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Requests for reprints should be addressed to Scott M. Grundy, MD, PhD, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390.
Center for Human NutritionDepartment of Internal Medicine, University of Texas Southwestern Medical Center, DallasThe Veterans Administration North Texas Health Care System at Dallas
Center for Human NutritionThe Veterans Administration North Texas Health Care System at DallasDepartment of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas
Statins are among the most widely prescribed drugs. They reduce risk for atherosclerotic cardiovascular disease by lowering serum apolipoprotein B-containing lipoproteins, particularly low-density lipoprotein (LDL) cholesterol (LDL-C).
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
The latter slows progression of atherosclerotic lesions, reduces coronary plaque rupture, and decreases likelihood of acute cardiovascular syndromes (ie, myocardial infarction and stroke).
Cholesterol Treatment Trialists’ (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
They are strongly recommended for patients with clinical atherosclerotic cardiovascular disease (secondary prevention). Major forms of clinical atherosclerotic disease are a history of myocardial infarction, stroke, and various forms of peripheral arterial disease. Moderate-intensity statins are commonly prescribed for patients at risk for new-onset atherosclerotic disease (primary prevention).
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Cholesterol Treatment Trialists’ (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
This document reviews factors responsible for intolerance and discontinuation of statins and offers an empiric approach to overcoming these problems (Figure 1).
Figure 1Causes of statin discontinuation and empiric approaches to secondary prevention and primary prevention.
Statin noncompliance can be defined as discontinuing therapy for whatever reason. The term statin intolerance is here used to name discontinuation due to perceived side effects. Statin noncompliance results from 4 main causes. First, high on the list are breakdowns in the health care system. Second, because of widespread misrepresentation of the safety of statins, anticipations of side effects commonly lead to discontinuation (nocebo effect). Third, symptoms related to disorders of the musculoskeletal system and other organs often are misconstrued as being statin related. And fourth, muscular symptoms sometimes can result from true statin myotoxicity. Each of these causes can be reviewed briefly.
Compliance Breakdown in Health Care Settings
Many factors plague the health care system and contribute to long-term statin discontinuation rates of 50% or more.
These causes include limited access to medical care, hand-offs to multiple clinicians, cost of drugs or insurance coverage, lack of discharge counseling, incorrect drug doses, anticipated side effects, failure to motivate or educate patients, burdens of polypharmacy (pill burden), conflicting comorbidities, inadequate caregiver participation, and a variety of socioeconomic factors.
Many media or book claims have ulterior motives, that is, promotion of alternative therapies such as various nutritional regimens, holistic medicine, and other treatment regimens. That the nocebo effect underlies many claims of statin intolerance seems quite reasonable.
However, few studies directly quantify the impact of this effect on statin adherence. Some investigators claim that statin RCTs indirectly support nocebo in clinical practice. In RCTs, rates of discontinuation of statin therapy, although substantial, are similar in treatment and control arms.
Not all investigators agree that the nocebo effect accounts for claims of statin side effects; in particular, the occurrence of true statin myotoxicity could lie hidden under the many other factors leading to discontinuation in statin RCTs.
Misattribution of Statin Side Effects to Unrelated Musculoskeletal Disorders
A variety of musculoskeletal symptoms from other causes may be blamed on statins. More than one-third of adults, particularly older adults, have acute or chronic musculoskeletal disorders.
Treatment with statins may focus attention of patients to one or more of these disorders. It is the clinical experience of one of the authors (SMG) that patients referred to lipid clinic for statin intolerance frequently have another musculoskeletal condition that underlies the complaint. In this regard, Lakey et al
reported that approximately one-third of patients referred for statin intolerance have a different musculoskeletal disorder. Examples of the latter include vertebral disc disease (spondylosis), other causes of low back pain, various arthritic disorders, connective tissue diseases, musculoskeletal trauma, fibromyalgia, and tendinitis.
Other Side Effects Attributed to Statin Therapy
The medical literature contains many reports of adverse effects of statins that are unrelated to muscle. Although some of these appear to be real effects, their clinical significance is often overblown.
