Overview

PART I

  • Overview – Cholesterol
  • What are statins?
  • How simvastatin works and how it might affect Alzheimer’s
  • How cholesterol is related to Alzheimer’s
  • Considerations for treatment with simvastatin (Zocor)

PART II

  • Side effects of simvastatin (Zocor)
  • Simvastatin (Zocor) dosage considerations
  • Drug interactions with simvastatin (Zocor)
  • Food interactions with simvastatin (Zocor)
  • Alternatives to simvastatin
  • Combination therapies with simvastatin
  • Discontinuing simvastatin therapy
  • Final thoughts

Overview – Cholesterol

Since the discovery of cholesterol in gallstones in the year 1784, thirteen Nobel Prizes have been awarded for research devoted to the study of cholesterol and cholesterol medications. Why is it so important to study cholesterol? This waxy, fatty substance is primarily produced in the liver and is an essential part of all human cells.

Cholesterol does the following:

  • It helps synthesize hormones such as estrogen and testosterone.
  • It forms the substance that absorbs and digests fat from our food.
  • It helps our skin retain moisture.
  • It blocks absorption of some harmful compounds.
  • It manufactures vitamin D.

Cholesterol has important functions, making it an essential substance in the body. However, if concentrations of cholesterol in the blood get too high, cholesterol can become a “silent killer.” It is known to be a major factor in heart attacks and strokes caused by a thickening and hardening of the arteries (called atherosclerotic cardiovascular disease). There is also evidence that high cholesterol is a risk factor in the development and progression of Alzheimer’s disease and other types of dementia.

What are Statins?

There were many milestones that led to the discovery of the drugs we know today as statins. Unraveling the complicated synthesis and transport mechanisms of cholesterol’s 30 enzyme reactions were critical steps in identifying the enzyme “HMG-CoA reductase”, which controls the rate of cholesterol production in the liver. More cholesterol comes from our liver than from our diet, which is why controlling the manufacture and delivery of cholesterol is vital. So, what are statins and why are they so important?

Statin medications are a class of drugs called “HMG-CoA reductase inhibitors”. Statin drugs were introduced in 1987 as a cholesterol lowering alternative, and simvastatin (brand name Zocor) was one of the first drugs developed. This new class of drugs was slow to be accepted because long-term therapy was required in people who were not showing symptoms of disease. However, as more evidence about the preventable aspects of heart disease, stroke, and dementia began to negate the idea that these diseases were strictly related to aging, the use of statins increased and has now exceeded $20 billion in annual sales. Drugs in this class, such as simvastatin (Zocor), help reduce the risk of stroke, as well as vascular changes associated with Alzheimer’s disease. For 40 years, statins have been used to safely lower bad cholesterol levels and improve the quality of life of people around the world.

How Simvastatin Works and How it Might Affect Alzheimer’s Disease

The statin mechanism of action is almost as complicated as the process of making cholesterol. The fatty make-up of cholesterol molecules requires a special, water-soluble coating for transport. The water-soluble coating is made of lipoproteins that surround the molecule of cholesterol, allowing the molecule to be carried in the blood, delivered to the tissues, and then returned to the liver for disposal.

There are six classes of lipoproteins, but statin drugs are designed to control the two types of lipoproteins that affect atherosclerosis (a disease in which plaque accumulates in your arteries) and atherosclerotic cardiovascular disease (ASCVD) the most:

  • Low-density lipoprotein (LDL), or “bad cholesterol”, responsible for carrying cholesterol from the liver to other tissues where cholesterol is needed for its many important functions
  • High-density lipoprotein (HDL), “good cholesterol”, responsible for gathering cholesterol molecules and returning them back to the liver for removal

Bad Cholesterol (LDL)

LDL cholesterol, or bad cholesterol, makes up most of the body’s cholesterol supply. It gets its reputation from the role it plays in damaging the lining of arteries and building dangerous plaques that narrow arteries. LDL also causes inflammatory changes that can rupture the plaques and completely block arteries. High levels of LDL cholesterol put you at greater risk for heart disease and stroke. Lowering the amount of this bad cholesterol in the blood is the primary goal of treatment with simvastatin (Zocor) and other statin drugs.

