Inactivated Protein Lowers Risk of Coronary Heart Disease by 53%

By Allison Proffitt 

 

November 12, 2014 | A sequencing study published tomorrow in the New England Journal of Medicine has further characterized the activity of the Niemann-Pick C1-like 1 protein (NPC1L1). Carriers of inactivating mutations of NPC1L1 were found to have a 53% lower risk of coronary heart disease and an average LDL cholesterol level 12 mg per deciliter lower than that of noncarriers. 

 

An interesting finding on its own, the paper (DOI: 10.1056/NEJMoa1405386) could carry weight in an ongoing discussion about cholesterol drugs.  The NPC1L1 protein is the target for Merck’s cholesterol drug ezetimibe—sold commercially alone as Zetia and in combination with simvastatin as Vytorin. In drug discovery, it’s essential to choose your targets wisely

 

Ezetimibe lowers low-density lipoprotein (LDL) in the blood by inhibiting the activity NPC1L1 in the liver and intestines, explains Sekar Kathiresan, a senior author on the study, Broad associate member, and director of preventive cardiology at Massachusetts General Hospital.  “We reasoned that maybe there are people walking around who naturally have a mutation in the NPC1L1 gene that breaks that gene.” (Kathiresan lists among his disclosures an investigator-initiated grant from Merck, but said that the grant is unrelated to this research.) 

 

Kathiresan and his team conducted exome sequencing on 20,000 individuals: 10,000 who had had heart attacks at a young age—suggesting a genetic component—and 10,000 who had not. 

 

The researchers found 15 mutations that were expected to inactivate NPC1L1. About 1 in 650 participants were found to have heterozygous inactivating mutations. (No one in this cohort had a homozygous mutation; Kathiresan estimates that he would need about 1 million samples to find someone who is homozygous.) 

 

 “With [those data] in hand,” Kathiresan said, “we said ok… the people that carry that mutation, do they have lower amount of blood LDL cholesterol, and more importantly, do they have a lower risk of heart attack.”

 

The team genotyped the most common of the mutations, p.Arg406X, in 22,590 participants with coronary heart disease and 68,412 controls and found that carriers of an NPC1L1 inactivating mutation had an average LDL cholesterol level 12 mg per deciliter lower than that of noncarriers. Carriers also had a 53% lower risk of coronary heart disease. 

 

“What’s remarkable is the effect on LDL is nearly identical [between drug treatment and mutation],” Kathiresan said. “If you take a pill of ezetimibe, you basically lower your LDL by about 15 mg/deciliter. People who carry the mutation have about 12 mg/deciliter lower LDL.” 

 

That question—whether or not LDL lowered by taking an ezetimibe pill actually decreases the risk of heart attack—is being addressed by the closely-watched IMPROVE-IT study (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial). The trial looked at cardiovascular outcomes for statin treatment alone compared to statin plus ezetimibe, and results will be announced next week. 

“It’s natural to think that because the genetic variant reduces the risk of heart attack that automatically means that the drug should reduce risk of heart attack in a clinical trial,” Kathiresan said. “[But] you can’t automatically draw that conclusion.” 

 

One difference between natural decrease of LDL and the decrease brought on by a pill, he points out, is the timing. “We’re seeing that lifelong inactivation [of NPC1L1] reduces risk of coronary disease by 50%. On Monday, we’ll see what [reduction of risk] comes from four years of treatment starting at age 55 or 60.” 

 

Comparing the two will have major implications for how we consider coronary heart disease treatment and prevention, Kathiresan said. “A small amount of LDL change over a lifetime could have profound effects on coronary heart disease. The major issue with LDL might not be how low you get it, but actually long you treat.” 

 

“I don’t know if it has to be a drug regimen,” he adds. “I’m a preventive cardiologist. I would hope that it’s lifestyle!” 

 

The IMPROVE-IT results are set to be announced on November 17 at the American Heart Association Meeting. Predictions abound, though a Merck accounting filing on Monday seemed promising. The accounting disclosure in a regulatory filing suggests that after unblinding the data, Merck doesn’t expect the results to significantly diminish the remaining value of the drugs, the Wall Street Journal reported on Monday. 

 

Regardless of the IMPROVE-IT results, Kathiresan’s findings will still be telling for the cardiovascular drug space, he said. NPC1L1 now joins three other genes that have been found to offer protective effects for against heart or metabolic disease. (PCSK9 and AP0C3 have also been found to protect against heart disease, and SLC30A8 has been shown to protect against type 2 diabetes.)

 

Kathiresan describes it as the hottest idea in drug development: “Looking for mutations that protect against disease and then developing medicines that mimic the natural successes of the genome… In this case, we’re saying, ‘Let’s find the natural experiment where genes are broken by mutations and as a result of that people have reduced risk of disease.’”