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November 8, 2007 (Orlando) — Results of a randomized trial show that simvastatin, but not pravastatin, appears to interfere with sleep quality and increase sleep problems, as assessed by patients.

"Simvastatin users exhibited significantly worse subjective sleep, relative to either placebo or pravastatin, despite comparable sleep ratings at baseline," lead author Beatrice Golomb, MD, from the University of California at San Diego School of Medicine, told attendees here at the American Heart Association 2007 Scientific Sessions.

Their findings are "important but also timely," she said, since more patients are being switched to simvastatin as it goes off patent," Dr. Golomb said. However, she cautioned that their study defines neither the precise nature of the sleep problems nor the mechanisms that may be involved.

Not everyone will have sleep problems with simvastatin, but if they do occur, she said, "then it might be prudent to consider a change of medication to a different statin."

To Sleep, Perchance to Dream

Since statins were first released, case reports and case series have cited instances of sleep disturbance and insomnia on statins, Dr. Golomb said. More recently, nightmares have been reported as adverse effects on statins, and a number of clinical trials and studies of statins have cited insomnia as an adverse effect.

A number of clinical trials have directly evaluated the impact of statins on sleep, she noted; some of these were placebo controlled and randomized, with either a crossover or parallel design, although they had quite small sample sizes and short durations of follow-up. Many of the studies compared placebo with lipophilic statins such as lovastatin or simvastatin with the hydrophilic statin pravastatin because lipophilic statins can cross the blood-brain barrier.

Most of those studies found no effect on sleep, except one, which showed simvastatin adversely affected sleep relative to pravastatin, although neither was significantly different than placebo.

For this study, Dr. Golomb and colleagues used an adapted version of the tool used in that study, the Leeds Sleep Scale, measuring sleep quality, because it had been able to distinguish between the 2 drugs in that prior study and because, Dr. Golomb said, "it looks at the sleep outcome that is most relevant to patients, which is how does your sleep feel to you."

Noncardiac Effects of Statins

The current study, called the University of California, San Diego (UCSD) Statin Study, was a double-blind, randomized, placebo-controlled trial evaluating noncardiac effects of statins. A total of 1016 men older than 20 years and postmenopausal women were enrolled if they had low-density lipoprotein (LDL)-cholesterol levels between 115 and 190 mg/dL, no known cardiovascular disease or diabetes, and fasting blood glucose of below 140 mg/dL. At the time the study began, statin therapy was considered optional for these subjects.

They were randomized to receive 40 mg of pravastatin, 20 mg of simvastatin (considered pharmacologically equivalent), or placebo, and followed up for 6 months. Sleep was a prespecified secondary endpoint of this trial.

Sleep was assessed by the adapted Leeds Sleep Scale, rating sleep quality on a scale of 0 to 30, and a sleep-problems scale, where patients rated their general experience of sleep problems without defining the nature of the problems, on a scale of 0 to 10 at baseline, and then rated them from "much better" to "much worse" on a 5-point scale.

At baseline, the 3 randomized groups were equivalent in terms of their sleep quality and sleep problems. On follow-up, however, "the simvastatin group reported significant worsening relative both to the placebo group and the pravastatin group in both the sleep-quality outcome and the sleep-problem outcome," Dr. Golomb said. Pravastatin did not differ significantly from placebo on either of these measures.

Their study is limited to some degree by including only 1 lipophilic and 1 hydrophilic statin, the relatively low doses used at the time the study was begun, and the lack of assessment of a dose response. It's also not clear if these effects would be different in the groups that were excluded from the study, she noted.

The mechanism of this difference is also unclear, she said. It may relate to the lipophilicity of simvastatin vs hydrophilicity of pravastatin, the difference in cholesterol lowering, which was greater with simvastatin, or some other unknown factors.

What is clear is the importance of sleep to good health, function (including memory and cognition), mood, well-being and safety, Dr. Golomb concluded, "so the importance in terms of potential ramifications to health of sleep problems is quite large."

Modest Increase in Risk

Asked to comment on these findings for Medscape Neurology and Neurosurgery, Roger Blumenthal, MD, from Johns Hopkins University Medical Center in Baltimore, Maryland, called the current study "one of the more persuasive ones so far that there is a modest increased risk with simvastatin vs pravastatin, and it's good for physicians to be aware of this."

In their practice, they have not seen a big difference in sleep disturbances, he said, "at least what's been reported to us, but nowadays there's a much bigger push for managed care to want us to switch people to generic simvastatin, and Vytorin, which is simvastatin and ezetimibe in combination, is slowly but surely growing in frequency." The "flipside," he added, is that pravastatin is not as potent as simvastatin or atorvastatin, which tend to be metabolized in a similar way.

"So it's a provocative study but still relatively small," Dr. Blumenthal said. "In my mind, the absolute differences are modest, but it's important, I think, that physicians need to be aware that drugs in the same class may differ and have side effects.

"Probably the first step if someone complains of sleep disturbances with cholesterol-lowering medicine is to take it earlier in the day, and if that doesn't work, then to switch to a different statin," he added.

Dr. Golomb's group, he concluded, "is one of few groups throughout the world that has tried to look at side effects of statins over the long term. We await future studies that can clarify why 10 out of 100 people in my experience just don't tolerate statins for one side effect or another."

The study was funded by the National Heart, Lung, and Blood Institute. Coauthor Joel Dimsdale has disclosed an unrelated grant from Sepracor. All other authors have disclosed no relevant financial relationships.

American Heart Association Scientific Sessions 2007: Abstract 3725. Presented November 7, 2007.

Pearls for Practice

• Despite comparable sleep ratings at baseline, patients taking simvastatin had significantly worse subjective ratings of sleep vs either placebo or pravastatin. Both the sleep quality and sleep problem outcomes were worse for simvastatin vs placebo, whereas pravastatin did not differ significantly from placebo on either measure.
• The mechanism of this difference is unclear, but it may relate to simvastatin being lipophilic, whereas pravastatin is hydrophilic; to the difference in cholesterol lowering, which was greater with simvastatin; or to some other unknown factors. For patients reporting sleep problems with simvastatin, it may be helpful to take the statin earlier in the day, or if that does not alleviate the sleep disturbance, to consider changing to a different statin.

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