June 2011 Issue

One Pill, Many Benefits? — Statins’ Potential May Extend Beyond Lowering Cholesterol
By Megan Tempest, RD
Today’s Dietitian
Vol. 13 No. 6 P. 32

When diet and exercise aren’t enough, statins can effectively bust high LDL levels. But can they also help treat cancer, liver disease, and more?

Despite RDs’ best efforts to promote sound diet- and lifestyle-based interventions, the first line of defense against elevated cholesterol is often a pharmaceutical one.

Statin drugs refer to a large class of medications known as HMG-Co A reductase inhibitors, which essentially block the metabolic pathway that produces cholesterol in the body. The Mayo Clinic reports that, in addition to inhibiting cholesterol synthesis, statins may encourage the body to reabsorb existing cholesterol. Experts believe statins reduce serum LDL levels and prevent plaque build-up in artery walls, thus protecting against blocked blood vessels and heart attack.

Michael Hudson, MD, a cardiologist at Henry Ford Hospital in Detroit, believes statins are one of the most important breakthroughs in cardiovascular disease (CVD) medicine in the last century and are an essential component of reducing stroke and heart attack risk in patients with CVD. He strongly supports their use: “They unequivocally reduce the risk of heart disease and stroke, regardless of your cholesterol level. For those [who] have diagnosed cardiovascular disease, statins are one of the most effective treatments for their condition, even if they have a perfect diet.”

According to the American Heart Association (AHA), statin drugs are highly effective in reducing LDL cholesterol levels in the blood and pose very few immediate short-term side effects. Other benefits include ease of administration and few known drug-drug interactions. Statin use is contraindicated in pregnant women, people with current or chronic liver disease, and anyone with a known statin allergy. The AHA recommends that drug therapy be considered for patients when they’ve been unable to adequately treat elevated cholesterol levels through dietary changes, physical activity, and weight loss.

Generally speaking, the medical community has embraced the use of statins for preventing and treating CVD. Now, research is pinpointing statins’ potential health benefits beyond simply lowering cholesterol. This article highlights recent research suggesting that statins may eventually become a viable treatment for myriad medical conditions.

Beyond CVD Prevention and Treatment
Cancer
Epidemiological studies have strongly suggested that statins may be useful in treating and preventing certain cancers, particularly prostate cancer, a significant cause of death among men in the United States. Statins may work by lowering serum levels of prostate-specific antigens.

Scientists at Kyushu University in Japan investigated the potentially therapeutic effects of statins on prostate cancer in the February issue of The Prostate. They found that statins decreased androgen receptor proteins via proteolysis, which in turn lowered androgen sensitivity and cell proliferation in androgen receptor-positive prostate cancer cells.

Researchers at the University of Georgia published their research on the statin-prostate cancer link in the February issue of the Journal of Pharmacology and Experimental Therapeutics. The study focused on simvastatin, a drug widely used for preventing cardiovascular events such as stroke and heart attack that is, according to the authors, “well known for its effects on cell proliferation and inflammation, two key processes that also determine the rate of tumor growth.” (See sidebar for a list of commonly prescribed statins.)

Based on their findings, the team concluded there are therapeutic benefits of simvastatin in treating prostate cancer but not without acknowledging that “although a growing body of evidence suggests that statins have the potential to reduce the risk of many cancers, there are discrepancies over the pro- and anticancer effects of statins.”

In the December 2010 issue of Gynecologic Oncology, Taylor-Harding and colleagues assessed fluvastatin’s ability to work synergistically with the chemotherapy drug cisplatin to inhibit the proliferation of epithelial ovarian cancer cells. Combined treatment with both drugs showed significantly greater inhibition of cell proliferation than when the drugs were administered alone. Combined treatment with these two drugs caused premature cell apoptosis and cell cycle arrest, demonstrating what the authors consider a “plausible therapeutic role for statins in the adjuvant treatment of ovarian cancer.”

Colorectal cancer treatment may also benefit from statin therapy, as evidenced by a meta-analysis of randomized clinical control trials and epidemiological studies conducted by French researchers Bardou and colleagues in November 2010. The team found a modest yet statistically significant protective effect of statin drugs, attributed to their ability to sensitize colorectal tumors to chemotherapy and potentially inhibit the metastatic properties of colorectal cancer.1

German researchers Relja and colleagues also reported statins’ tumor-suppressing capability in the November 2010 issue of the International Journal of Molecular Medicine. They found that simvastatin has the ability to induce tumor cell apoptosis in hepatic cancer and exert an antiproliferative effect.

Neurological Damage
Another growing area of scientific interest in statin drugs is their potential to treat neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Further research is needed to validate this potential function of statin drugs and to pinpoint the precise mechanism of action.

