Statin Therapy in the Older Patient: When to Use It, What to Watch For, and When to Stop

Coronary heart disease (CHD) affects nearly 18 million Americans. As the predominant cause of death, it is estimated that over one million individuals suffer from acute cardiovascular events such as myocardial infarctions and over 600,000 new stroke cases are diagnosed annually in the United States.^1,2 Managing elevated cholesterol levels should begin with lifestyle management including adhering to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight. These recommendations remain a crucial component of health promotion and cardiovascular risk reduction, both prior to and in conjunction with the use of any medication to manage cholesterol and lipid levels.

Dyslipidemia is one of the major risk factors for developing CHD, and cholesterol-modifying therapy has proven to be beneficial in the primary and secondary prevention of the complications associated with CHD. As such, lipid-lowering therapy, primarily with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), has become the mainstay of therapeutic guidelines for the management of these conditions.

Statin medications are a very powerful group of medications that lower low-density lipoprotein (LDL) levels and are widely used in clinical practice. They inhibit the enzyme HMG-CoA reductase, an enzyme that is critically involved in the rate-limiting step of cholesterol biosynthesis in the liver. Within weeks of starting treatment with a statin medication, there is a decreased rate of cholesterol synthesis, leading to a reduction in blood cholesterol levels.² Statin therapy has the goal of reducing adverse cardiovascular events such as myocardial infarctions and cerebrovascular embolic strokes. In individuals with heart failure, use of a cholesterol-lowering agent has increasingly favorable effects on decreasing inflammation, diminishing oxidative stress, and improving vascular performance.^1,2 Multiple studies have demonstrated that statins decrease CHD and lower death rates, as well as reduce the incidence of myocardial infarctions (MIs), strokes, peripheral vascular disease, deep vein thrombosis, and pulmonary embolism.² Statins are effective in both men and women, primarily in middle-aged and older persons treated in the setting as either primary or secondary prevention. They reduce the risk of essentially every clinical manifestation of the atherosclerotic process; they are easy to administer and are generally well accepted by a large percentage of the adult population.

Caution should be exercised when considering statin use in the older adult population, and in particular in individuals who are frail or are older than 85 years of age. An evaluation of the individual clinical situation should take into consideration the potential harms of therapy and weigh benefits against concerns about adding another agent to the medication regimen. The possibility of patient non-adherence to the prescribed plan of care should also be considered. The decision to prescribe statins should also take into account potential medication interactions, major organ effects (liver and kidney), and memory concerns.² Statins are efficacious in managing lipid levels, but are they for everyone? Furthermore, once prescribed, should they be taken indefinitely?

Current Recommendations

The Third Report of the National Cholesterol Education Program³ (Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults--Adult Treatment Panel III, or ATP-III) presents another dilemma for healthcare providers who work with older adults in long-term care settings. The ATP-III now recommends that patients with one or two risk factors (age greater than 45 years in men or greater than 55 years in women, family history of premature coronary heart disease, hypertension, high-density lipoprotein (HDL) cholesterol concentrations less than 40 mg/dL, and smoking) should be encouraged to maintain low-density lipoprotein (LDL) cholesterol concentrations at a level of 100 mg/dL or lower. The patient groups for who statin therapy is strongly recommended are listed in Table 1.

These recommendations provide guidelines, but the issue may become a dilemma in the care of older adults, given the increased risk of polypharmacy and medication interactions, gait disturbances, increased risk of falls, increased blood glucose levels with an increased incidence of diabetes mellitus, developing liver toxicity, and myopathies that are associated with the use of statin agents.^4,5 The question becomes: do the benefits of treating hypercholesterolemia with statin agents outweigh the risks?

Many argue that the benefits may outweigh the risks if these new events can be prevented in an otherwise functional older patient, because statins have been proven to reduce mortality due to stroke, heart failure, and coronary artery disease. Each patient should be evaluated on a case-by-case basis, and patients should be made aware of the possible side effects as well as the risks of treatment. Older patients must be educated and allowed to make an informed decision in their own care. The goals of care need to be mutually established between the clinician and the patient, taking into account quality of life issues and anticipated long-term expectations for length of life as well as quality of life. If the statin agent causes daytime fatigue and sleepiness, gait disturbances with potential falls, or other adverse effects, is there a true benefit from the patient’s perspective?

