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).1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar Statins inhibit cholesterol synthesis in the liver, which increases expression of LDL receptors and lowers serum LDL-C.2Endo A A historical perspective on the discovery of statins.Proc Jpn Acad Ser B Phys Biol Sci. 2010; 86: 484-493Google Scholar The latter slows progression of atherosclerotic lesions, reduces coronary plaque rupture, and decreases likelihood of acute cardiovascular syndromes (ie, myocardial infarction and stroke).3Baigent C Blackwell A et al.Cholesterol Treatment Trialists’ (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Google Scholar High-intensity statins can reduce cardiovascular events by half.4Ridker PM Danielson E Fonseca FA et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N Engl J Med. 2008; 359: 2195-2207Google Scholar 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).1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar They lower cardiovascular events by approximately one-third.3Baigent C Blackwell A et al.Cholesterol Treatment Trialists’ (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Google Scholar Unfortunately, the potential benefit of statins has not been fully realized due to a high prevalence of drug discontinuation. Over the long term, at least half of all patients started on statins will discontinue them. This is true in both randomized controlled trials (RCTs)5Navar AM Roe MT White JA et al.Medication discontinuation in the IMPROVE-IT trial.Circ Cardiovasc Qual Outcomes. 2019; 12e005041Google Scholar and clinical practice.6Toth PP Granowitz C Hull M Anderson A Philip S Long-term statin persistence is poor among high-risk patients with dyslipidemia: a real-world administrative claims analysis.Lipids Health Dis. 2019; 18: 175Google Scholar This document reviews factors responsible for intolerance and discontinuation of statins and offers an empiric approach to overcoming these problems (Figure 1). 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. Many factors plague the health care system and contribute to long-term statin discontinuation rates of 50% or more.6Toth PP Granowitz C Hull M Anderson A Philip S Long-term statin persistence is poor among high-risk patients with dyslipidemia: a real-world administrative claims analysis.Lipids Health Dis. 2019; 18: 175Google Scholar, 7Avorn J Monette J Lacour A et al.Persistence of use of lipid-lowering medications: a cross-national study.JAMA. 1998; 279: 1458-1462Google Scholar, 8Benner JS Glynn RJ Mogun H et al.Long-term persistence in use of statin therapy in elderly patients.JAMA. 2002; 288: 455-461Google Scholar 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.9Hirsh BJ Smilowitz NR Rosenson RS et al.Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome: opportunities for improvement.J Am Coll Cardiol. 2015; 66: 184-192Google Scholar Some experts believe that many patients who are prescribed statins anticipate side effects, and these concerns become self-fulfilling (nocebo effect).10Barsky AJ Saintfort R Rogers MP et al.Nonspecific medication side effects and the nocebo phenomenon.JAMA. 2002; 287: 622-627Google Scholar,11Moon J Cohen Sedgh R Jackevicius CA Examining the nocebo effect of statins through statin adverse events reported in the Food and Drug Administration adverse event reporting system.Circ Cardiovasc Qual Outcomes. 2021; 14e007480Google Scholar Claims of statin dangers come from the press, books, the internet, family and friends, and misinformed medical personnel.12Lowenstern A Navar AM Li S et al.Association of clinician knowledge and statin beliefs with statin therapy use and lipid levels (a survey of US practice in the PALM Registry).Am J Cardiol. 2019; 123: 1011-1018Google Scholar 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.13Tobert JA Newman CB The nocebo effect in the context of statin intolerance.J Clin Lipidol. 2016; 10: 739-747Google Scholar,14Newman CB Preiss D Tobert JA et al.Statin safety and associated adverse events: a scientific statement from the American Heart Association.Arterioscler Thromb Vasc Biol. 2019; 39: e38-e81Google Scholar 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.15Hopewell JC Offer A Haynes R et al.Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.Eur Heart J. 2020; 41: 3336-3342Google Scholar The argument is made that this similarity in discontinuation speaks against any unique adverse effects of statins.16Wood FA Howard JP Finegold JA et al.N-of-1 trial of a statin, placebo, or no treatment to assess side effects.N Engl J Med. 2020; 383: 2182-2184Google Scholar 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.17Ganga HV Slim HB Thompson PD A systematic review of statin-induced muscle problems in clinical trials.Am Heart J. 2014; 168: 6-15Google Scholar 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.18Blyth FM Briggs AM Schneider CH Hoy DG March LM The global burden of musculoskeletal pain–where to from here?.Am J Public Health. 2019; 109: 35-40Google Scholar 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 al19Lakey WC Greyshock NG Kelley CE et al.Statin intolerance in a referral lipid clinic.J Clin Lipidol. 2016; 10: 870-879.e3Google Scholar 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. 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.20Thompson PD Panza G Zaleski A Taylor B Statin-associated side effects.J Am Coll Cardiol. 