CI = 0.23 to 0.49; <i>p</i> < 0.001) and BMI (β = 0.36; 95%CI = 0.23 to 0.49; <i>p</i> < 0.001). <b>Conclusions:</b> Human genetic evidence supports the metabolically favourable effects of ACLY inhibition on body weight distribution, in contrast to HMGCR inhibition. These findings should be used to guide and prioritize ongoing clinical development efforts.