JUN 30, 2014 12:00 AM PDT

Research Results May Lead to the First Major New Heart-Disease- Fighting Drugs in Years

WRITTEN BY: Peter Micheli
With about 720,000 Americans having one each year, heart attacks are still a leading killer in the U.S. Still, since statins roared on the scene in the 1980's no major new drugs have been approved for lowering the risk of heart disease.

This may be about to change due to the findings of two independent just-published studies, one by the Cambridge, MA-based Broad Institute and another by Copenhagen University Hospital. Both identified mutations in a gene that keep levels of triglycerides in the blood very low for a lifetime. Although statins can be used to keep heart-disease causing LDL cholesterol low, high levels of triglycerides can still lead to heart attacks. The studies show that people who have mutations in the APOC3 gene had much lower levels of triglycerides and much lower heart attack risk than those without the mutations. The APOC3 gene creates a protein that slows the removal of triglycerides from the bloodstream. Scientists theorize that in people who have the mutation, the protein is greatly decreased, keeping triglycerides levels low.

Also, high levels of HDL (the "good" cholesterol) were long thought to help prevent heart attacks. But, clinical trials of HDL-raising drugs have failed to prove that, suggesting that HDL may be less important than believed. "Everyone's been looking for what are the pathways - what are the key ways that people get heart attacks beyond LDL cholesterol," said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and an associate member of the Broad Institute who led the new study. "For 20 to 30 years, people have been thinking it's HDL, and trying to raise HDL. This work suggests it's actually the triglycerides that are important."

These two recent studies echo findings of research conducted among the Amish in 2008. About 1 in 20 Amish people carry a mutation in the APOC3 gene as compared to 1 in 150 in the general American population. Among the mutation-carrying Amish, it was found that their triglyceride levels didn't spike after drinking a fatty, 1,500 calorie milkshake and that this effect was found over their lifetimes, leading to much less coronary artery disease.

The study findings are expected result in efforts to develop drugs that mimic the effect of the triglyceride-lowering mutations. Dr. Daniel J. Rader, the director of the Preventive Cardiovascular Medicine and Lipid Clinic, who was not involved with the studies, said, "We've been looking for something beyond statins. After we have put people on high-dose statins, what else can we do? Essentially nothing."

A small California company, ISIS, already has a drug in development that lowers triglycerides by counteracting the APOC3 gene. In tests it has been shown to reduce levels by 71%. The ISIS drug, however, was being developed as an "orphan" drug for the small group of people who have triglyceride levels so high they can be fatal (over 1,000 mg/dL). (Normal levels should be 150 mg/dL or less.) It is the most important drug in our pipeline," said Dr. Stanley Cooke, ISIS's chief executive. "Trust me, these data are really exciting."

Still the small company has no plans to test whether its drug will prevent heart attacks in the general population. Such as study would have to go on for years and require very deep pockets.

But, for drug companies the stakes are huge. Pfizer's cholesterol-lowering drug, Lipitor, became the best-selling drug in history, with annual sales of $11 billion. The potential for such a big playoff should set the large pharmaceutical companies on a determined quest for triglyceride-lowering drugs.
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