An Evidence-Based Guideline for Treating Dyslipidemia in Statin-Intolerant Patients

      Highlights

      • How to rechallenge the statin-intolerant patient on statin therapy.
      • Looking for secondary causes of statin associated muscle symptoms.
      • Secondary nonstatin therapies for the treatment of dyslipidemia.

      Abstract

      The purpose of this report is to inform nurse practitioners and other health care providers about how to treat dyslipidemia in the statin-intolerant patient while simultaneously achieving optimal cardiovascular outcomes for this patient population. This report will briefly explain how to rechallenge the statin-intolerant patient and the secondary therapies that are available to decrease cardiovascular morbidity and mortality. Algorithms for rechallenging the statin-intolerant patient and secondary therapies are also provided.

      Keywords

      This activity is designed to augment the knowledge, skills, and attitudes of nurse practitioners and other health care providers in decreasing the rate of patients who are statin intolerant and improve CV outcomes, as demonstrated by a score of at least 70% on the CE evaluation quiz.
      At the conclusion of this activity, the participant will be able to:
      • a.
        Describe statin-associated muscle symptoms (SAMS) caused by statin intolerance
      • b.
        Explain how to effectively rechallenge a patient on a statin
      • c.
        Identify secondary non-statin therapies to utilize in the statin intolerant patient
      The authors, reviewers, editors, and nurse planners all report no financial relationships that would pose a conflict of interest. The authors do not present any off-label or non-FDA-approved recommendations for treatment.
      This activity has been awarded 1 Contact Hour of which 1.0 credit is in the area of Pharmacology. The activity is valid for CE credit until October 01, 2023.
      To receive CE credit, read the article and pass the CE test online at www.npjournal.org/cme/home for a $5 fee.

      Introduction

      Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the gold standard for lowering low-density lipoprotein cholesterol (LDL-c), thus reducing cardiovascular (CV) disease morbidity and mortality. Since their inception in 1987, statins have resulted in an average 21% reduction in CV morbidity and mortality.
      • Toth P.P.
      • Patti A.M.
      • Giglio R.V.
      • et al.
      Management of statin intolerance in 2018: still more questions than answers.
      Generally, statins are safe, but there are reports of adverse events. The most common adverse events associated with statins are myalgias and myopathy.
      • Toth P.P.
      • Patti A.M.
      • Giglio R.V.
      • et al.
      Management of statin intolerance in 2018: still more questions than answers.
      Adverse events have caused patients to discontinue statins, which leaves providers searching for treatment that has equivalent benefits as statin therapy for statin-intolerant patients. The International Lipid Expert Panel defines statin intolerance as,The inability to tolerate at least two different statins—one statin at the lowest starting average daily dose and the other statin at any dose, intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities, symptom or biomarker changes resolution or significant improvement upon dose decrease or discontinuation, symptoms or biomarker changes not attributable to established predispositions such as drug-drug interactions and recognizes conditions increasing the risk of statin intolerance.
      • Banach M.
      • Rizzo M.
      • Toth P.P.
      • et al.
      Statin intolerance-an attempt at a unified definition. Position paper from an international lipid expert panel.
      When caused by a statin, myalgia/myopathy is known as statin-associated muscle symptoms (SAMS).
      • Toth P.P.
      • Patti A.M.
      • Giglio R.V.
      • et al.
      Management of statin intolerance in 2018: still more questions than answers.
      Statin intolerance is most commonly associated with SAMS, causing nonadherence with statin therapy and significantly increasing the risk of acute CV events in patients.
      • Toth P.P.
      • Patti A.M.
      • Giglio R.V.
      • et al.
      Management of statin intolerance in 2018: still more questions than answers.
      Importantly, these adverse events have resulted in patients discontinuing statin therapy and increasing their risk of a CV event. Overall, providers have had to determine the next best step(s) for their patients. After a review of current evidence, this report will help equip providers with the tools they need to successfully treat the statin-intolerant patient through statin rechallenging and selecting the best secondary nonstatin therapies to achieve optimal CV morbidity and mortality outcomes for patients.

