Saving Statins

Thom Graves Media Recent findings have some researchers and health professionals calling statins the next aspirin. Some 25 million people worldwide take these enzyme inhibitors to lower cholesterol, creating a nearly $20 billion (US) market in the process. But just as aspirin has expanded its repertoire beyond headaches, statins are showing promise in treating ailments such as Alzheimer disease, multiple sclerosis, and osteoporosis, and some researchers think they could prevent cancer. Nevertheless, dangerous side effects temper this enthusiasm; a few patients have experienced rare muscle degeneration.1 And while some quip that drinking water should be statinated, researchers remain dubious. "No one should ever consider putting [a statin] in the water. It's still a drug. It still causes adverse effects, and its use must be monitored by a physician," says Larry Sparks, senior scientist at Arizona's Sun Health Research Institute. Statins are designed to target just one enzyme, HMG coA reductase, near the beginning of the cholesterol synthesis pathways. Despite the single target, however, statins can have far-reaching effects. First, cholesterol itself is a precursor to a variety of bioactive compounds, including the steroid hormones and vitamin D. Furthermore, HMG coA reductase affects a cascade of diverging pathways, including those that synthesize the antioxidant coenzyme Q and those that prenylate key proteins such as Ras and Rho. "All of the intermediate compounds between HMG coA reductase and cholesterol are being reduced, and this offers a gold mine for looking at other things," says David Kritchevsky, of the Wistar Institute in Philadelphia. Just as a greater understanding of aspirin's mechanisms of action has inspired the development of more specific COX inhibitors, Kritchevsky says that a better understanding of statins' roles in divergent and downstream pathways will aid in developing more specific drugs that directly harness statins' off-target effects. "We never paid attention to these compounds ... but they just offer fantastic potential for discovering new compounds that act on many diseases other than atherosclerosis," he says. A PILE OF EVIDENCE "Statins definitely reduce your incidence of stroke ... so from that standpoint, statins will reduce the risk of dementia," says Len Kritharides, an associate professor at the University of Sydney in Australia. Researchers also are hopeful that statins can combat dementia caused by Alzheimer disease (AD). After all, high cholesterol is a risk factor for AD, and products from the Alzheimer susceptibility gene ApoE form a complex in the brain with cholesterol and the low density lipoprotein receptor. Sparks first glimpsed the relationship between cholesterol and AD when he was a forensic scientist sorting brain slides. "All the demented people were in the heart disease pile," he says. With this clue in hand, he looked for the tell-tale AD protein b-amyloid in the brains of cholesterol-fed rabbits, a great model for heart disease that had until then been ignored by AD researchers. "They had all kinds of b-amyloid in their brains," he says. When he stopped feeding them cholesterol the b-amyloid went away, and when they received cholesterol-lowering drugs it didn't build up in the first place.2 Sparks says that cholesterol doesn't necessarily cause AD, but instead fuels the fire once the other important players such as b-amyloid are in place. "Cholesterol promotes the production of this toxin, b-amyloid," he says, but then other environmental and genetic factors cause it to build up to disease-causing levels. Cholesterol may influence b-amyloid production by increasing the exposure of the b-amyloid precursor protein (APP) to b-secretase, which processes APP into toxic fragments. Or, cholesterol may inhibit b-secretase, which produces nonharmful fragments. And although the roles of inflammation and immune response in AD are far from dogma, a variety of studies have suggested that statins could modulate both. They might work, for example, by reducing C-reactive protein levels in the plasma and inhibiting the activation of NF-kB by isoprenylation.3,4 Thus, it is tempting to theorize that statins could influence the development of AD through anti-inflammatory or immunomodulatory action. DOWNSTREAM EVENTS There is little doubt that the immune system is central to the disease process in multiple sclerosis (MS), and in a recent mouse study ator-vastatin restored movement to paralyzed animals and prevented further paralysis. "These effects [of statins] on the immune system are entirely independent of their effects on cholesterol," says Lawrence Steinman, professor of neurology and neurological science at Stanford University. CHOLESTEROL, INTERRUPTED: Drugs like statins and n-bisphosphonates act early in the cholesterol synthesis pathway.Click to view enlarged diagram (PDF, 34K) Statins influence the immune system and may influence MS outcomes by blocking the production of MHC class II antigen, which converts Th0 immune cells to the Th1 form that leads to inflammation. Steinman says they're working on the mechanism and believe it involves metabolites downstream of