Statins Frequently Cause Fatigue, Reduce Energy Levels

Statins are the most commonly prescribed drugs for treating patients with elevated cholesterol levels, as well as one of the most widely used classes of drugs in the U.S.

A review of the drug labels for statins currently available in the U.S. (see the table below) gives the impression that fatigue is not a common side effect of these drugs. However, a recent large, well-designed study published in the journal Archives of Internal Medicine (Archives) provides evidence that statins commonly cause fatigue and decreased energy level, resulting in significant impairment of some patients’ exercise tolerance and quality of life.

Statin Drugs Available in the U.S.

* Some statins also available in combination
** Do Not Use
***Do Not Use until Seven Years after Approval (2016)

The effect of statins on muscles

Drug-induced muscle injury, or rhabdomyolysis, is one well-known rare but serious side effect of all statins. Rhabdomyolysis typically causes muscle pain, tenderness and weakness, and it can result in kidney failure and death from heart-rhythm disturbance due to the release of large amounts of potassium from damaged muscle cells.

Fatigue with exertion and decreased energy level, likely resulting from a less severe adverse impact of statins on muscles, have also been recognized as more common but less well-characterized side effects of statins.

The drug labels for all of the currently marketed statins mention fatigue as a possible side effect. However, several of the labels only indicate that fatigue may be a sign of liver injury — a rare complication — whereas others note that fatigue has been reported as an adverse event following approval for marketing by the Food and Drug Administration (FDA).

The labels for two of the drugs provide data on the incidence of fatigue in subjects who participated in randomized, placebo-controlled trials. For example, the label for fluvastatin (LESCOL) notes that in one such trial, 4.7 percent of subjects receiving fluvastatin experienced fatigue, compared with 3.8 percent of subjects receiving a placebo. Likewise, the label for pravastatin (PRAVACHOL) states that fatigue occurred in 8.4 percent of pravastatin-treated subjects and 7.8 percent of placebo subjects participating in one large trial.

As the Archives study shows, such drug-label information underestimates the incidence of fatigue caused by statins.

Archives study overview

In a study published in Archives on Aug. 13, 2012, researchers conducted a randomized, placebo-controlled study designed to evaluate the effects of two statins, simvastatin (ZOCOR) and pravastatin, on several noncardiovascular outcomes, including fatigue and energy level. The study, called the University of California, San Diego, Statin Study, was funded by the National Institutes of Health.

The researchers enrolled 1,016 subjects. Eligible subjects were men age 20 years or older or postmenopausal women with a low-density lipoprotein cholesterol level of 115 to 190 milligrams per deciliter (mg/dL). Patients with existing cardiovascular disease or diabetes were excluded from the study, making use of statins in this study a primary prevention intervention.

The subjects were randomly assigned to receive simvastatin (20 mg), pravastatin (40 mg) or a placebo once daily. The study was double-blind, meaning neither the subjects nor the researchers knew to which group each subject was assigned.

Six months later, subjects were asked to rate their change from baseline in two categories — “energy level” and “fatigue with exertion” — using a five-point scale ranging from “much less” (-2) to “much more” (+2). A single score that combined the ratings for energy level and exertional fatigue was then calculated for each subject, with scores ranging from -4 to +4. A score of -4 meant the subject had a much lower energy level and much more exertional fatigue compared with baseline, whereas a +4 score meant the subject had a much higher energy level and much less exertional fatigue compared with baseline.

Archives study results

Data were available for analysis from 670 subjects assigned to receive one of the two statins and 342 subjects assigned to the placebo control group. Of these subjects, 213 in the statin groups and 110 in the placebo group were women.

For all subjects, the average combined score for energy level and exertional fatigue dropped 0.21 points from baseline in the statin subjects and only 0.06 points in the placebo subjects, indicating that treatment with a statin resulted in lower energy level and greater exertional fatigue compared with taking a placebo.

The difference between the statin and placebo groups was even greater when looking at women only. For women, the average combined score for energy level and exertional fatigue decreased 0.39 points from baseline in the statin subjects and only 0.08 points in the placebo subjects.

To better explain what this average drop means, the researchers noted that such a drop would arise if 4 in 10 subjects cited worsening in either energy level or exertional fatigue or if 2 in 10 subjects reported worsening in both measures or rated themselves “much worse” in only one of these measures.

The researchers also found that the drop in the average combined score was greater in the simvastatin group than in the pravastatin group (0.25 points versus 0.17 points for all subjects, respectively, and 0.47 points versus 0.31 points for women only, respectively). They noted that the greater degree of exertional fatigue and decreased energy level seen in the simvastatin-treated subjects was associated with a greater drop in cholesterol levels. This suggests that the more potent a statin is, the more likely it is to cause exertional fatigue and lower energy levels.

Implications of the study

The researchers noted that their results are important “given the central relevance of energy and functional status to well-being.” Patients who develop significant exertional fatigue and loss of energy are likely to perceive a much poorer quality of life. They went on to conclude:

These effects, germane to quality of life, merit consideration when prescribing or contemplating use of statins, particularly in groups without expected net morbidity/mortality benefit …[emphasis added]

Most important, the researchers reported that the occurrence of adverse effects correlated with reduced physical activity and exertional tolerance. Decreased activity may lead to weight gain, increased blood pressure, and the development or worsening of diabetes, all of which are risk factors for developing cardiovascular disease that could negate the intended benefit of taking statins in the first place.

What You Should Do

Before starting a statin, you should discuss with your physician whether dietary changes and increased exercise could lower your cholesterol. If a statin is necessary, make sure your doctor starts with a low dose and only increases the dose as needed to achieve the desired reduction in cholesterol. Periodic blood tests will be needed to assess your response to the statin.

Upon starting the statin, you should monitor yourself for symptoms of fatigue, muscle weakness or pain. If any of these symptoms develop, contact your physician promptly. In some cases, changing to a lower dose or a different statin might be reasonable. For severe symptoms, discontinuation of the statin and substitution of another type of cholesterol-lowering medication may be appropriate.

Consumers may report serious adverse events or product quality problems to the FDA’s MedWatch Adverse Event Reporting program. Please find contact information below:

• Online: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088