Good Cholesterol (HDL)

HDL cholesterol is known as good cholesterol because of the role it plays in eliminating cholesterol from arterial plaques and returning cholesterol to the liver for removal. The HDL cholesterol-removal process helps increase the inside diameter of the arteries and improve blood flow. Decreasing the size of arterial plaques also helps reduce the chance of plaques rupturing and causing blockage. Increasing the amount of good cholesterol, an added benefit of statin drugs, is not fully understood, and it is not consistent in all patients.

Another potential benefit that is not fully understood is the role that simvastatin (Zocor) might play in delaying the symptoms and progression of Alzheimer’s disease. High cholesterol (hyperlipidemia) is a known risk factor for developing Alzheimer’s and other types of dementia. Simvastatin (Zocor), lovastatin, and atorvastatin are the only statins that appear to cross the blood brain barrier. Currently we don’t understand if this ability to enter the brain contributes to statin side effects, or if it contributes to improving dementia outcomes. Much more research is needed before the statin mechanism of action in the brain is completely understood. As for now, the reason most statin drugs are prescribed is to lower cholesterol.

Cholesterol and Alzheimer’s

Research has clearly identified several cardiovasular and cholesterol-related risk factors in the development of Alzheimer’s disease and other types of dementia. Diabetes, hypertension, smoking, and high LDL cholesterol, are just a few of the factors associated with the vascular changes, plaque formations, and inflammation linked to progressive cognitive decline. There is also an inheritable gene mutation that seems to be associated with high LDL. This affects the body’s ability to transport cholesterol in the brain, and it influences the formation of plaques in Alzheimer’s.

The gene mutation has been identified as apolipoprotein E-4 allele (ApoE4), the gene most affiliated with Alzheimer’s disease. Individuals who carry this mutation have problems with cholesterol transport mechanisms in the brain that affect memory, learning, and brain cell repair. A recent literature review indicates a significant improvement in cognition in statin-treated, ApoE4 individuals, suggesting that statin use may be beneficial for AD-prone individuals.

However, other studies found that statin use late in life offered no protection against the onset of dementia or against continued cognitive decline. Thus, research in the treatment and prevention of Alzheimer’s with simvastatin, or other statin drugs, has yielded mixed findings. More studies are needed that measure cognition as the primary outcome of statin treatment. In addition, patients may benefit from earlier and more prolonged statin treatment than is typically tested.

Despite the lack of conclusive evidence in the treatment of Alzheimer’s and dementia, statin drugs continue as the drug of choice for reducing the risk of heart attack and stroke in patients who cannot control their cholesterol with lifestyle changes. There is also a connection between atherosclerosis, AD, and dementia, and statins are effective in reducing atherosclerosis. Keep an eye out for new research that will hopefully provide greater clarify on these links.

Considerations for Treatment With Simvastatin (Zocor)

There are several considerations you must discuss with your primary care provider before beginning treatment with simvastatin (Zocor). Among those are age, family history, modifiable risk factors, ASCVD risk assessment, the presence of any other health conditions, and the type of cholesterol abnormalities (dyslipidemias) present. Each category has its own risk profile in the development of ASCVD and in your ability to take a statin drug for treatment.

According to the 2013 Guidelines of the American College of Cardiology and the American Heart Association, there are four types of high-risk individuals who benefit from the use of statins:

  • Anyone who has already been diagnosed with atherosclerotic cardiovascular disease (ASCVD)
  • Anyone with an initial elevation of LDL cholesterol greater than 190 mg/dL
  • Diabetics age 40 to 75 with LDL cholesterol 70-189 mg/dL
  • Non-diabetics who do not have ASCVD but are age 40 to 75 with an LDL cholesterol level of 70-189 mg/dL and a 10-year ASCVD calculated risk greater than 7.5%.