Nursing Home Patients

The lifestyle in the nursing home population generally is different from the lifestyle the older patient experienced in their previous home setting. For example, they are typically offered a diet low in cholesterol, discouraged from using tobacco products, and provided some degree of exercise, although this is not the case for all nursing home settings. Some of the most complicated and frail older adults residing in nursing homes have moderately elevated lipid levels. There are a significant number of patients in this setting who are not able to make an informed choice, and the clinician is burdened with the decision to treat or not to treat. A study by Ziesmer et al.⁶ found that 51% of older adults in the nursing home setting had a diagnosis of hypertension and that 94% of those with hypertension also had clinical cardiovascular disease, target organ damage, and/or diabetes mellitus.

Statin therapy has proven to be effective for improving outcomes in the older patient in the nursing home setting (decreasing incidence of myocardial infarctions and cerebrovascular accidents) by lowering cholesterol in these patients who are at risk for experiencing vascular events, though current guidelines do not recommend use of this therapy in low-risk patients. However, the results of a new study published in The Lancet⁷ suggest these guidelines may be revisited. This recent study has indicated that, in individuals who are at ‘low-risk’ for cardiovascular events, a reduction of LDL cholesterol levels with a statin reduced the risk of major vascular events (eg, myocardial infarctions, stokes, and blood clots), irrespective of age, sex, baseline LDL cholesterol levels or previous vascular disease, and of vascular and all-cause mortality. It was noted that a reduction in major vascular events was just as significant in individuals who were considered to have a low risk as in individuals considered to have a higher risk. For example, in individuals with a 5-year risk of less than 10% of experiencing a major vascular event, each 1 mmol/L reduction in LDL cholesterol level produced an absolute reduction in major vascular events of about 11 per 1,000 over 5 years.⁷

According to the study authors, the benefits of LDL-lowering statin therapy greatly exceed risks in a majority of older individuals with cardiovascular disease. As such, it has been suggested that present guidelines governing statin use should be revised to include lower-risk patients.

Statin Popularity

Statins are the single most prescribed category of agents in the United States today, and they are often prescribed on a long-term basis or for the patient’s lifetime. Since a typical patient is prescribed a statin agent for an extended period of time over many years, there are many chances for adverse events, including complications due to unforeseen changes in the health status of the patient. Statins are most often used in middle-aged and older adult patients, who tend to be taking multiple medications for other health conditions. This increases the likelihood of complications and poses safety concerns regarding drug interactions and increased risk of drug toxicity.^8,9

The Heart Protection Study, PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), and SAGE (Study of Global Aging and Adult Health) revealed the benefits of statin treatment on atherosclerosis and stroke prevention. However, the data is somewhat controversial in the population of patients ≥80 years of age, though there was a benefit for individuals <80 years of age.^2,10 Further evidence from the CREDO-Kyoto Registry Cohort-2 suggested that among adults aged 80 years or older who had undergone cardiac revascularization, incidences of major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction and stroke) were significantly lower in those treated with statins than in those that did not receive statins.¹¹

Precautions with Statin Use in Older Adults

Prescribers should balance a consideration of harms of any therapy in the older population especially those 85 and older against their benefits. Concerns are increased when adding any medication for an older patient who is being prescribed multiple medications or prescribing a statin as a preventative agent. Discussion of metabolic issues (increasing glucose levels and development of diabetes mellitus), musculoskeletal complications (gait disturbances, myalgia, myositis, and the very rare rhabdomyolysis), medication interactions, major organ effects (liver and kidney), and memory concerns should ensue between the prescriber and the patient.¹² Prescribers should consider if the older adult patient who is being considered for initiation or continuation of a statin agent will benefit significantly and whether these benefits significantly exceed the risks. The issues of polypharmacy, non-adherence, drug–drug interactions, and individual preference should be considered.^1,2

Dosing

When choosing statin therapy in the older patient, it is important to consider that adverse events are dose-related; ie, the higher the dose, the more incidence of medication toxicity and the occurrence of adverse events. Dosing should be optimized to obtain target lipid levels in the older adult population. Recommendations for dosing of statins in older adult patients are provided in Table 2.