According to Wood and colleagues from the University of Minnesota, the support for statin-induced neuroprotection comes in part from studies using animal models and cell culture. “Important information has resulted from that work, but there continues to be a lack of progress on basic issues pertaining to statins and brain that impedes advancement in understanding how statins alter brain function.”2

In the January 2010 issue of Neurotherapeutics, researchers at Duke University School of Medicine addressed statins’ neuroprotective potential, referring to preclinical studies showing a significant benefit from statins in treating traumatic brain injury and other related neurological conditions such as intracerebral hemorrhage and subarachnoid hemorrhage. The authors reported that previous studies had defined several mechanisms by which statins provided benefits after traumatic brain injury. An ongoing clinical trial being conducted by researchers at Universidad Autónoma de San Luis Potosí in Mexico is exploring this important relationship.

Having previously observed statins’ potential to improve amnesia and disorientation following moderate head injury, the investigators now seek to analyze the immunomodulating effects of statins on head injury. They postulate that rosuvastatin may play a role in preventing secondary damage in traumatic brain injury that is believed to result from the body’s immunological response.3

Based on a broad review of animal research, observational studies, randomized control trials, and meta-analyses, researchers from the Hotchkiss Brain Institute at the University of Calgary concluded that statins’ role in managing subarachnoid hemorrhage is promising but still largely unclear, asserting that “statins should not, at this time, be considered standard care.”4 In fact, a study by Ricard and colleagues, published in the November 2010 issue of the Canadian Journal of Neurological Sciences, emphasized the need for caution until further research better defines the effect of statins on brain injury. These investigators analyzed 71 subjects who were taking statins at the time of intracranial hemorrhage and found that treatment with statins may be a risk factor for increased intracranial hemorrhage volume in the presence of spontaneous brain hemorrhages and may contribute to hemorrhages’ volume progression.

A systematic Cochrane Database review, “Statins for Multiple Sclerosis,” by Wang and colleagues, published in December 2010, sought to evaluate the efficacy and safety of statin therapy in treating multiple sclerosis. According to the authors, statins have shown notable benefits in treating multiple sclerosis in previous experimental and preliminary clinical studies. However, based on their review, they concluded that insufficient evidence currently exists to support the use of statins as a means of treating this condition, and further randomized controlled trials are needed to clarify this relationship.

Inflammatory Disease
Using statins to treat inflammatory disease may also be on the horizon. A February 2011 issue of the American Journal of Cardiology published the study “Effects of Maximal Atorvastatin and Rosuvastatin Treatment on Markers of Glucose Homeostasis and Inflammation” conducted by Thongtang and colleagues from Tufts University in Boston. The team analyzed 252 hyperlipidemic men and women who were randomly prescribed atorvastatin or rosuvastatin for a six-week period. Both drugs were found to be very effective in lowering LDL cholesterol and triglyceride levels in the subjects, while rosuvastatin was shown to be more effective in increasing HDL cholesterol. Both drugs were found to significantly decrease median C-reactive protein levels; however, they also significantly increased median insulin levels from baseline.

In the December 2010 issue of Aging, Japanese researchers Yudoh and Karasawa published their study examining the anti-inflammatory potential of statin drugs, focusing on their ability to prevent catabolic stress-induced chondrocyte aging and degeneration of articular cartilage in individuals with osteoarthritis. Based on their finding, they concluded that statin medications are a potentially effective therapeutic agent for protecting articular cartilage against the progression of osteoarthritis.

Liver Disease
Ongoing research is demonstrating statin drugs’ potential to prevent and treat liver disease. As published in the January issue of the American Journal of Gastroenterology, Foster and colleagues analyzed 1,005 men and women (as part of the St. Francis Heart Study) to determine whether statin therapy may be an effective treatment option for patients with nonalcoholic fatty liver disease (NAFLD). They concluded that the use of atorvastatin in combination with vitamins C and E is effective for reducing the risk of hepatic steatosis by 71% in healthy individuals with NAFLD at baseline following four years of therapy.

In a December 2010 issue of the Lancet, Athyros and colleagues published the Greek Atorvastatin and Coronary Heart Disease Evaluation Study, a posthoc analysis of the safety and efficacy of long-term statin therapy for cardiovascular events in patients with coronary heart disease and abnormal liver tests. Drawing from a sample of 437 subjects with moderately abnormal liver tests at baseline, possibly associated with NAFLD, 227 who were treated with statins showed substantial improvement in liver tests, while 210 not treated with statins displayed further increases in liver enzyme concentrations. The investigators concluded that statin treatment is safe and can improve liver function while reducing cardiovascular morbidity in patients with mild to moderately abnormal liver tests that may be related to NAFLD.

The benefit of statins for individuals with chronic hepatitis C infection was the focus of a study by Rao and Pandya of the Kansas City Veterans Affairs Medical Center, published in the January issue of Gastroenterology. The authors reported that people with hepatitis C are two to three times more likely to develop type 2 diabetes and thus have a lower chance of achieving a sustained virological response. The findings led the authors to conclude that statins are associated with improved sustained virological response among both diabetic and nondiabetic patients with hepatic C receiving combination antiviral treatment.

