Statin Adverse Effects: Implications for the Elderly
by Beatrice A. Golomb, M.D., Ph.D.
Geriatric Times May/June 2004 Vol. V Issue 3

Statins, or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (e.g., atorvastatin [Lipitor], simvastatin [Zocor]), are among the best-selling prescription drugs in the world and are widely viewed as very safe and effective. Their benefits to coronary artery disease have been copiously documented and are incontrovertible. In addition, statins have been shown to benefit survival in a large study of middle-aged men with, or at high risk for, heart disease (Scandinavian Simvastatin Survival Study Group, 1994). Nonetheless, all drugs have potential adverse reactions despite their potential benefits. Understanding these risks is vitally important, particularly in elderly patients in whom both risks and benefits differ relative to younger patients.

Evidence suggests the balance of benefits to risks may be less favorable in the elderly: Cholesterol becomes a less potent predictor of cardiovascular problems, and adverse reactions from drugs, including statins, may become more prominent. While patients at high risk for cardiovascular disease receive mortality benefit from statins in studies predominating in middle-aged men (Scandinavian Simvastatin Survival Study Group, 1994), no trend toward survival benefit is seen in elderly patients at high risk for cardiovascular disease (Shepherd et al., 2002). A less favorable risk-benefit profile may particularly hold for p

Patients older than 85, in whom benefits may be more attenuated and risks more
amplified (Weverling-Rijnsburger et al., 1997). In fact, in this older group, higher
cholesterol has been linked observationally to improved survival.

This paper will review a selection of the risks and adverse effects of statins that
have special implications for elderly patients.

Muscle Problems

Muscle problems are the most common reported adverse effects of statins, according to an observational database maintained by the University of California at San Diego Statin Study group. Perhaps the most feared adverse effect of statins is rhabdomyolysis--a condition in which there is severe breakdown of muscle tissue
that may be toxic to the kidneys and result in kidney failure or death. The muscle breakdown commonly leads to a strong elevation in blood levels of muscle enzyme creatine kinase (CK). Creatine kinase levels often exceed 10 times the upper limit of normal in cases of frank rhabdomyolysis. Fatal rhabdomyolysis occurred with increased frequency with cerivastatin (Baycol) when used at higherdoses or in combination with gemfibrozil (Lopid); cerivastatin was removed from the U.S. market in 2001. Rhabdomyolysis occurs with all statins, although the actual frequency of occurrence is quite low.

Physicians are most familiar with rhabdomyolysis, and many suppose that for muscle pain to be statin-associated, it must induce muscle symptoms throughout the body coupled with elevation of CK levels. However, this reflects only one manifestation of statin-associated muscle symptoms. Some patients have only new focal pain or new fatigue, and may have mild or no elevation in CK levels. In some instances these symptoms progress to rhabdomyolysis--one reason to take these symptoms seriously--but many times they do not.

An important double-blind, crossover biopsy study showed that some patients receiving statin therapy with non-CK-elevating muscle pain have objectively documentable, partially reversible mitochondrial myopathy (Phillips et al., 2002). Even in the absence of rhabdomyolysis or CK elevation, major effects on function and quality of life may occur (Golomb et al., 2003). It is important to note that in both our experience and that of others, muscle symptoms precipitated by statins may not in all cases completely recover; this is consistent with the finding that, pathologically, the myopathy may not completely reverse.

Adverse muscle problems from statins, in addition to rhabdomyolysis, take a variety of forms (Table). Shortness of breath sometimes accompanies statin-associated muscle problems. The "respiratory exchange ratio"--the ratio of carbon dioxide exhaled per oxygen inhaled--is altered in people with statin myotoxicity (Phillips et al., 2004). Occasionally, shortness of breath is the predominant symptom. Patients may experience marked shortness of breath that occurs following initiation of statin therapy and is sustained while statins are continued for which no etiology is identified on extensive cardiopulmonary workup. These symptoms resolve completely with statin discontinuation.

Muscle problems associated with statins may be more common among the elderly. In the 2002 American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute Clinical Advisory on the Use and Safety of Statins, Pasternak et al. noted the following factors that may increase the risk for statin-associated myopathy:

advanced age (especially >80 years, women > men);
small body frame and frailty;
multisystem disease;
multiple medications;
perioperative periods; and
concurrent use of certain medications.

These factors are especially common among the elderly, which places them at increased risk for development of muscle problems with statins.

Muscle problems associated with statins may be more debilitating among the elderly. When muscle problems occur, they may have more impact on the elderly. Elderly patients more commonly have already declined in muscle strength and function; and are often already on, or perched near, the steep part of the curve relating muscle strength to physical function, independence and the ability to perform activities of daily living. Thus, the same amount or proportion of compromise in muscle function may have a substantially more profound impact on quality of life in elderly patients. In addition, reductions in physical function, indexed by reductions in lower extremity function, are linked to self-reported disability, hospitalizations, admissions to nursing homes and mortality from all causes (Guralnik et al., 2000, 1995, 1994; Penninx et al., 2000). Reductions in lower extremity function are associated with reduced physical activity (McDermott et al., 2002), so that such patients may lose the protection that exercise is reported to afford against a host of conditions.

Cognitive Loss

Cognitive problems also occur with statins and may also have more impact in elderly patients. Two randomized trials that were designed to assess cognitive effects of statins have shown worsening in cognitive function (Muldoon et al., 2002, 2000). In addition, several case reports (King et al., 2003, 2001; Orsi et al., 2001) and one large case series (involving 60 patients) (Wagstaff et al., 2003) have reported deleterious cognitive effects of statins on memory and cognitive function.