Moreover, the US Food and Drug Administration does not recommend routine monitoring of transaminase levels. In patients with impaired fasting glucose concentrations, statin treatment sometimes raises plasma glucose to the level of categorical diabetes.
Despite worry about this “induction of diabetes,” risk–benefit ratios almost always favor statin treatment. Occasionally, patients taking statins complain of mental confusion (“brain fog”). In these patients, a cause-and-effect relationship has not been proven. Statins are sometimes accompanied by proteinuria, but this is due to a benign tubular proteinuria
Still, in a minority, a variety of sensory side effects, mainly muscular discomfort, limit compliance. Many of those who discontinue statins may have other causes of muscle symptoms, but a subgroup of patients with muscle symptoms seemingly have mild but true myotoxicity.
That statins can produce muscle damage is unquestioned. Rarely, they cause severe myopathy (rhabdomyolysis), which results from high statin levels in plasma and increased exposure to skeletal muscle. Various mechanisms underlying symptoms have been proposed, but best evidence suggests that statins can impair muscular mitochondrial oxidative capacity.
Normally, systemic statins are kept very low due to hepatic extraction and degradation; but if disposal is impaired, blood levels increase, causing muscle dysfunction and even rhabdomyolysis.
Most susceptibility factors for severe but rare myopathy have been learned through clinical experience. Most common are advanced age, female sex, Asian ethnicity, low body mass index, small body frame, frailty, alcohol abuse, surgery with severe metabolic demands, diabetes, chronic renal disease, reduced vitamin D levels, and heavy or unaccustomed exercise.
Statin-associated muscle symptoms: impact on statin therapy–European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Polymorphisms in genes responsible for catabolism of transmembrane transport of statins have been reported to be associated with increased risk of rhabdomyolysis.
Several drugs impair or compete with statin catabolism, raise blood levels, and precipitate rhabdomyolysis (eg, illicit drugs [cocaine, amphetamines], antipsychotics, fibrates [notably gemfibrozil], amiodarone, verapamil, warfarin, cyclosporine, macrolide antibiotics, azole antifungals, protease inhibitors, nefazodone, and large quantities of grapefruit [>1 quart per day]).
Rhabdomyolysis on statin treatment is rare; much more common is statin-induced myalgia. The prevalence of myalgia depends on susceptibility factors and statin dosage; on average, intolerance to myalgias appears to affect 5%-10% of patients.
Presumably, these are mild forms of myopathy. But objective evidence of myopathy (eg, raised creatine kinase) is rarely present. Common symptoms include muscle pain, weakness, and cramping.
Strategies to Manage Statin Intolerance and Discontinuation
The problems of statin-associated side effects and long-term drug noncompliance are complex and not always easily resolved. Statin discontinuation due to perceived side effects (statin intolerance) should be distinguished from other causes of drug discontinuation. There are suggestions on ways to differentiate true statin intolerance from other causes.
These approaches are not widely used, and their utility is not well established. Because statin intolerance is largely subjective, it is difficult to discern whether symptoms are due to statin toxicity or result from other factors (eg, nocebo effects or co-existing musculoskeletal disorders). For this reason, an empiric approach to patient management of so-called statin intolerance appears to be most practical. The following summarizes key steps in an empirical approach to statin noncompliance.
Maximize Control of Other Risk Factors
Although statins can reduce atherosclerotic disease events by 35%-50%, they do not fully eliminate residual risk from other causes. To maximize risk reduction, control of all major risk factors (eg, hypertension, cigarette smoking, diabetes, metabolic syndrome) is needed. This usually involves combining lifestyle changes with drug therapies. In patients in whom an optimal dose of statin therapy cannot be achieved, maximal control of other risk factors becomes especially important.
Develop Management Plan to Realize Long-Term Compliance
Maintenance of statin therapy over the long term is best achieved by the creation of a multilayered management system. Key steps are the following: establish a competent management team, designate a knowledgeable clinician to lead the team; carry out a meaningful risk discussion to facilitate communication between clinician and patient;
if possible, identify causes of noncompliance; if necessary, refer patient to a lipid clinic for expert care; and importantly, establish routine follow-up and monitoring.