Altering modifiable risk factors with lifestyle changes is typically considered adequate treatment of high LDL cholesterol levels in patients who do not meet the above criteria. It is important to understand that even though lifestyle changes such as diet, weight loss, exercise, smoking cessation, blood pressure regulation, and blood sugar control are considered the first line of therapy, they must be continued for maximum benefit when statin therapy is started. There is added benefit to lowering LDL cholesterol and raising HDL cholesterol when these methods are combined.

The final consideration when choosing a statin medication for high cholesterol is what type of cholesterol problem has been diagnosed. Each statin is approved by the Food and Drug Administration (FDA) to treat specific cholesterol problems. Simvastatin (Zocor) is approved for different specific cholesterol disorders including:

  • Primary hypercholesterolemia
  • Mixed dyslipidemia
  • Primary prevention of coronary events
  • And several other disorders (your provider will help you understand what type of cholesterol problem you have and the best way to treat it)

Side Effects of Simvastatin (Zocor)

Simvastatin (Zocor) and other statin drugs have a generally safe drug profile, meaning they are well tolerated by most patients. Minor statin side effects that have been reported by some individuals include:

  • Headache
  • Rash
  • GI discomfort such as gas
  • Upset stomach (dyspepsia)
  • Cramps
  • Constipation
  • And abdominal pain

Many of these side effects are mild and will dissipate as your body gets used to taking the medication.

Additionally, there are some more serious adverse effects that should be reported to your provider immediately if they occur:

  • Any changes that indicate liver problems, including yellowing of skin or eyes
  • Pain in the right upper abdomen
  • Nausea
  • Vomiting
  • Or unexplained weight loss

Changes that may indicate kidney problems include:

  • Dark-colored urine
  • Difficulty urinating
  • Pain or burning with urination
  • And swelling

Muscle problems are a side effect that can range from mild to life threatening. It is therefore crucial to report symptoms including:

  • Muscle aches
  • Tenderness
  • Weakness
  • Muscle wasting
  • Cramps
  • Spasms
  • Or stiffness

Patients with diabetes must also monitor closely for increased hunger, thirst, and urination, fruit-like breath odor, sweating, or changes in the level of consciousness.

Mr. B’s story

Mr. B was recently admitted to a skilled nursing facility after a brief hospital stay for repeated falls and a possible rib fracture. He is 84 years old, lives by himself, and his youngest daughter Bonnie lives just down the street. Bonnie checks on Mr. B before and after work every day. For the last month, Bonnie noticed Mr. B having more trouble with his short-term memory, and he called her to the house three times because he had fallen. Every time he fell, Mr. B had a perfectly good explanation: the linoleum was slippery in the bathroom, his stockinged feet were slick when he was walking to the closet, or the cute little area rug in the entryway that his wife had insisted on getting before she passed. But for this latest fall that landed him in hospital, he couldn’t remember what had happened, and he couldn’t remember Bonnie’s phone number, so he was on the floor in the kitchen for a while before Bonnie got home from work. Mr. B is getting stronger every day, but he is still complaining of muscle pain and his memory seems to have gotten worse since he left the hospital. Bonnie is very concerned that her dad may not be able to live alone anymore, and she decided to talk to the doctor about her dad’s safety . . .

Bonnie spoke with the physician about her dad’s recent falls, listing all his medications and his worsening memory. She was relieved to find out that some of Mr. B’s problems were possibly due to his statin therapy that he had been on for years. The doctor discontinued the statin for the remainder of his stay at the skilled nursing facility. Two weeks later, Mr. B was beginning to show improvement in his cognition, and his strength had improved enough for him to be discharged back to his home. Bonnie decided it would be safest to have him stay at her house with a daytime caregiver until they could see his primary care provider and reassess Mr. B’s ability to live alone safely. Mr. B is improving every day and Bonnie is feeling much better about getting him back to his own home.

