Developing Drugs to Lower Cholesterol

With the elucidation of the pathway of cholesterol synthesis by Konrad Bloch and others, pharmaceutical companies became interested in finding an inhibitor of the cholesterol synthesis. The first such inhibitor was MER-29, known as triparanol. Triparanol inhibited the final step in cholesterol biosynthesis and led to accumulation of a precursor of cholesterol des- mosterol. Unfortunately, the accumulation of this drug resulted in cataract, hair loss, and other side effects. It was withdrawn in the early 1960s due to these adverse reactions.

This experience made the pharmaceutical companies cautious about the development of an inhibitor of cholesterol synthesis. The next class of lipid-lowering drugs to be developed were called fibrates or fibric acid derivatives. The mechanisms by which fibrates lower blood cholesterol levels are still uncertain. They are most effective for reducing cholesterol and LDL-C in individuals who have elevations in cholesterol and LDL-C but with normal triglyceride levels.

The first such fibrate, clofibrate, Atromid-S, was approved by the FDA in the 70s, and it decreased LDL-C by about 10%-15% and raised HDL by about 10%, but decreased TG by 30% or more. In the World Health Organization Study of clofibrate, there was a decrease in non-fatal MIs but an increase in overall mortality due mainly to adverse events in the gastrointestinal tract, including GI malignancies.

These results provided further caution to pharmaceutical companies in the development of cholesterollowering agents. In the meantime, a Dow ion exchange resin was used as a bile acid seques- trant called cholestyramine, which was used in the Coronary Primary Prevention Trial. This was sponsored by the National Heart, Lung, and Blood Institute. It was difficult to recruit patients and the drug had limited patient acceptance due to common gastrointestinal side effects, including bloating and constipation. Participants took only Уг the prescribed dose of the drug. In this 7-year trial, LDL was lowered by 12.6%, HDL was increased by 3%-5%, and there was a significant reduction in CHD by 19%.

The Coronary Primary Prevention Trial was the first definitive trial to test the lipid hypothesis, which aimed to reduce total cholesterol, LDL cholesterol, and coronary events? This was an important trial, even though it did not lead to widespread use of bile acid sequestrants, and cholestyramine did not receive FDA approval for an indication to reduce coronary events. Nonetheless, the Coronary Primary Prevention Trial was an important milestone in that it led to the adoption/establishment by the NIH of the National Cholesterol Education Program and subsequently, to a series of cholesterol guidelines over the years, continuing to the present.

NHLBI also supported a trial using ileal bypass surgery called POSCH, which resulted in reduction of LDL cholesterol and decrease in myocardial infarctions. The POSCH study demonstrated this benefit of ileal bypass surgery, which, like bile acid sequestrants, decreased the absorption of bile acids, resulting in an upregulation of LDL receptors in the liver.

Beginning in the 1980s, removal of LDL by apheresis became available. In apheresis, patient’s blood is filtered through a column which binds LDL and apoB-containing proteins. The process takes 2-4 hours per treatment and must be repeated on a weekly or biweekly basis. However, it is quite effective in reducing LDL and apoB-containing proteins for individuals for whom drug therapy is not available or effective.