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.