Simvastatin (Zocor) Dosage Considerations

There are many factors that play into the selection of the most appropriate statin drug therapy and dosage for each individual. Simvastatin (Zocor) is used for low to moderate-intensity statin therapy:

  • Low-intensity therapy is started for patients who have attempted to lower their LDL cholesterol levels with lifestyle modifications, and require less than a 30% reduction in LDL (bad cholesterol) levels. Simvastatin is given in a daily 10 mg tablet for this result.
  • Moderate-intensity therapy is started when the patient needs to lower their bad cholesterol level by 30 to 50%. Simvastatin (Zocor) is given in 20 or 40 mg daily doses to achieve this goal. In 2011, the FDA placed new dosing restrictions on simvastatin, limiting the maximum daily dose to 40 mg. This action was taken due to increased reports of serious muscular side effects related to the 80 mg simvastatin doses.

One of the most important aspects of statin therapy is taking the drug properly. Our bodies produce cholesterol primarily at night. Working with the natural rhythm of the body, statins are most effective when taken with the evening meal or at bedtime. It is also important to note that these drugs must be taken for 4 to 6 weeks before maximum effects are achieved, and statin drugs must be taken for the long term to maintain the effects.

Drug Interactions with Simvastatin (Zocor)

Statin medications have an interaction profile that includes over 200 medications, five different diseases, and two food substances. It is also very important to note that statins shouldn’t be used during pregnancy, as the cholesterol lowering effects of statins may have harmful effects on a developing fetus. Potential harm to the fetus far outweighs any cholesterol-lowering benefit the mother may experience while taking a statin drug during pregnancy.

Drug classes that have severe interactions with simvastatin (Zocor) are primarily drugs that inhibit a liver enzyme called CYP3A4. Medications that inhibit this enzyme will raise simvastatin, lovastatin, fluvastatin, and atorvastatin to dangerous levels in the blood, with possible harm to the muscles, kidneys, and liver.

Drugs that should be avoided when taking simvastatin include:

  • Macrolide antibiotics
  • Azole antifungal drugs
  • HIV protease inhibitors
  • Amiodarone
  • And cyclosporine, just to name a few

If you are taking antibiotics for a short course, or have been started on long-term HIV or immunosuppression therapy, talk to your doctor about your statin drug. There are other statins that can be taken safely with this type of medication.

Research has uncovered five diseases with possible moderate to severe interactions with simvastatin (Zocor), and other statin drugs:

  • Liver disease
  • Renal dysfunction (poor kidney function)
  • Rhabdomyolysis (breakdown of muscle tissue that harms or destroys kidney tissue)
  • Cognitive impairment (confusion, memory problems, forgetfulness, including dementia)
  • And diabetes

Diabetics are listed as one of the high-risk groups that benefit from statin drugs, but they must be monitored very closely for blood sugar changes and kidney damage to maximize the treatment for high cholesterol.

Food Interactions With Simvastatin (Zocor)

Food interactions include grapefruit juice and alcohol. Grapefruit juice inhibits CYP3A4 and should be given the same consideration as the above drug classes. Consuming alcohol with statins increases your chances of developing liver toxicity, and statins should be avoided altogether if you have alcoholic hepatitis.

When you are taking simvastatin, or any other medication for that matter, you should always discuss all of your health conditions and any other medicines you are taking with your physician to avoid any harmful interactions.

Alternatives to Simvastatin

Lifestyle modifications are the most beneficial alternative to long-term treatment with cholesterol lowering medications. Patients who are not able to reach cholesterol goals with lifestyle changes and the addition of simvastatin (Zocor) have many other alternatives in the statin class of drugs. Each statin medication is FDA-approved for specific health indications and can be prescribed based on the percentage cholesterol needs to be lowered. Other drugs used to lower bad cholesterol include Niacin, Ezetimibe, bile-acid sequestrates, and fibrates, all of which have different side effect profiles with varying degrees of severity.

Combination Therapies With Simvastatin

Simvastatin is available as a combination drug with Niacin for the treatment of high cholesterol and high triglycerides. Ezetimibe is combined with simvastatin (Vytorin) to lower cholesterol when lower doses of simvastatin are needed to reduce side effects. Simvastatin is also available in combination with an oral diabetic treatment for diabetic patients who want to take a single pill for treatment of high cholesterol and type 2 diabetes.

