The class
Drug-target Mendelian randomization links genetically lower CETP to longer human lifespan (Aging 2023)
Original title: Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study
Using drug-target Mendelian randomization with genetic variants for nine lipid-lowering drug targets from Global Lipids Genetics Consortium genome-wide association data, researchers examined causal effects of long-term lipid-lowering therapy on cancer and aging-related outcomes. Beyond established reductions in atherosclerotic cardiovascular disease risk, genetically proxied lipid-lowering variants of PCSK9, CETP, LPL, LDLR and APOC3 were all associated with longer human lifespan. Lipid-lowering ANGPTL3 and LDLR variants were linked to reduced colorectal cancer risk, ANGPTL3 to lower gastric cancer risk, LPL variants to reduced hypertension, type 2 diabetes, fatty liver disease and bladder cancer risk, PCSK9 and HMGCR to reduced osteoporosis risk, and APOB to reduced thyroid cancer risk, providing genetic evidence that newer nonstatin lipid-lowering therapies, including CETP-targeted approaches, may extend lifespan alongside reducing several cancers and cardiometabolic diseases.
Original abstract
Background: Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases.
Methods: A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes (HMGCR, PCKS9, NPC1L1, LDLR, APOB, CETP, LPL, APOC3, and ANGPTL3) were extracted as exposures from the summary data of Global Lipids Genetics Consortium Genome-Wide Association Studies (GWAS). GWAS summary data of cancers and noncancerous diseases were used as outcomes. The inverse-variance weighted method was applied as the main statistical approach. Sensitivity tests were conducted to evaluate the robustness, pleiotropy, and heterogeneity of the results.
Results: In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of PCKS9, CETP, LPL, LDLR, and APOC3 were associated with longer human lifespans (q<0.05). Lipid-lowering variants of ANGPTL3 and LDLR were associated with reduced risks of colorectal cancer, and ANGPTL3 was also associated with lower risks of gastric cancer (q<0.05). Lipid-lowering LPL variants were associated with decreased risks of hypertension, type 2 diabetes, nonalcoholic fatty liver disease, and bladder cancer (q<0.05). Lipid-lowering variants of PCKS9 and HMGCR were associated with decreased risks of osteoporosis (q<0.05). Lipid-lowering APOB variants were associated with a decreased risk of thyroid cancer (q<0.05).
Conclusions: Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.