statins but upstream of cholesterol synthesis. "Some of these are unexpected and of immense importance in modulating the immune system," he says. "Another area [in which] statins may have unexpected activity is in cancer, because the same pathways that are at work in the immune system are also in play in neoplastic cells," says Steinman. Jane Cauley, professor of epidemiology at the University of Pittsburgh agrees but also cautions that epidemiological studies have, at best, provided mixed results. "The studies are not consistent, and the epidemiological data is not strong showing a relationship between total cholesterol and the development of cancer." Nevertheless, she was inspired to undertake a large, prospective, observational study after reviewing the long-term cancer follow-up results from the Scandinavian simvastatin survival study (4S). People in the study had a lower risk of dying of cancer. The results were not statistically significant, but Cauley says they were, "hypothesis generating," particularly when viewed in light of animal data showing that statins inhibit tumor growth. And indeed, her study found a reduction in breast cancer in women who take both statins and other cholesterol-lowering drugs.5 UNKNOWNS ABOUND Cauley, too, acknowledges she doesn't know how statins mechanistically exert their effects, but because the incidence of cancer was reduced whether patients used statins or other cholesterol-lowering drugs, she suspects the effect is directly related to cholesterol levels. Cauley also notes other possible statin mechanisms that could be influencing cancer. In addition to immunomodulation and anti-inflammatory effects, researchers have presented studies showing that statins may activate enzymes that degrade cell-cycle proteins, which is clearly something that could have an effect on cancer cells. Even lowering of lipids alone could lead to an indirect effect such as a change in sex steroid levels that perturb cancer. Despite the uncertainty, Cauley says the collection of data is promising. "[It] suggests that this whole idea is not just a statistical fluke, but there is some biological plausibility," she says. Osteoporosis appears the least likely candidate to have a statin connection. "Bone density doesn't seem to have any connection to cholesterol," says Kritchevsky. Nevertheless, in 1999 Gregory Mundy showed that statins increased the expression of bone morphogenetic protein-2 (BMP-2) and enhanced new bone formation in mice.6 Furthermore, bisphosphonates, drugs that inhibit bone resorbtion, act in the metabolic pathway between HMG coA reductase and cholesterol. As with AD, multiple sclerosis, and cancer, no randomized, controlled human clinical trial has been done yet to prove a benefit. After-the-fact analysis of patients from the cholesterol-lowering trials showed that patients got fractures at the same rate whether they were taking statins or not. These trials have limitations because enrollees may not have been at high risk of osteoporosis in the first place. For example, such trials tended to have fewer women than men enrolled as well as people who would have been too young to show clinical signs of osteoporosis. Despite the limitations, Kritharides is reluctant to dismiss the studies' negative findings. "They are incredibly powerful because they are randomized and controlled," he says. Even so, Kritharides says the results from other observational studies warrant further research into the effect of statins on osteoporosis. The good news about statins is that despite concerns about rare side effects, these drugs, which so many people already rely on to reduce their risk of atherosclerosis, could also be reducing their risk of diseases such as cancer and AD. If statins are indeed found to prevent or treat other conditions, Food and Drug Administration approval is likely to be accelerated because of the existing data from the millions of people already using them, says Steinman. "Instead of taking 10 years, you could just work with the established compound." Mignon Fogarty (mignon@welltopia.com) is a freelance writer in Santa Cruz, Calif. References 1. E. Laise, "The Lipitor dilemma," Smart Money, 12:90-6, November 2003. 2. D.L. Sparks et al., "Cholesterol and cognition: rationale for the AD cholesterol-lowering treatment trial and sex-related differences in b-amyloid accumulation in the brains of spontaneously hypercholesterolemic Watanabe rabbits," Ann NY Acad Sci, 977:356-66, 2002. 3. P.M. Ridker et al., "Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators," Circulation, 100:230-5, 1999. 4. A. Hilgendorff et al., "Statins differ in their ability to block NF-kB activation in human blood monocytes," Int J Clin Pharmacol Ther, 41:397-401, September 2003. 5. J.A. Cauley et al., "Lipid lowering drug use and breast cancer in older women: A prospective study," J Womens Health, 12:749-56, October 2003. 6. G. Mundy et al., "Stimulation of bone formation in vitro and in rodents by statins," Science, 286:1946-9, 1999. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? 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Saving Statins

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