Individuals with a naturally-occurring heterozygous mutation in NPC1L1, a gene that encodes the Niemann–Pick C1-like 1 protein, have a lower plasma LDL-cholesterol level and a reduced risk of coronary heart disease (CHD) compared with noncarriers. These findings, from the Myocardial Infarction Genetics Consortium investigators, were published in The New England Journal of Medicine.

NPC1L1 regulates cholesterol transport in the intestine and is targeted by ezetimibe, which lowers LDL-cholesterol levels by ∼50%. However, whether ezetimibe actually decreases the risk of CHD in patients is unclear, and has been investigated in the IMPROVE-IT trial. The consortium investigators used a genetic approach to determine whether mutations in NPC1L1 that decrease the protein's activity by 50% have a similar effect on LDL-cholesterol level to that of ezetimibe, and whether this effect translates into a lowering of CHD risk.

The team sequenced the exons of NPC1L1 in 7,364 individuals with CHD and 14,728 individuals who did not have the disease, and identified 15 mutations. The investigators then genotyped a further 22,590 patients with CHD and 68,412 control participants for the presence of the most common NPC1L1-inactivating variant, p.Arg406X. In individuals for whom plasma lipid levels were available (n = 42,813), those who were heterozygous carriers for p.Arg406X had a significantly lower LDL-cholesterol level (mean adjusted difference −12 mg/dl [0.31 mmol/l]; P = 0.04) than noncarriers.

Interestingly, patients with CHD were less likely to be a heterozygous carrier of an NPC1L1-inactivating mutation than healthy individuals (carrier frequency 0.04% versus 0.09%). This difference equates to a 53% reduced risk of developing CHD in carriers of the mutation (OR 0.47, 95% CI 0.25–0.87, P = 0.008).

These results mimic the effect of ezetimibe on LDL-cholesterol levels, and suggest that this drug will also lower the risk of CHD. Indeed, the investigators of the IMPROVE-IT trial, who presented data at the AHA Scientific Sessions 2014 in Chicago, IL, USA, confirm that adding ezetimibe to statin therapy does indeed lower the risk of adverse cardiovascular events.