Risk Assessment

Patient choice needs to be considered when evaluating if a statin agent is appropriate for the older patient. Risk factors for developing complications associated with statin therapy should be assessed (Table 3). Advanced age poses a risk to women more so than to men. Patients who are frail or have small body frames may be at risk of having higher blood concentrations of the drug. Patients with multisystem disease or who are taking multiple medications are likely to have complications; although, individuals with a fatty liver, if confirmed, may improve with lipid-lowering therapy. Patients who are perioperative, have a history of elevated alanine transaminase levels, or are of Asian descent, may also have a higher risk of complications.

Medication Interactions

Almost 250 drugs (720 brand and generic products in total) are known to interact with many of the statin agents.^13,14 Specific concomitant medications that have demonstrated significant interaction with statins and led to adverse events are listed in Table 4. Additionally, ingesting large quantities of grapefruit juice (usually more than 1 quart per day) can cause interactions that lead to adverse events.²

The statin drug classification is a sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrate. Strong CYP3A4 inhibitors are predicted to significantly increase statin exposure (especially lovastatin). A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold and the drug interaction appears to result in rhabdomyolysis. The effect of itraconazole on lovastatin exposure can therefore be extrapolated to other strong CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, human immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, and nefazodone. A close examination of concurrent medication use should be done prior to initiation of statin medications.¹⁵

Potential Complications of Statin Therapy

Adverse Events

The most commonly reported adverse events associated with use of statin agents are daytime muscle fatigue or daytime sleepiness, decreased quality of sleep at night, and generalized weakness, which can lead to falls as well as a decreased quality of life.¹³ Some other adverse events reported with use of statin therapy include: memory loss and confusion; and increases in blood sugar levels and development of diabetes mellitus.

Cognitive Decline

A commonly reported adverse event is decline in cognitive functioning.¹³ There have been reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use which exhibited symptoms either beginning at the onset of use or after years of ongoing use of a statin. These cognition problems may not be serious and are reversible upon statin discontinuation, and symptoms resolved at an average of 3 weeks.¹⁶ A 2013 study conducted a systemic review and meta-analysis of the short-term and long-term effects of statin agents on cognition in patients without baseline cognitive dysfunction, short-term data are most compatible with no adverse effect of statins on cognition, and long-term data may support a beneficial role for statins in the prevention of dementia.¹⁷ Pooled data from this same study showed a 29% reduction in development of dementia in patients on statins.

Development of Diabetes Mellitus

Statin use has been found to modestly increase blood glucose levels, leading to worsening of diabetes and increase the risk of developing diabetes mellitus.¹⁸ One study reported a 2.8-fold increase incidence of renal events in individuals with diabetes mellitus.¹³ In the PROVE-IT–TIMI trial, high-dose statins led to statistically significant increase in glycemia.¹³

The associations between diabetes mellitus and statin use have raised concerns over the widespread use of statin medications in patients at lower risk for cardiovascular disease. There have been reported increases in glycosylated hemoglobin (HbA1c) and fasting serum glucose levels with statin use. Individuals who are at greater risk of developing diabetes mellitus are those having at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m² or higher, or glycated hemoglobin A1c greater than 6%. In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy were shown to exceed the hazard of developing diabetes, including in participants at high risk of developing diabetes. In these individuals, glucose levels and glycated hemoglobin (HbA1c) should be evaluated 6–12 weeks after initiation of therapy and with onset of symptoms.¹⁸

Muscular Complaints

There are four interrelated terms for muscle problems that can occur with statins: myopathy, myalgia, myositis, and rhabdomyolysis.