In clinical practice, beyond the need to explore factors responsible for statin noncompliance, clinicians are often faced with complaints of statin intolerance. The following suggests clinical approaches for this particular problem.
For Statin Intolerance in Patients with Clinical Atherosclerotic Disease, Maximize LDL Lowering
Patients with clinically manifest atherosclerotic disease are at high risk for further cardiovascular events. The most effective way to reduce future events is to maximize lowering of LDL-C. Statin therapy typically is the first step to achieve this aim. Atherosclerotic disease seems to be a strong motivator for drug adherence. Greatest success in maintaining statin therapy occurs in patients with established atherosclerotic disease.
Moreover, these patients are commonly followed by specialists who are well informed in the details of statin therapy.
For secondary prevention, high-intensity statins are preferred (ie, atorvastatin 40-80 mg/d or rosuvastatin 20-40 mg/d). The aim is to lower LDL-C by >50%;
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
These patients will either have a relatively high baseline LDL-C, or they cannot tolerate a high-intensity statin. The following treatment scheme may be helpful in atherosclerotic disease patients with statin intolerance. First, challenge again with the same statin and dose; this may be successful. If not, try a different high-intensity statin; if necessary, reduce the statin dose to moderate intensity. Some investigators believe that so-called hydrophilic statins (pravastatin, rosuvastatin) are better tolerated than lipophilic statins (atorvastatin, lovastatin, simvastatin); but such has not been proven by rigorous trials.
Once statin alternatives are exhausted, an oral non-statin agent can be added to the tolerated statin dose. Such agents are ezetimibe,
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
In one major clinical trial, addition of ezetimibe to statin therapy safely reduced LDL-C to well below 70 mg/dL and achieved incremental risk reduction.
For statin-intolerant patients with atherosclerotic disease, if an LDL-C <70 mg/dL is not achieved with statins + oral non-statins, consideration should be given to including a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. In 2 major RCTs, adding a PCSK9 inhibitor to maximally tolerated statin (with or without ezetimibe) strikingly lowered LDL-C levels and further reduced atherosclerotic disease risk.
Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial.
Current US recommendations favor addition of a PCSK inhibitor primarily for very high-risk patients when LD-C cannot not be reduced to <70 mg/dL with oral agents. Most statin-intolerant patients tolerate well a PCSK9 inhibitor.
For Statin-Intolerant Patients Without Atherosclerotic Disease, Give Priority to Patients with Subclinical Atherosclerosis (Primary Prevention)
Statins are being employed in many patients without clinical atherosclerotic disease (primary prevention). RCTs demonstrate that statins safely reduce the likelihood of new-onset atherosclerotic disease. Consequently, 2013 American Heart Association/American College of Cardiology cholesterol treatment guidelines
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
defined “statin eligibility” as a 10-year risk for hard atherosclerotic disease events of ≥7.5%. Risk was estimated with algorithms developed from 5 large cohorts (pooled cohort equations).
2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Although this approach is sound in principle, several follow-up reports showed that pooled cohort equations overestimate risk in some US subpopulations.
Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: a special report from the American Heart Association and American College of Cardiology.
Recent studies, moreover, demonstrated that many subjects with pooled cohort equation-defined statin eligibility have no detectable coronary atherosclerosis, that is, they have zero coronary artery calcium (Figure 2).
Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
For any statin-intolerant patient with zero coronary calcium, there is no need to consider statin treatment for at least a decade. A sizable portion of such patients will remain free of coronary calcium.
Figure 2Sex-based coronary artery calcium (CAC) across age groups. P < .001 for trends among men and women.
Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
A second category of coronary calcium includes the coronary calcium range of 1-99 Agatston units. In the range of 1-9 Agatston units, 10-year risk for atherosclerotic disease is marginally higher than for zero coronary calcium.
