11.4.1 Therapy of hypercholesterolemia

The obvious way of treating the various forms of hypercholesterolemia is to try and lower the blood cholesterol level. What therapeutic principles are available to do this? Several:

Limiting the dietary intake of cholesterol. Since cholesterol occurs only in animals but not plants, an obvious way of restricting intake of cholesterol is or reduction of meat and eggs in favour of fruit and vegetables.
Vegetables are also rich in poly-unsaturated fatty acids (those with several C=C double bonds) and in carbohydrate fibers, which seem to have a greater favourable effect than restriction of cholesterol itself.
Inhibition of intestinal uptake of cholesterol. This can be done with sitosterol, a plant sterol that has no role in human metabolism. The mechanistic aspects of this inhibition are not clear but it appears to be some kind of competition, which in turn suggests a specific uptake mechanism for cholesterol. Uptake can also be inhibited by ezetimibe and other recently developed drugs. The target protein in the intestinal membrane that ezetimibe binds to has been identified, but the mechanistic details of cholesterol transport are unsettled.
Inhibition of endogenous cholesterol synthesis. The most important class of synthesis inhibitors are the statins, for example lovastatin, which mimic mevalonate in structure and block the active site of HMG-CoA reductase (Figure 11.4-1).
Promotion of cholesterol elimination, by way of bile acid depletion.

As stated above, bile acids are derived from cholesterol. Out of the considerable amount of bile acids secreted (several grams per day), approximately 95% are taken up again in the terminal ileum (the lowest section of the small intestine) and recycled. Cholestyramine is a granular polymer that combines hydrophobic and cationic binding sites, which interact avidly with the hydrophobic and anionic moieties of bile acid molecules. Ingested cholestyramine will bind bile acids and take them along down the pipe. To replace the lost bile acids, the liver will increase their synthesis and therefore deplete the pool of cholesterol.

Apart from bile acids, cholesterol itself is also secreted into the bile, and bile acids help to keep it dissolved. A drawback of cholestyramine is that, by depleting bile acids, it promotes the precipitation of cholesterol, leading to the formation of cholesterol bile stones.

While for maximum effect the different principles are often combined, inhibition of synthesis with statins is the most effective single principle and nowadays has a prominent place in therapy.