Does the Nocebo Effect Explain Statin Muscle Complaints?

Connie B. Newman, MD

March 02, 2017

Editorial Collaboration

Medscape &

Statins are used by about 25 million adults in the United States.[1] The first, lovastatin,[2] was approved about 30 years ago, and since then these drugs have been prescribed to reduce cardiovascular (CV) events and mortality in patients both with and without CV disease.[3,4]

Here's what you need to know.

1. Statins reduce cardiovascular risk.

Numerous randomized controlled trials have found that statins reduce myocardial infarction (MI), ischemic stroke, and vascular mortality, starting with the Scandinavian Simvastatin Survival Study.[5]

A meta-analysis of randomized controlled trials including 170,000 participants found that participants on statin therapy had a 22% reduction in risk, per every 1-mmol/L (39 mg/dL) reduction in low-density lipoprotein cholesterol (LDL-C), for major vascular events (coronary heart disease, ischemic stroke, and revascularization procedures) compared with those on placebo or standard therapy. There was also a 10% risk reduction in total mortality for every 1-mmol/L reduction in (LDL-C.[4]

These effects were similar across age, sex, baseline LDL-C, and previous vascular disease.

A separate meta-analysis also found that patients with low CV risk (below 10%) had CV benefits from statin therapy.[6] This suggests that reducing LDL-C levels by 80-120 mg/dL (2-3 mmol/L) would reduce CV risk by 40% to 50% within a few years. Effects on vascular disease and mortality were found to be similar in men and women of equivalent CV risk.[7]

2. Benefits of statins outweigh any safety risk; serious adverse effects are rare

Statin-induced myopathy is defined[8] here and in the prescribing information for most statins as unexplained muscle pain or weakness with an elevation of creatinine kinase (CK) greater than 10 times the upper limit of normal (ULN). Myopathy related to statins is rare and occurs in less than 0.1% of patients.[9]

Its most severe form, rhabdomyolysis, is even less frequent. Rhabdomyolysis is characterized by muscle cell necrosis and marked elevations in CK (greater than 40-fold ULN) and may cause renal failure, possibly due to myoglobinuria.[10]

The mechanism of statin-induced myopathy is still unknown. The first cases were described in 1988 in patients taking lovastatin, including several patients with a kidney transplant using concomitant cyclosporine, which is now known to be an interacting medication.[11,12,13]

When a patient presents with myopathy, the statin should be stopped and an evaluation conducted for other causes, such as strenuous exercise or other diseases, as well as for medications that interact with statins.[14,15] Rhabdomyolysis is managed with prompt intravenous hydration, careful correction of electrolyte disturbances, and monitoring of CK, creatinine, and other measures of renal function.[16] CK levels should start to decrease within days of drug cessation and subsequently return to normal.

Other serious adverse effects caused by statins are severe liver dysfunction, which is extremely rare (0.001%),[17] new-onset diabetes,[18] and possibly hemorrhagic stroke in patients with prior cerebrovascular disease[19] but not in those with no history of stroke.[20]

New-onset diabetes occurs in 0.2% of patients treated with statins per year and is dose-related..[18,21,22] It usually presents in patients with risk factors for the disease such as impaired glucose tolerance and features of the metabolic syndrome.[23] The increased risk for new-onset diabetes is apparent at the group level, but it is not possible to ascertain whether new-onset diabetes in an individual patient is caused by their statin treatment.

For this reason, and because the extra two cases of diabetes per 1000 patient-years of treatment are more than balanced by preventing 6.5 CV events,[21,24] patients who develop diabetes during statin treatment should continue the statin.

3. Muscle symptoms with no or minimal increases in CK are usually not pharmacologically related to statin therapy.[25]

Although such symptoms have been attributed to statins, double-blind, placebo-controlled, randomized trials (which can assess causality)[9] do not bear this out. Some observational studies[26,27] have suggested that 10%-25% of patients treated with statins complain of muscle symptoms; however, in the vast majority of cases, patients cannot distinguish between a statin and a placebo under double-blind conditions, demonstrating that these symptoms are usually not pharmacologically related (see the next point).[9,25,28,29]

In the largest observational study, involving more than 100,000 US patients,[30] and in a survey of over 800 physicians worldwide,[31] about 10% of US patients treated with statins reported an adverse event that caused them to discontinue statin therapy, and about half of these symptoms were muscle-related. Muscle symptoms associated with statin use are called "statin-associated muscle symptoms" (SAMS), a term that does not imply that the symptoms are caused by the statin.[32]

Patients are described as "statin intolerant" when they stop taking a statin because of symptoms that may or may not be caused by the drug. Discontinuation of statin treatment increases the risk for CV events, including MI and CV death.[33]

The incidence of statin intolerance varies by country, with higher incidence in English-speaking countries.[31] Although the media and some clinicians have asserted that muscle symptoms such as myalgia—without increased CK—are caused by statins, statin CV outcome trials have found no difference between statin and placebo groups[9,25,29]; these randomized, double-blind trials are numerous, include a broad array of patient types, and are large and long-term, the gold standard for evaluating drug safety. In two of these trials, investigators asked about muscle symptoms specifically[34,35]; neither showed any difference between statin and placebo.