Although not expressly designed to assess cognition, results from the Heart Protection Study (HPS) (Heart Protection Study Collaborative Group, 2002) and PROSPER trial (Shepherd et al., 2002) did not show that statin therapy had favorable or deleterious effects on cognitive measures that were tested. Several factors may help to explain the discrepancy between findings from these large and smaller trials targeted at testing cognition. First, different measures of cognition were used that may not have tapped the areas in which problems occur. The telephone survey measure in the HPS, for instance, would not have captured visuomotor coordination and processing speed, which the other trials suggested may be particularly affected.

Second, the large trials enrolled people at high risk for cardiovascular disease who experience benefit from statins to nonfatal stroke, which may lead to improvements in cognition that may help to balance out harms to cognition from other mechanisms. Although there are trends toward increases in fatal stroke with statins in most of the large statin trials, those who have died cannot complete cognitive surveys. The impact on total number of strokes was unaffected in the PROSPER trial with its sole focus on the elderly population. In the PROSPER trial, the number of reduced transient ischemic attacks and nonfatal strokes was actually matched by a similar number of increased fatal strokes.

Finally, the HPS used what is termed an "active run-in." For six weeks, participants considered for enrollment were placed on simvastatin, and those who were not fully compliant were dropped from the study. Participants who perceived problems on the drug, including cognitive problems, may have dropped the study themselves or skipped pills intentionally. In addition, participants who developed memory problems may have had trouble remembering to take the pills even if they did not recognize deterioration in cognitive function. This run-in process may have excluded participants who developed cognitive problems on the drug, selecting only those who did not experience problems. Over one-third of those who were interested in enrolling were excluded following this compliance run-in.

Because statins reduce nonfatal stroke (and cognition is obviously not measured in people who have experienced fatal stroke), benefits by statins for cognitive function in those in whom a stroke was averted might be expected. It must be emphasized that the randomized trial evidence has, to date, uniformly failed to show cognitive benefits by statins and has supported no effect or frank and significant harm to cognitive function.

Analogous to the case for muscle adverse effects, the impact of cognitive adverse effects from statins, when they occur, may be more profound in the elderly. Elderly patients have more commonly already experienced some decline in cognitive function, and more commonly are in a vulnerable range in which additional impairment can have an impact on independence and safety. Indeed, a number of studies show that even modest reductions in cognition in the elderly are linked to increased mortality, even when the reductions remain within the nondemented range, and even when other health factors have been controlled for (Bassuk et al., 2000; Frisoni et al., 1999; Korten et al., 1999; Smits et al., 1999). In this context, adverse cognitive effects must be taken seriously not only for their intrinsic impact on quality of life, but for their potentially weighty implications for mortality.

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Other Adverse Effects

A large variety of other adverse effects have been reported with statins, including (but not limited to) gastrointestinal and neurological effects, psychiatric problems, immune effects (e.g., lupus-like syndrome), erectile dysfunction and gynecomastia (breast enlargement in men), rash and skin problems, and sleep problems.

Of particular note for the elderly population, the PROSPER trial found a significant 25% increase in incident cancer in participants over age 70 randomized to statin therapy versus placebo (Shepherd et al., 2002). Because statins have been reported to cause cancer in animals, the significant increase in cancer cannot be dismissed as necessarily a fluke. While a similar increase has not been seen in studies of statins in younger participants, older people have poorer stores of the cancer-protecting antioxidant nutrients that low-density lipoprotein cholesterol helps to transport to tissue (so that the increase in risk may occur selectively in elderly). Even if the fractional change in risk were similar, the elderly have a higher risk of cancer, increasing the number of cancer events that would manifest.

Low cholesterol is also linked to infection, including development of postoperative infection (Leardi et al., 2000) and predicts mortality and adverse outcomes in hospitalized patients (Crook et al., 1999). While some of this could be due to illness causing lower cholesterol, it may also be that low cholesterol contributes to illness; indeed, animal studies suggest lipoproteins may serve to protect against bacterial endotoxin-induced death (Read et al., 1993).

Statins may produce irritability or short temper in some people, a problem that occurs with statin therapy and resolves with its discontinuation (Golomb et al., 2004). For elderly patients who depend on others for assistance, irritability and its impact on the relationship with caregivers may have special implications.

Heart failure may also occur in patients taking statin therapy. In some people, the myopathic effects of statins may impair heart pumping function (Silver et al., 2003). However, in patients with reduced pumping function due to coronary artery blockages, statins may help heart pumping by improving blood flow to the heart (Node et al., 2003). It depends on the person whether benefit or harm dominates with statin therapy.

Discussion

Observational studies show that as age increases within the elderly age range, high cholesterol flattens then reverses as a risk factor for mortality (Weverling-Rijnsburger et al., 1997). Although it remains to be fully clarified whether these findings have relevance to cholesterol-lowering treatment, the exclusive major randomized trial of statins conducted in the elderly does nothing to dispel a possible causal association, as it did not show benefit of statins to survival. The impact was completely neutral on mortality despite selecting for an elderly population at only moderately older age and selecting for particularly high risk of heart disease--the elderly group in whom greater benefits and lower risks would be expected (Shepherd et al., 2002). There are reasons for concern that still older people--those elderly not selecting for high cardiac risk and those who are frailer than clinical trials generally select--might fare less well. Caution should be exercised in provision of statins as with all treatments in elderly patients. Any time a patient develops a new problem or worsening of an existing problem, the medication list should be reviewed and a possible contribution by medications should be considered. This principle is by no means confined to statins. It is particularly true in elderly patients who may be on many medications with interacting effects, and in whom ability to withstand adverse drug reactions may be attenuated.

Acknowledgement

Dr. Golomb would like to thank Tram Dang for research assistance and Janis Ritchie, R.N., for administrative assistance.

Dr. Golomb is on the faculty of the department of medicine and family and preventive medicine at the University of California, San Diego. Her research focuses on the risks and benefits of medical interventions.

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