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Lowering Cholesterol: Beyond Statins

A new crop of drugs look to drop lipid levels and prevent heart disease by targeting genes.

By Timothy Gower // Winter 2011
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Some of the first humans to receive compactin and lovastatin in the late 1970s and early ’80s were patients with familial hypercholesterolemia, an inherited condition marked by soaring levels of LDL cholesterol from birth that, if left untreated, can cause heart attacks early in life. Researchers continue to study people with extreme lipid profiles, both high and low, in hopes of developing novel cholesterol-lowering drugs. Many doctors agree that although statins are powerful medications, some patients would benefit from additional new therapies to bring down their LDL cholesterol even more.

Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital, has been scrutinizing the genetic profiles of an extended St. Louis family with low LDL levels; none of its 38 members has any history of coronary artery disease. In a recent study published in the New England Journal of Medicine, Kathiresan and his colleagues reported that four members who have mutations on a gene called ANGPTL3—which, in its normal state, raises LDL by some unknown mechanism—had LDL levels of only 33 milligrams per deciliter on average, far lower than the typical reading of 130 mg/dL.

In an earlier study, investigators at the University of Texas Southwestern Medical Center at Dallas found that 2.6% of African Americans have mutations on a gene called PCSK9—and an astonishing 88% reduced risk for heart attacks. Functioning PCSK9 genes are responsible for a protein that destroys LDL receptors, allowing less cholesterol to be removed from the blood, explains UTSW gastroenterologist Jay Horton. Ironically, statins actually turn up the activity of PCSK9. “Potentially, if you could block the action of PCSK9, it would work at least additively with the statin, if not synergistically,” he says.

Pharmaceutical manufacturers have already begun testing drugs that target ANGPTL3 and PCSK9. One such company, Regeneron, recently reported that an injected drug that targets PCSK9 proved to be safe in early human trials—and lowered LDL cholesterol by as much as 60%. However, even if this line of research fails to produce a viable drug, more targets await. After studying the genomes of 100,000 men and women, Kathiresan and his colleagues recently published in Nature a study that identified 95 gene regions linked to the regulation of lipid levels. He predicts that the research will yield new therapies for reducing LDL within a decade.

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