Mortensen MB, Dzaye O, Bødtker H, et al. Interplay of risk factors and coronary artery calcium for CHD risk in young patients [online ahead of print]. JACC Cardiovasc Imaging. 2021 Jun 16:S1936-878X(21)00374-0. doi:10.1016/j.jcmg.2021.05.003
Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).
for patients with statin intolerance, a statin can reasonably be delayed for a decade, followed by rescanning. By these criteria, statin therapy can be withheld in most statin-intolerant women and at least half of men prior to age 65 years.
If the clinician–patient risk discussion favors LDL lowering in statin-intolerant patients with coronary calcium 1-99 Agatston units, the following strategy can be considered. Generally, for primary prevention, a moderate-intensity statin is first-line therapy. Most commonly used are atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, lovastatin 40 mg, or pravastatin 40 mg. These agents reduce LDL-C by 30%-40% and will decrease atherosclerotic disease events by 25%-35%.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
For statin-intolerant patients, a lower-intensity statin can be tried (eg, fluvastatin XR 80 mg daily or rosuvastatin 5 mg daily or every other day). In addition, a non-statin can be started, for example, ezetimibe 10 mg or bile acid sequestrant. Another non-statin, bempedoic acid, is currently being evaluated in patients with statin intolerance. The aim is to reduce LDL-C as much as possible. However, in primary prevention, PCSK9 inhibitors are rarely employed.
If coronary calcium is ≥100 Agatston units, 10-year risk consistently exceeds 7.5%;
Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
For statin-intolerant patients, the same strategy as outlined above for coronary calcium 1-99 Agatston units can be applied to attain maximal LDL lowering.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
most patients with diabetes, 40-75 years of age, and without atherosclerotic disease, are candidates for statin therapy. This is justified on several reports that patients with type 2 diabetes are at high risk for future cardiovascular events, often approximating that of established atherosclerotic disease.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
indicates that zero coronary calcium in patients with diabetes confers relatively low 10-year rates of atherosclerotic disease events. Thus, it seems worthwhile to measure coronary calcium in any patient with diabetes who claims statin intolerance. If the coronary calcium score is zero or 1-99 Agatston units, withholding statins for 5 to 10 years prior to rescanning is worthy of consideration. Many patients will show no coronary calcium progression upon rescanning and the warranty period can be extended. A few patients with zero coronary calcium scores nonetheless develop atherosclerotic disease, and a substantial portion of these are either cigarette smokers or have diabetes.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
showed that many patients of this type have zero or low coronary calcium and low rates of atherosclerotic disease. Among these with statin intolerance, drug treatment can be delayed until coronary calcium progression has been demonstrated. If a patient with persistently severe hypercholesterolemia has rapidly advancing atherosclerosis as indicated by progressive coronary calcium, a PCSK9 inhibitor can be considered.
In summary, for patients with established atherosclerotic disease who are statin intolerant, emphasis should be given to maximal lowering of LDL-C. This should be achieved by a combination of a lower dose of a statin (if tolerated) combined with non-statin drugs. If LDL-C cannot be reduced to <70 mg/dL, a PCSK9 inhibitor can be added (if affordable). For statin-intolerant patients without atherosclerotic disease, priority should go to detection of coronary calcium, the strongest predictor of future atherosclerotic disease events. If pooled cohort equations calculate a 10-year risk ≥7.5% and if coronary calcium = 0, an LDL-lowering drug can be withheld for at least a decade; if coronary calcium = 1-99 Agatston units, LDL-lowering drugs are optional, but may not be necessary pending future coronary calcium scanning; and if coronary calcium is ≥100 Agatston units, an effort should be made to reduce LDL-C as much as possible with a lower dose statin + oral non-statin drugs.
References
Grundy SM
Stone NJ
Bailey AL
et al.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Statin-associated muscle symptoms: impact on statin therapy–European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins.
Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.
Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: a special report from the American Heart Association and American College of Cardiology.
Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort.
Mortensen MB, Dzaye O, Bødtker H, et al. Interplay of risk factors and coronary artery calcium for CHD risk in young patients [online ahead of print]. JACC Cardiovasc Imaging. 2021 Jun 16:S1936-878X(21)00374-0. doi:10.1016/j.jcmg.2021.05.003
Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).
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