Two meta-analyses of double-blind, randomized trials lasting an average of 3 years[36] and 5 years[9] found a very small difference (0.3%) in muscle symptoms in the statin group compared with the placebo group, which was not statistically significant. One of these meta-analyses evaluated discontinuation of statins because of muscle symptoms and found no difference in the statin and placebo groups (P = .37).[9]

Recent trials conducted specifically in patients with intolerable SAMS have shown that, under double-blind conditions, most patients could not distinguish between the statin and placebo.[37,38] Discontinuation due to muscle symptoms in ODYSSEY ALTERNATIVE was similar among patients randomly assigned to atorvastatin 20 mg daily, alirocumab, or ezetimibe.[38]

The GAUSS-3 trial[39] also evaluated 491 patients with statin intolerance due to muscle symptoms, using a double-blind crossover design comparing atorvastatin 20 mg with placebo (for a 10-week treatment period); that study found that:

  • 27.1% had no symptoms on either treatment or had intolerable muscle complaints on both atorvastatin and placebo;

  • 42.6% had symptoms on atorvastatin but not placebo; and

  • 26.5% had symptoms on placebo but not atorvastatin.

Taking the results at face value, the difference between 42.6% and 26.5%—which is 16.1% or 1 in 6—could represent patients in this population of "statin-intolerant" people who had muscle symptoms that were caused by the statin. Even this small fraction may be overestimated, as there is reason to believe that some patients in GAUSS-3 may have unblinded themselves.[28]

4. The nocebo effect may cause patients to attribute background muscle symptoms to the statin.

Muscle symptoms are common in the middle-aged population taking statins.

The difference between the muscle symptom data from observational studies and data from randomized trials is due to the nocebo effect.

The nocebo effect (Latin for "I do harm") explains why some patients misattribute symptoms to their exposure to a chemical or medication or any other agent believed to cause harm.[40,41,42] In the context of SAMS (without significantly elevated CK) or other adverse events perceived to be caused by statins, the nocebo effect is strengthened by exaggerated reports readily available online about the dangers of taking statins and by warnings appropriately communicated by physicians and patient information leaflets about myopathy/rhabdomyolysis.[28]

In some cases, the patient becomes more conscious of background aches and pains when learning about the adverse effects of statins; in other cases, new muscle symptoms arise. Because a placebo-controlled rechallenge is not possible in the clinic, the return of symptoms upon rechallenge with the same or a different statin may well be a nocebo effect.[28]

Whatever the etiology, these muscle symptoms are real to the patient and must be carefully addressed by the physician in order to keep the patient on a statin.

5. Although most SAMS are not caused by statins, treatment of these patients is a challenge.

Techniques to minimize the nocebo effect in patients starting statins may help prevent statin intolerance. Clinicians should avoid communications that create negative expectations about statins[28]; they should emphasize the benefits of statins in reducing CV disease[32] and indicate that serious muscle side effects are very unlikely and are easily detected with a blood test (CK).[28]

Clinicians should inform patients that muscle aches and pains are common in middle age and beyond and usually are due to other causes.[43] Rechallenge with the same statin at the same or lower dose—or with a different statin—is often successful, as shown in a large cohort study of over 100,000 patients: 6579 patients who had discontinued a statin because of an adverse event were re-challenged. Over 90% were taking the same or another statin a year after reporting the adverse event.[30]

In some patients, alternate-day dosing may be necessary, with the aim of later increasing the frequency to daily.[44] If further LDL-C reduction is still needed, other agents can be added to the maximally tolerated statin dose, such as ezetimibe or bile acid sequestrants and, in selected patients, PCSK9 inhibitors.

The CV benefits of statins are backed by a vast database, and statins have a favorable benefit/risk profile. When a statin is recommended by guidelines, keeping the patient on a statin is critically important.

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Follow Connie Newman, MD, on Twitter: @ConniesMedicine.

In association with the Endocrine Society


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