Myopathy is a general term for disease of the muscles, and it is characterized by general muscle weakness. In statin treatment, myopathy is used to describe any problem related to muscles, whether or not the problem is actually related to the statin.

Myalgia refers to pain in the muscles. Muscle pain is often seen with statin-based myopathy; however, painless myopathy from statin therapy is also common and may be more harmful because it is often ignored. If the patient has not instructed to look for this, the issue may not reported or, if the patient reports weakness without pain, the problem may not recognized as constituting a true myopathy.

Myositis is inflammation of the muscle that can be confirmed by histologic findings through a muscle biopsy. Muscle biopsy is the gold standard for diagnosing a statin-induced myopathy; however, they are rarely done due to pain involved in the procedure, inconvenience, and cost of biopsies making them impractical in most settings. Since the word myositis is probably best reserved for biopsy-proven myopathy, it is not of much use. Creatine phosphokinase (CPK) levels are sometimes performed to confirm a diagnosis but a study has shown that patients without an elevation of their level can still have myositis on biopsy. Thus, CPK levels are not definitive to rule out a myositis.

Rhabdomyolysis is the extreme form of myopathy, in which the muscle tissue is so inflamed that it begins to break down and if the patient is left on the statin causing the problem-the muscles break down in large quantities. The result of this breakdown is a large amount of myoglobin (muscle protein) into the bloodstream, which must be filtered and removed by the kidneys. The kidney is not accustomed to excrete large amounts of myoglobin, leading to the kidney becoming overwhelmed and thus leading to kidney damaged. Although the kidney is capable of recovering over time in ideal circumstances, but rhabdomyolysis can be fatal due to acute renal failure and sequelae to other organs. Most cases of rhabdomyolysis do not lead to death but they often result in an acute illness and usually require hospitalization.^19,20,21

Gait Disturbances

Individuals who are taking a statin agent may report myopathy which leads to gait disturbances and an increased incidence of falls in the older patient. General overall health and gait issues should be a factor in determining if a statin agent is appropriate for the older patient.^20,21

Sleep Quality & Day-time Sleepiness

Statin agents have shown to affect sleep quality as well as sleep problems. Certain statin agents have been significantly linked to tiredness and irritability. Simvastatin in particular causes issues with sleep more so than other statin agents. Also reported were sleep problems which were correlated with tiredness, irritability, and cognition.²²

Cataract

Cataracts are common in the older population and causes poor vision.²³ A study by Leushen et al.²⁴ investigated if the antioxidant effects of statin therapy would slow the natural aging of the eye and decrease the incidence of cataract development. The study actually found there was an increased incidence of cataract development in statin user vs non-statin users. Thus, recommendations were made to for clinicians to conduct a risk-benefit evaluation prior to use of a statin agent as primary preventative therapy in the older patient.

Cancer

There is ample evidence to conclude that statin therapy may promote cancer in certain segments of the population.^24,25 One randomized trial of older adults (age >70) showed significant increase in incidence of cancer with statin use relative to placebo.¹³ Currently, the indications for statin therapy are based on lipoprotein levels, prevalent cardiovascular disease, other vascular risk factors, and family history. Recommendations are being made to also take into consideration prevalent cancer, a past history of cancer, and overall immunocompetence.

Monitoring of Statin Therapy

The ATP III recommendations for monitoring the initiation and long-term management of statin therapy are provided in Table 5. Up to 5% of older patients will have some degree of muscle complaints while taking statin therapy, which could affect their mobility and quality of life.¹⁶ Therefore, primary healthcare providers will often be faced with real or potential complications of statin therapy. It has been reported that higher doses of a statin drug resulted in more muscle complaints. Being aware of a patient’s risk and using the lowest effective dose minimizes the occurrence of such adverse events. Most clinicians agree that a majority of these patients who present with abnormalities either do not require discontinuation of therapy or require only brief interruption of therapy.^1,2 Be cautious that routine monitoring could potentially identify patients with isolated increased transaminase levels, which might lead to unnecessary discontinuation of statin therapy.^1,2,26 Judicious and systematic use of laboratory testing will minimize needless and premature discontinuation of statin therapy.