2016; 67: 2395-2410Google Scholar Statins commonly cause modest increases in serum transaminase levels, but pathological changes in liver morphology have not been found.21Tolman KG The liver and lovastatin.Am J Cardiol. 2002; 89: 1374-1380Google Scholar It is rarely necessary to discontinue statin treatment due to increases in transaminases.22Bays H Cohen DE Chalasani N Harrison SA The National Lipid Association's Statin Safety Task ForceAn assessment by the Statin Liver Safety Task Force: 2014 update.J Clin Lipidol. 2014; 8: S47-S57Google Scholar 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.23Ridker PM Pradhan A Cardio- vascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.Lancet. 2012; 380: 565-571https://doi.org/10.1016/S0140-6736(12)61190-8Google Scholar 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 proteinuria24Verhulst A D'Haese PC De Broe ME Inhibitors of HMG-CoA reductase reduce receptor-mediated endocytosis in human kidney proximal tubular cells.J Am Soc Nephrol. 2004; 15: 2249-2257Google Scholar and not to glomerular disease. Rarely, peripheral neuropathy and acute pancreatitis are attributed to statins. In 80%-90% of patients who are committed to therapy, statins are well tolerated.25Bruckert E Hayem G Dejager S Yau C Bégaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Google Scholar,26Parker BA Capizzi JA Grimaldi AS et al.Effect of statins on skeletal muscle function.Circulation. 2013; 127: 96-103Google Scholar In many who discontinue statins for nonspecific reasons, informed counsel can effectively re-establish and maintain therapy.27Zhang H Plutzky J Skentzos S et al.Discontinuation of statins in routine care settings: a cohort study.Ann Intern Med. 2013; 158: 526-534Google Scholar 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.5Navar AM Roe MT White JA et al.Medication discontinuation in the IMPROVE-IT trial.Circ Cardiovasc Qual Outcomes. 2019; 12e005041Google Scholar 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.16Wood FA Howard JP Finegold JA et al.N-of-1 trial of a statin, placebo, or no treatment to assess side effects.N Engl J Med. 2020; 383: 2182-2184Google Scholar,28Päivä H Thelen KM Van Coster R et al.High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.Clin Pharmacol Ther. 2005; 78: 60-68Google Scholar, 29Schirris TJ Renkema GH Ritschel T et al.Statin-induced myopathy is associated with mitochondrial complex III inhibition.Cell Metab. 2015; 22: 399-407Google Scholar, 30Wu JS Buettner C Smithline H Ngo LH Greenman RL Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications.Muscle Nerve. 2011; 43: 76-81Google Scholar, 31Allard NAE Schirris TJJ Verheggen RJ et al.Statins affect skeletal muscle performance: evidence for disturbances in energy metabolism.J Clin Endocrinol Metab. 2018; 103: 75-84Google Scholar 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.32Mancini GB Baker S Bergeron J et al.Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group update (2016).Can J Cardiol. 2016; 32: S35-S65Google Scholar,33Stroes ES Thompson PD Corsini A et al.Statin-associated muscle symptoms: impact on statin therapy–European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.Eur Heart J. 2015; 36: 1012-1022Google Scholar Polymorphisms in genes responsible for catabolism of transmembrane transport of statins have been reported to be associated with increased risk of rhabdomyolysis.34Turner RM Pirmohamed M Statin-related myotoxicity: a comprehensive review of pharmacokinetic, pharmacogenomic and muscle components.J Clin Med. 2019; 9: 22Google Scholar Various diseases of muscle metabolism also may predispose statin myotoxicity.32Mancini GB Baker S Bergeron J et al.Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group update (2016).Can J Cardiol. 2016; 32: S35-S65Google Scholar 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.25Bruckert E Hayem G Dejager S Yau C Bégaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Google Scholar,26Parker BA Capizzi JA Grimaldi AS et al.Effect of statins on skeletal muscle function.Circulation. 2013; 127: 96-103Google Scholar 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. 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.35Rosenson RS Baker SK Jacobson TA Kopecky SL Parker BA The National Lipid Association's Muscle Safety Expert PanelAn assessment by the Statin Muscle Safety Task Force: 2014 update.J Clin Lipidol. 2014; 8: S58-S71Google Scholar,36Taylor BA Thompson PD Statin-associated muscle disease: advances in diagnosis and management.Neurotherapeutics. 2018; 15: 1006-1017Google Scholar 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. 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. 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;37Martin SS Sperling LS Blaha MJ et al.Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA Guidelines.J Am Coll Cardiol. 2015; 65: 1361-1368Google Scholar 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.38Benner JS Tierce JC Ballantyne CM et al.Follow-up lipid tests and physician visits are associated with improved adherence to statin therapy.Pharmacoeconomics. 2004; 22: 13-23Google Scholar 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. 