      Background

      Current evidence shows 2 clear routes to manage the issue of treating patients who are statin intolerance. The first route is to rechallenge the patient, and the second is to use alternative nonstatin therapy if the patient has a true statin intolerance.
      As many as 25 million men and women in the United States are currently prescribed a statin. Up to 10% of these patients discontinue statin therapy due to reported symptoms attributed to statin therapy; however, once the statin is discontinued, the patient should be rechallenged.
      • Newman C.B.
      • Preiss D.
      • Tobert J.A.
      • et al.
      Statin safety and associated adverse events: a scientific statement from the American Heart Association. [published correction appears in Arterioscler Thromb Vasc Biol. 2019 May;39(5):e158].
      Complete statin intolerance is a rare phenomenon, occurring in only 1% of cases.
      • Banach M.
      • Jankowski P.
      • Jóźwiak J.
      • et al.
      PoLA/CFPiP/PCS guidelines for the management of dyslipidemias for family physicians 2016.
      Intrinsic risk factors for statin intolerance include age older than 80 years, female sex, Asian ethnicity, family history of myopathy, and preexisting kidney, liver, or underactive thyroid disease. Extrinsic modifiable risk factors include high-dose statins, excessive alcohol intake, drug interactions, excessive exercise, and grapefruit juice intake.
      • Fitchett D.
      • Hegele R.
      • Verma S.
      Statin intolerance.
      Additional adverse effects of statin use include rhabdomyolysis, which has been reported at a rate of 0.1%. In general, less than 1% of muscle-related symptoms are directly associated with statins. Severe liver toxicity is rare but occurs in 0.001% of patients. Statin therapy can increase the risk of developing diabetes mellitus in 1.2% of patients.
      • Newman C.B.
      • Preiss D.
      • Tobert J.A.
      • et al.
      Statin safety and associated adverse events: a scientific statement from the American Heart Association. [published correction appears in Arterioscler Thromb Vasc Biol. 2019 May;39(5):e158].
      These adverse effects typically dissipate when statin therapy is discontinued. However, providers may refuse to rechallenge patients with statins due to concerns of adverse effects recurring, and patients may refuse rechallenge. Most patients who stop statin therapy should tolerate a statin, but the key is to find the right statin and dose that works for them. Poor CV outcomes, such as irreversible, permanent damage to the heart from a myocardial infarction or the brain from an ischemic stroke, should provide enough concern to rechallenge patients on statins. It is pertinent that patients and providers are educated that statin adverse effects are reversible but that opting not to take a statin may result in permanent organ function loss and even death. Additionally, patients and providers should be aware that even if patients experience statin-related adverse effects with 1 statin, they may not experience those with another statin.
      In patients with complete statin intolerance, lowering LDL-c to goal levels is still important; however, reducing CV outcomes is even more critical. Studies relating to specific CV risk outcomes of alternative medications are limited. Nonstatin medications, such as fenofibrates, bile acid sequestrants (BASs), and niacin, have been studied but do not have any CV outcome data.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      However, there is a potential for CV risk reduction with the development of newer medication classes such as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, ezetimibe, and bempedoic acid.
      There are a handful of timely CV outcome randomized control trials, such as the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes),
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease.
      Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER),
      • Laufs U.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid in patients with hyper cholesterolemia and statin intolerance.
      Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103) (IMPROVE-IT),
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      and Evaluation of the Efficacy and Safety of Bempedoic Acid (ETC-1002) as Add-on to Ezetimibe Therapy in Patients With Elevated LDL-C (CLEAR Tranquility),
      • Szarek M.
      • White H.D.
      • Schwartz G.G.
      • et al.
      Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial.
      that make a case for prescribing these medications to lower LDL-c and potentially improve CV outcomes for patients who have a true statin intolerance. The focus should not only be on improving LDL-c levels but also on using medications that also improve overall CV outcomes and mortality. Each class of nonstatin LDL-c reduction medications is reviewed for LDL-c reduction percentage, CV outcome data, cost, and adverse effects.