Deciding to Discontinue Statin Therapy

In the older patient who has had a previous myocardial infarction or cerebrovascular event, discontinuation of the statin may increase risks of death due to increased incidence of myocardial infarctions (MIs) and increase neurological damage with embolic strokes thus it is contraindicated to discontinue statins in individuals who have a known history of cardiovascular disease.^1,2 And in individuals who do not have a history of MI or embolic strokes, statin use is still encouraged because of the benefits of lowering risks of such acute cardiovascular events. But in some older patients, the benefits statin use may not outweigh the burden of therapy. Clinicians who chose to discontinue statin therapy should follow a protocol (Figure 1).^26,27

Conclusion

Treating dyslipidemia and lowering cholesterol levels in patients does have a result in decreasing the incidence of cardiovascular events. Statin therapy has proven to be efficacious and efficient in managing dyslipidemia and improving health but judicious prescribing and monitoring are required. Most individuals who have cardiovascular disease will benefit from long-term use of statins to prevent myocardial infarctions and strokes. Though in some older adults, the burden of the therapy outweighs the benefits due to the high potential for adverse effects.

Treatment of heart disease in the complex and/or frail older adult patient may be more complicated and requires a holistic, interdisciplinary approach. Decisions should be made about diagnostic procedures, treatments, or palliative care, and healthcare providers must carefully consider the overall goals for each individual cardiac patient. Every treatment or monitoring procedure should be viewed within the context of maximizing that individual’s quality of life while not placing undue burden onto the patient with unnecessary treatments and medications. In older adults with a known history of cerebrovascular disease or myocardial infarction, many experts encourage continuation of statin therapy. In older adult patients whose cholesterol levels are low (<100 mg/dL), it should be the healthcare provider to take into consideration several factors to determine if statin therapy should be continued. And in the older adult patient who has a mildly elevated cholesterol level (<190 mg/dL), the decision should fall to the healthcare provider to weigh the burden of treatment versus the benefits of lowering the cholesterol levels and the patient’s health status.

All experts propose that older patients with a known history of cardiovascular disease, especially those who have a history of a cardiac event, should receive aggressive therapy to lower cholesterol levels. This should be done judiciously and the clinician must be observant for any signs of muscle weakness, muscle pain, or muscle atrophy. The treatment goals of the individual and/or their family must always be taken into consideration. 

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14.    Simvastatin Drug Interactions. Drugs.com. http://www.drugs.com/drug-interactions/simvastatin.html. Accessed June 7, 2015.

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16.    Seehusen DA, Asplund CA, Johnson DR, Horde KA. Primary evaluation and management of statin therapy complications. South Med J. 2006;99(3):250‚Äì256.

17.    Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88(11):1213‚Äì1221.

18.    Shah R, Goldfine A. Statins and risk of new-onset diabetes mellitus. Circulation. 2012;126:e282‚Äìe284.

19.    Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581‚Äì585.

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21.    Lowe R, Marrs J, Saseen J. Patterns of serum laboratory monitoring for safety and efficacy in patients on chronic statin therapy. Therapeut Adv Drug Saf. 2012;4(1):9-17.

22.    Phend C. AHA: some statins may disrupt sleep. Medpage Today. http://www.medpagetoday.com/MeetingCoverage/AHA/7301. Published online November 8, 2007.

23.    Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I. Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol. 2013;131(11):1427‚Äì1434.

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25.    Takahashi HK, Nishibori M. The antitumour activities of statins. Curr Oncol. 2007;14:246‚Äì247.

26.    Pineda A, Cubeddu LX. Statin rebound or withdrawal syndrome: does it exist? Curr Atheroscler Rep. 2011;13(1):23‚Äì30.

27.    Gotto AM Jr. Statin therapy and the elderly: SAGE advice? Circulation. 2007:115(6):681‚Äì683.