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.39Sigglekow F Horsburgh S Parkin L Statin adherence is lower in primary than secondary prevention: a national follow-up study of new users.PLoS One. 2020; 15e0242424Google Scholar 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%;1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar this will reduce atherosclerotic disease events by 40%-50%.1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar A general rule is the lower, the better for LDL-C (within reason). For most patients, LDL-C should be reduced to <70 mg/dL.1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar However, many patients will fail to achieve this level of LDL lowering with a high-intensity statin alone.40LaRosa JC Grundy SM Waters DD et al.Intensive lipid lowering with atorvastatin in patients with stable coronary disease.N Engl J Med. 2005; 352: 1425-1435Google Scholar 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,41Stein EA Ballantyne CM Windler E et al.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.Am J Cardiol. 2008; 101: 490-496Google Scholar,42Cannon CP Blazing MA Giugliano RP et al.Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372: 2387-2397Google Scholar bile acid sequestrants, and bempedoic acid.43Thompson PD MacDougall DE Newton RS et al.Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance.J Clin Lipidol. 2016; 10: 556-567Google Scholar 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.42Cannon CP Blazing MA Giugliano RP et al.Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372: 2387-2397Google Scholar 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.44Murphy SA Pedersen TR Gaciong ZA et al.Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial.JAMA Cardiol. 2019; 4: 613-619Google Scholar,45Schwartz GG Steg PG Szarek M et al.Alirocumab and cardiovascular outcomes after acute coronary syndrome.N Engl J Med. 2018; 379: 2097-2107Google Scholar 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.46Nissen SE Stroes E Dent-Acosta RE et al.Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.JAMA. 2016; 315: 1580-1590Google Scholar 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 guidelines47Stone NJ Robinson JG Lichtenstein AH et al.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.J Am Coll Cardiol. 2014; 63: 2889-2934Google Scholar 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).48Goff Jr, DC Lloyd-Jones DM Bennett G et al.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.J Am Coll Cardiol. 2014; 63: 2935-2959Google Scholar Although this approach is sound in principle, several follow-up reports showed that pooled cohort equations overestimate risk in some US subpopulations.49Lloyd-Jones DM Braun LT Ndumele CE et al.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.Circulation. 2019; 139: e1162-e1177Google Scholar 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).50Tota-Maharaj R Blaha MJ Blankstein R et al.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.Mayo Clin Proc. 2014; 89: 1350-1359Google Scholar These individuals are at low risk for cardiovascular events over the next 10-15 years (ie, <5% incidence).51Dzaye O Dardari ZA Cainzos-Achirica M et al.Warranty period of a calcium score of zero: comprehensive analysis from MESA.JACC Cardiovasc Imaging. 2021; 14: 990-1002Google Scholar,52Valenti V Ó Hartaigh B Heo R et al.A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9,715 individuals.JACC Cardiovasc Imaging. 2015; 8: 900-909Google Scholar 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. 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.53Mortensen 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.2021.05.003Google Scholar Overall 10-year risk for coronary calcium 1-99 Agatston units ranges from 5%-7.5%.54Budoff MJ Young R Burke G et al.Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).Eur Heart J. 2018; 39: 2401-2408Google Scholar Although some investigators favor use of statin therapy in this range,55Orringer CE Blaha MJ Blankstein R et al.The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduction.J Clin Lipidol. 2021; 15: 33-60Google Scholar 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%.1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar 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%;54Budoff MJ Young R Burke G et al.Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).Eur Heart J. 2018; 39: 2401-2408Google Scholar here an LDL-lowering drug therapy is preferred.1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar,15Hopewell JC Offer A Haynes R et al.Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.Eur Heart J. 2020; 41: 3336-3342Google Scholar 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. According to 2018 cholesterol guidelines,1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar 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.1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar On the other hand, a recent report56Razavi AC Wong N Budoff M et al.Predicting long-term absence of coronary artery calcium in metabolic syndrome and diabetes: the MESA study.JACC Cardiovasc Imaging. 2021; 14: 219-229Google Scholar 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. Cholesterol treatment guidelines1Grundy 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.Circulation. 2019; 139: e1082-e1143Google Scholar recommend that patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL) generally should be treated with a statin. A recent report57Sandesara PB Mehta A O'Neal WT et al.Clinical significance of zero coronary artery calcium in individuals with LDL cholesterol ≥190 mg/dL: the Multi-Ethnic Study of Atherosclerosis.Atherosclerosis. 2020; 292: 224-229Google Scholar 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.
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Apr 1, 2024
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