      Statin Rechallenge

      The consensus throughout the evidence is consistent in that rechallenging a patient on statin therapy is always the first and most crucial step to treating a statin-intolerant patient with dyslipidemia. In all instances and encounters for patients with dyslipidemia, a healthy lifestyle should be encouraged. Education and resources should be provided on smoking cessation and weight loss. Physical activity should be encouraged with at least 10,000 steps taken daily or 150 minutes weekly of moderate physical activity. A diet low in saturated fats, such as the Mediterranean diet or portfolio diet, should also be encouraged.
      • Fitchett D.
      • Hegele R.
      • Verma S.
      Statin intolerance.
      The National Lipid Association has developed a statin-associated muscle symptom (SAMS) clinical index that is a useful tool to aid providers in determining whether SAMS is likely caused by statin therapy.
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
      The SAMS clinical index is a point-based clinical tool that looks at the area and pattern of myalgia in the patient, onset of symptoms, and what happens when the patient is dechallenged and rechallenged.
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
      Often, myalgia and myopathy result from another cause but are quickly blamed on a statin by both patients and providers.
      If a patient presents with mild or severe SAMS symptoms, the first step would be to stop the statin and order a creatine kinase (CK) level. If the CK level is less than 4 times the upper limit of normal (ULN), hold the medication for 2 to 4 weeks. If myopathy does not resolve, resume statin therapy and investigate other causes because the statin is likely not the cause of myopathy in this patient. If SAMS does resolve, rechallenge with a statin at a lower dose or switch to a different statin.
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
      If a patient presents with mild or severe SAMS symptoms, but the CK level is greater than 4 times ULN or the patient has muscle weakness, stop statin therapy for 6 to 8 weeks. Once symptoms resolve, attempt to rechallenge with a lower dose of the same statin or a different statin. It is preferable to use a highly effective statin that results in a higher yield of LDL-c reduction, such as rosuvastatin or atorvastatin. If myopathy continues after 8 weeks, resume the statin at a lower dose and consider another cause because the statin is likely not the cause of myopathy in this patient.
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
      If a patient’s CK level is greater than 10 times ULN, consider rhabdomyolysis and immediately discontinue statin therapy. Refer the patient to a higher level of care to treat the adverse effect and consider statin intolerance. Treat dyslipidemia with secondary nonstatin lipid-lowering therapy (Figure 1).
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
      Figure thumbnail gr1
      Figure 1Statin rechallenge algorithm. CK = creatine kinase; CoQ10 = coenzyme Q10; LDL-c = low-density lipoprotein cholesterol; SAMS = statin-associated muscle symptom; ULN = upper limit of normal. Adapted from Ward et al,
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.
       2019.
      In all cases of presumed SAMS, consider prescribing the patient coenzyme Q10 (CoQ10) supplementation. A meta-analysis found that SAMS may be related to CoQ10 deficiency due to statin therapy reducing circulating CoQ10 in the body.
      • Qu H.
      • Guo M.
      • Chai H.
      • Wang W.T.
      • Gao Z.Y.
      • Shi D.Z.
      Effects of coenzyme Q10 on statin-induced myopathy: an updated meta-analysis of randomized controlled trials.
      Daily CoQ10 supplementation may decrease the SAMS symptoms of muscle weakness, cramps, and tiredness. A dose of 100 to 200 mg daily of CoQ10 supplementation is suggested as long as the patient is taking a statin to reduce SAMS symptoms.
      • Taylor B.A.
      • Lorson L.
      • White C.M.
      • Thompson P.D.
      A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy.
      If SAMS return a second time after restarting statin therapy, stop the statin and obtain a CK level. If SAMS is likely caused by the statin, the provider may use intermittent dosing, add on CoQ10, trial another statin with a different metabolic pathway, or lower the current statin dose.
      • Banach M.
      • Jankowski P.
      • Jóźwiak J.
      • et al.
      PoLA/CFPiP/PCS guidelines for the management of dyslipidemias for family physicians 2016.
      Intermittent dosing is a treatment regimen where the patient takes a statin every other day. Daily dosing results in 15% more LDL-c reduction compared with intermittent dosing. To optimize LDL-c to target range for a patient using intermittent dosing, secondary therapy like ezetimibe may be warranted for further LDL-c reduction. If practical, prescribing the maximum tolerated dose of rosuvastatin is recommended due to its superior half-life of 19 hours. Atorvastatin can also be considered because its half-life is 14 hours. Intermittent dosing does not offer as much CV protection compared with daily dosing; therefore, daily dosing of statins is optimal if patients can tolerate it.
      • Arca M.
      • Pigna G.
      Treating statin-intolerant patients.
      If SAMS returns for a third time despite intermittent dosing, switching statins, and CoQ10 supplementation, the patient should be deemed statin intolerant as defined by the International Lipid Expert Panel due to an inability to tolerate at least 2 different statins with 1 at the recommended daily dose and another at any dose.
      • Banach M.
      • Jankowski P.
      • Jóźwiak J.
      • et al.
      PoLA/CFPiP/PCS guidelines for the management of dyslipidemias for family physicians 2016.
      The next step would be to use nonstatin-based cholesterol-lowering medications.
      • Ward N.C.
      • Watts G.F.
      • Eckel R.H.
      Statin toxicity: mechanistic insights and clinical implications.

