The recent clinical trial showing ezetimibe (whose trade is Zetia and is part of the combination anti-cholesterol pill known as Vytorin) may have increased cancer incidence and deaths has sparked interest in possible causes.
The trial — known as the SEAS trial — was an effort to show the combination pill reduced heart disease. Ezetimibe is unique in that it inhibits cholesterol absorption (as opposed to removing cholesterol from the blood like statins). But ezetimibe also inhibits absorption of dietary plant sterols, and one plausible theory is that the reduction in sterol absorption in the patients in the SEAS trial may have increased their risk of contracting cancer.
Plant sterols, also known as phytosterols, resemble cholesterol in structure but are found exclusively in plant-based foods like fruits, vegetables, nuts and whole grains. If present in foods in sufficient quantity, the Food and Drug Administration has even permitted food manufacturers to claim these foods “may lower the risk of heart disease.” The health claim was approved solely on the basis of clinical trials that showed that plant sterols lower LDL (“bad”) cholesterol. No clinical trial has been conducted that tests the ability of plant sterols to prevent heart attacks and strokes. (Sound familiar? See this GoozNews.)
Plant sterols have also been studied for their anticancer effects. So far, these studies have taken three forms:
1. Epidemiological studies that link diets high in plant sterols to a lower incidence of cancer.
2. Studies in which plant sterols are tested for their effects on cancer cells.
3. Studies in which animals are injected with cancer cells and or cancer-causing chemicals, and a group receiving a plant sterol-enriched diet is compared with a control group.
Numerous population studies have shown that the incidence of colon, breast and protate cancers are relatively low in Asian countries, and that when Asians move to western countries and consume more animal-based diets, the rates of these cancers increase. A series of case control studies carried out at major hospitals in Uruguay has investigated the role of dietary phytosterols in the risk of specific cancers. Total plant sterol intake was associated with specific protective effects in lung, breast, stomach and esophageal cancer. Case control studies are considered less reliable than randomized placebo-controlled trials, however, and no such trials have yet been conducted.
A number of experiments have been conducted in mice and rats, in which animals fed a plant sterol-enriched diet were injected with chemical carcinogens or human cancer cells. For example, one study found that in mice injected with human breast cancer cells, a 32 to 42 percent reduction in tumor size was observed in the group fed a diet enriched in beta-sitosterol, the most common plant sterol. Similar results have been achieved in animal models of prostate cancer and colon cancer.
Tissue culture studies
A number of studies have exposed various types of human cancer cells to plant sterols and have found a slowing of the progression of cells from one stage to another, something that is abnormal in cancer cells. In addition, plant sterols have been found to cause the death of cancer cells, a process called apoptosis. Thirdly, plant sterols have been shown to inihibit changes in cells that take place when tumor cells metastasize. Fourth, studies have shown an increase in growth of cells that are part of the human immune system, such as natural killer cells, which could be protective against cancer. See the studies discussed in this review articles for details.
A tentative hypothesis is that ezetimibe, by inhibiting absorption of dietary plant sterols in the Vytorin group in the SEAS trial, could have promoted the development and/or progression of cancer. Several physicians and scientists contacted by GoozNews thought it was a plausible theory. After looking at some of the studies discussed above, a friend who is an oncologist wrote that “the links you sent certainly provide a plausible explanation for the observed increased cancer risk in the SEAS study.”
It is still uncertain whether ezetimibe in fact increases cancer risk and, if it does, whether plant sterols have anything to do with it. But the connection between sterol consumption and cancer risk reduction is certainly worth investigating further.