Statins Linked to Fatigue in Randomized Study

June 11, 2012

Moderate doses of both simvastatin and pravastatin were associated with tiredness and exertional fatigue in what is thought to be the first randomized study to look at such adverse effects with statins [1].

The study, published online June 11, 2012 as a letter to the Archives of Internal Medicine, was conducted by a group led by Dr Beatrice Golomb (University of California, San Diego).

They explain that low energy and fatigue have been described by patients receiving statins and in observational studies, but to their knowledge, this is the first randomized evidence of such effects. They add that doctors should be alert to patients reporting such symptoms when on statins and, given the importance of energy levels for quality of life, the possibility of these side effects needs to be considered when making the decision whether to prescribe a statin, especially in patients with less to gain from their use.

The study enrolled 1016 subjects (692 men; 324 women) with LDL levels of 115 to 190 mg/dL and no cardiovascular disease or diabetes who were randomized to simvastatin 20 mg, pravastatin 40 mg, or placebo for six months.

Results showed a significant adverse effect on energy and fatigue with exertion associated with statin use, which was more common in women than men. Both simvastatin and pravastatin contributed to this effect. The authors also point out that there was a significant relation between the reduced energy reported and actual activity, which could in turn lead to an increase in cardiovascular clinical events.

"These findings are important, given the central relevance of energy and functional status to well-being," the authors write. They add: "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, extending to 'high-risk' primary prevention and women and elderly persons (including those with coronary artery disease)."

Golomb commented to heartwire : "Statins are fine in patient populations where a mortality benefit has been shown--ie, men under 70 with heart disease or primary-prevention patients with raised CRP or who smoke. But I would think twice for other groups. Primary-prevention patients who don't smoke or don't have raised CRP are far more likely to experience an adverse effect than to have a cardiac event."

She estimated that fatigue could affect between 20% and 40% of patients taking statins. "Observational data suggest the effect tracks with the potency of the agent, so it may be more of an issue with the newer, more potent statins," she added.

For the study, patients rated their own changes from baseline in "energy" and "fatigue with exertion" assessed at six-month follow-up and scored on a five-point scale from "much less" (−2) to "much more" (+2) vs baseline. Results showed an average reduction of 0.25 points with simvastatin and a reduction of 0.17 points with pravastatin, but larger effects with both agents in women.

Change in Energy and Exertional Fatigue Outcome (Energyfatigex Score) for Placebo vs Statins

Group Placebo Statin p Simvastatin p Pravastatin p
All -0.06 -0.21 0.005 -0.25 0.002 -0.17 0.06
Women -0.08 -0.39 0.01 -0.47 0.004 -0.31 0.07

The authors explain that a 0.4 mean difference in the EnergyFatigEx score, which was seen for women receiving simvastatin vs placebo, could occur if four in 10 people cited worsening in either energy or exertional fatigue; two in 10 described both as "worse" or either as "much worse"; or one in 10 characterized both components as "much worse."

Results of a logistic regression analysis, adjusted for baseline levels, suggested that both simvastatin and pravastatin had a significant adverse effect on EnergyFatigEx score.

Logistical Regression Analysis: Change in EnergyFatigEx Score

Group Mean change p
Statin -0.51 0.001
Simvastatin -0.68 0.001
Pravastatin -0.33 0.03

The study was funded by the National Institutes of Health.