Abstract 15585: Using Genetics To Explore Whether The Cholesterol-lowering Drug Ezetimibe May Cause An Increased Risk Of Cancer
Introduction: Ezetimibe reduces plasma levels of low-density lipoprotein(LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1(NPC1L1). However, results from a randomized trial have raised concern that ezetimibe might increase the risk of cancer.
Hypothesis: We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk of cancer.
Methods: We included 67,257 individuals from the Danish general population. Of these, 8,333 developed cancer and 2,057 died of cancer during follow-up from 1968 to 2011. To mimic the effect of ezetimibe, we calculated a weighted genotype score (from <2.0 to ≥5.0) using four NPC1L1 variants. The score was based on the LDL cholesterol-lowering (=inhibitory) effect of each variant, and has previously shown to associate with a stepwise reduction in risk of ischemic vascular disease (=positive control). Variants were also grouped by a simple allele score. Finally, we tested the association between genotype score and allele score with risk of any cancer, death from any cancer, risk of death after a cancer diagnosis, and risk of 28 cancer subtypes.
Results: The cumulative incidence by age of any cancer or cancer death was not associated with genotype score(P-trend across genotype scores: 0.42 and 0.98, respectively). Hazard ratios(HRs) for genotype scores ≥5.0 versus <2.0 were 1.04(95% confidence interval: 0.92-1.19) for any cancer, 1.11(0.85-1.45) for cancer death, and 0.91(0-73-1.14) for death after a cancer diagnosis (P-trend across genotype scores: 0.42, 0.81, 0.98, respectively). In contrast, the corresponding HR for ischemic vascular disease was 0.82(0.71-0.95) (P-trend=0.002). Finally, genotype score did not associate with risk of cancer subtypes (all adjusted P-values≥0.28). Results were similar using allele scores.
Conclusions: Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer, cancer death, death after a cancer diagnosis, or risk of specific cancer subtypes. These results suggest that long-term treatment with ezetimibe does not increase the risk of cancer.
Author Disclosures: B.K. Lauridsen: None. S. Stender: None. R. Frikke-Schmidt: None. B.G. Nordestgaard: Honoraria; Modest; AstraZeneca, Merck, Pfizer, Omthera, Sanofi-Aventis, Regeneron, ISIS Pharmaceuticals, Fresenius and Aegerion. A. Tybjærg-Hansen: Honoraria; Modest; Eli Lilly, LGC Genomics.
- © 2015 by American Heart Association, Inc.