In the report “Prolonging Survival in Patients With Cirrhosis: Old Drugs With New Indications,” published in the December 2010 issue of Gastroenterology, Tsochatzis and colleagues pinpointed statin drugs for their hepatoprotective benefits, citing a double-blind randomized controlled trial that showed simvastatin had the ability to lower hepatic venous pressure gradient in patients with cirrhosis and significantly improve liver perfusion and function. The authors also noted statins’ ability to provide benefits beyond portal hypertension, such as to reduce risk of hepatocellular carcinoma (HCC). Making a case for further research, the authors stated, “Preventive therapies for HCC could substantially impact on waiting lists for liver transplantation, because 10%-15% of transplants are done solely for this indication. Statin-induced hepatotoxicity is not increased in the presence of liver disease and is rare.”

Statins’ Risks and Benefits
According to the Mayo Clinic, potential risks of long-term statin administration range from less serious side effects such as nausea, diarrhea, and muscle pain to more severe effects such as liver damage.

Hudson says higher doses of statin drugs may cause myalgia and muscle pain but pose only a small risk of liver injury. “A fair number of patients experience side effects like myalgia, especially with higher doses. Some of the other more serious concerns, like liver disease, have been greatly overstated. Statins are safer than most OTC [over-the-counter] meds like antacid or cold medicine,” he says.

Dawn E. Kopf, MMS, PA-C, of the Colorado Bariatric Surgery Institute in Denver, has observed similar side effects. “Myalgia and muscle cramping are the primary side effects that most of our patients complain about,” she says.

In response to the concern that long-term statin use may cause liver damage, her thoughts echo Hudson’s: “ I can think of a lot of other drugs that are more likely to promote liver damage, and I agree that the risk of liver damage related to statin drugs may be overstated. If you have a diagnosis or have family history of dyslipidemia, the benefits of taking a statin medication probably far outweigh the risks.”

While Kopf prefers that her patients achieve health benefits by nonpharmaceutical means and dietary changes, she concedes this strategy may not work for everyone. “If high cholesterol runs in your family—it’s in your genetic makeup—you probably can’t get away from developing it. In this case, I don’t see any risk or harm in being proactive,” she says. “For minor dyslipidemia, especially low HDL, I think diet and lifestyle changes, like eating an overall healthy diet, taking fish oil, or taking niacin, which has been clinically proven to raise HDL, are a great place to start. But when your LDL is high, statins are extremely beneficial.”

Christine Benesh, RD, LD, of the Cleveland Clinic Foundation, sees statin medications frequently prescribed for patients with elevated cholesterol levels and diagnosed CVD. “Statins can clearly help to lower cholesterol but are not intended to cure cardiovascular disease,” she says.

She reinforces the importance of adopting healthful lifestyle behaviors, including proper nutrition and exercise, rather than relying on statin drugs to do all the work. “People with cardiovascular disease and elevated cholesterol still need to follow a low-cholesterol, low-animal fat, and low-sodium diet. And exercise, with physician approval, is also very important,” she says.

As for the long-term effects of statin use and the potential health benefits outside of lowering cholesterol, Benesh is cautious but open to the possibilities: “Statins are relatively new drugs, and we do not really know the long-term side effects.”

Kopf is encouraged by the new research suggesting statins may provide significant means of treating medical conditions beyond CVD. “Research into using statins to treat certain forms of cancer is showing promising evidence. The mechanism in statin drugs that works to inhibit fat production in the liver may also prevents cell synthesis, tumor development, and mestastatis. Given the high prevalence of some of these cancers, why not try statin therapy?” she says.

While a fervent advocate of using statin medications for their known cardiovascular benefits, Hudson remains skeptical of the reported health benefits outside this realm. Regarding the growing body of research that suggests the benefits of statins in treating conditions such as cancer and neurological damage, Hudson isn’t convinced. “Several studies suggest benefits, for say cancer or dementia, but none of them are convincing,” he says. “Patients should not take a statin for those reasons. The major proven benefit of taking statin medications is to lower total and bad LDL and prevent heart attack and stroke.”

— Megan Tempest, RD, works at Presbyterian/St. Luke’s Medical Center in Denver and is a freelance writer.

 

Commonly Prescribed Statins
• Atorvastatin (Lipitor)
• Lovastatin (Mevacor)
• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Simvastatin (Zocor)

 

References
1. Bardou M, Barkun A, Martel M. Effect of statin therapy on colorectal cancer. Gut. 2010;59(11):1572-1585.

2. Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: A prescription to move the field forward. Ann N Y Acad Sci. 2010;1199:69-76.

3. Sanchez-Aguilar M, Gordillo-Moscoso A. Effect of rosuvastatin on cytokines after traumatic brain injury: Clinical randomized double blind study phase 2. In: ClinicalTrials.gov (Internet). Mexico: 2009. Available at: http://clinicaltrials.gov/ct2/show/NCT00990028. NLM identifier: NCT00990028.

4. Kramer AH. Statins in the management of aneurysmal subarachnoid hemorrhage: An overview of animal research, observational studies, randomized controlled trials and meta-analyses. Acta Neurochir Suppl. 2011;110(Pt 2):193-201.

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