Effects of Major Lipid-Lowering Drug Targets on Circulating Fatty Acids: A Mendelian Randomization Study

Background: The effects of major lipid-lowering therapies on circulating fatty-acid profiles are not fully characterized. We used Mendelian randomization (MR) to examine the effects of major lipid-lowering drug targets, proven to reduce CVD risk, on circulating fatty acids. Methods: We conducted a drug-target MR analysis assessing genetically proxied statins (HMGCR), PCSK9 inhibitors and ezetimibe (NPC1L1) on circulating fatty acids. Each drug target was proxied by variants associated with low-density lipoprotein cholesterol (LDL-c) within/near the respective gene. Summary associations with fatty acids were obtained from the largest available genome-wide association study comprising 7816 to 115,006 individuals of European descent. One functionally relevant genetic variant was used to proxy each drug target, so the Wald ratio was used to obtain causal estimates. Results: Genetically proxied inhibition of HMGCR, PCSK9, and NPC1L1 all reduced LDL-c, consistent with the expected drug effects. All three most clearly and consistently reduced polyunsaturated fatty acids, omega-6 and linoleic acid (LA) (e.g., statin on LA: −0.69, 95% confidence intervals: −0.80 to −0.58). In contrast, these genetically proxied lipid-lowering therapies had little effect on total omega-3s, eicosapentaenoic acid or arachidonate. Conclusions: Genetically proxied lipid-lowering therapies that protect against CVD were associated with lower circulating LA. The biological significance of this association and its relation to dietary intake and cardiovascular benefit remain uncertain.