Discontinuing Simvastatin Therapy

Discontinuation of cholesterol medication is not recommended without consulting your health care provider. Only 10 to 25% of patients taking statin medications reported the most common above-mentioned side effects, but studies of individuals taking statin drugs have reported a 45% increase in mortality from cholesterol related conditions when statin medication was not taken as prescribed.

If you are experiencing one of the major above-mentioned side effects, or you are having other unpleasant side effects, you should consult your provider immediately. Many of the side effects are reversible and may be reduced or eliminated by switching to another statin drug. Intolerance on one medication does not mean all medications in the class will cause side effects.

Final Thoughts

The connection between high lipid levels (hyperlipidemia) in the blood and the occurrence of Alzheimer’s and dementia has been well established in medical literature. Generally, it is known that better cardiovascular health translates to better brain health. Statin drugs like simvastatin have a proven track record in their ability to lower LDL levels and prevent ASCVD. Reducing the “silent-killer” effects of cholesterol is the focus of simvastatin, and other statin drugs.

It is important to know that statin drugs have a good safety record. They have been tested in large-scale clinical trials, and they continue to help people around the world avoid consequences of ASCVD, such as heart attack and stroke. More research and information is needed to determine how statins affect the onset and progression of dementia, but animal studies conducted for Alzheimer’s research show promise in decreasing neuroinflammation and amyloid-beta concentrations with statin use. Patients considering statin therapy need to discuss the benefits and risks of the medicine with their doctor before beginning any long-term drug therapy.

Sources

  • Burchum, J. R., & Rosenthal, L. D. (2016). Lehne’s Pharmacology for Nursing Care (9 ed.). Spokane, WA: Elsevier.
  • CDC. (2015, March 5). Healthy Aging: Alzheimer’s Disease. Retrieved March 3, 2017, from CDC.gov: https://www.cdc.gov/aging/aginginfo/alzheimers.htm
  • Drugs.com. (2017, March 2). Simvastatin Information from Drugs.com. Retrieved March 3, 2017, from Drugs.com: https://www.drugs.com/simvastatin.html
  • Endo, A. (2010, May 11). A historical perspective on the discovery of statins. (T. Beppu, Ed.) Proceedings of the Japan Academy, Series B Physical and Biological Sciences, 86(5), 484-493. doi:10.2183/pjab.86.484
  • FDA. (2015, May 22). Cholesterol and Statins Infographic. Retrieved February 25, 2017, from U. S. Food and Drug Administration: https://www.fda.gov/Drugs/DrugSafety/ucm295573.htm
  • FDA. (2017, February 16). FDA: Limit Use of 80 mg Simvastatin. Retrieved February 25, 2017, from www.FDA.org: https://www.fda.gov/forconsumers/consumerupdates/ucm257884.htm
  • Geifman, N., Brinton, R. D., Kennedy, R. E., Schneider, L. S., & Butte, A. J. (2017). Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimer’s Research & Therapy, 9(10), 1-10. doi:10.1186/s13195-017-0237-y
  • LaMattina, J. (2009, June 8). The Story of Statins. Chemical & Engineering News, 87(23), 61-63. Retrieved March 2, 2017, from http://cen.acs.org/articles/87/i23/Story-Statins.html
  • Liu, C., Kanekiyo, T., Xu, H., & Bu, G. (2013, February). Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. National Review of Neurology, 9(2), 106-118. doi:10.1038/nrneurol.2012.263.
  • McGuinness, B., Craig, D., Bullock, R., & Passmore, P. (2016). Statins for the prevention of dementia (Review). Cochrane Database of Systematic Reviews 2016(1), 1-48. doi:10.1002/14651858.CD003160.pub3.
  • Thompson, P. D., Panza, G., Zaleski, A., & Taylor, B. (2016, May 24). Statin-Associated Side Effects. Journal of the American College of Cardiology, 67(20), 2395-2410. doi:http://dx.doi.org/10.1016/j.jacc.2016.02.071

Posted 
August 7, 2017
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