      Nonstatin Dyslipidemia Treatment

      Patients who cannot tolerate statins are at an increased risk of CV events due to statins’ proven benefits both for LDL-c lowering and CV outcome data. In the past, secondary therapy has failed to achieve a 50% LDL-c reduction recommended by current guidelines or positive CV outcome data equivalent to that of statins.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • 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.
      However, newer classes of medications, including PCSK9 inhibitors, ezetimibe, and bempedoic acid, have emerged, and outcome trials are continuing to be performed, showing promising data to support secondary treatment in statin-intolerant patients. Long-standing drugs such as niacin, fenofibrates, and BASs will also be discussed.

       PCSK9 Inhibitors

      Two PCSK9 inhibitors, alirocumab and evolocumab, were approved as a subcutaneous injection given every 2 weeks by the US Food and Drug Administration (FDA) in 2015 for lowering LDL-c. They have averaged a 42% to 68% LDL-c reduction, which is significantly higher than any other secondary nonstatin therapy and is equivalent to statins.
      • Nissen S.E.
      • Stroes E.
      • Dent-Acosta R.E.
      • et al.
      Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.
      The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) trial
      • Nissen S.E.
      • Stroes E.
      • Dent-Acosta R.E.
      • et al.
      Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.
      compared the LDL-c reduction of ezetimibe to evolocumab. On average, the LDL-c reduction for evolocumab and ezetimibe was 54.5% and 16.7%, respectively.
      • Nissen S.E.
      • Stroes E.
      • Dent-Acosta R.E.
      • et al.
      Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.
      PCSK9 inhibitors have also demonstrated positive CV outcome data in randomized clinical trials when used in conjunction with statins. The ODYSSEY OUTCOME trial
      • Szarek M.
      • White H.D.
      • Schwartz G.G.
      • et al.
      Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial.
      compared nonfatal CV events of alirocumab to placebo in patients with acute coronary syndrome who were already receiving a high-intensity statin (atorvastatin, 40-80 mg, or rosuvastatin, 20-40 mg). The trial found that alirocumab treatment, when added to a high-dose statin, reduced the risk of first and subsequent nonfatal CV event in patients with acute coronary syndrome and was associated with a reduced risk of all-cause death.
      • Szarek M.
      • White H.D.
      • Schwartz G.G.
      • et al.
      Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial.
      The FOURIER trial
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease.
      compared evolocumab to placebo in patients with peripheral arterial disease who were already receiving a daily statin. The median LDL-c for patients who were on evolocumab plus statin therapy was 31 mg/dL. As a result of a low LDL-c average, patients with and without peripheral arterial disease experienced significantly reduced major adverse CV and limb events without additional adverse effects.
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease.
      In the future, additional CV outcome trials need to be performed to confirm the cardiovascular benefits of PCSK9 inhibitors, especially as monotherapy for patients who are unable to tolerate statins. As add on therapy, PCSK9 inhibitors significantly improve CV outcomes and may become a mainstay of therapy for statin-intolerant patients in the future due to their significant LDL-c reductions (if data shows they can reduce CV outcomes when used as monotherapy).
      The largest barrier to the use of PCSK9 inhibitors in practice today is cost. For PCSK9 inhibitors to be cost-effective and provide benefits in quality-adjusted life years, their cost would need to be as low as $250 to $350 a month.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • 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.
      Currently, the average monthly cost is $450 to $560. As of now, adverse events, which include flu-like symptoms and injection site soreness, are minimal; however, this class of medication is relatively new, so long-term safety data are unknown at this time.
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease.

       Bempedoic Acid

      Bempedoic acid is a prodrug that acts along the same pathway as a statin; however, bempedoic acid has lower rates of myalgia and myopathy adverse effects compared with statins. In a phase 3 clinical trial known as the Evaluation of the Efficacy and Safety of Bempedoic Acid (ETC-1002) in Patients With Hyperlipidemia and Statin Intolerant (CLEAR Serenity) trial,
      • Laufs U.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid in patients with hyper cholesterolemia and statin intolerance.
      bempedoic acid was compared with placebo in patients who were intolerant to 2 different statins. Results showed it reduced LDL-c an average of 21.4% and reduced high-sensitivity C-reactive protein by 23.4%. Bempedoic acid was also associated with a low risk of adverse events, including myopathy and new-onset diabetes.
      • Laufs U.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid in patients with hyper cholesterolemia and statin intolerance.
      The Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo (CLEAR Outcomes) trial (NCT02993406) is a randomized controlled trial currently underway with 14,000 participants. It will provide key data on the CV benefits of bempedoic acid (180 mg) as monotherapy for patients who are statin intolerant. The trial is estimated to be completed in December 2022.
      The CLEAR Tranquility study found that bempedoic acid is complementary to ezetimibe. Using these medications in conjunction may be useful to reduce LDL-c in statin-intolerant patients, but there are no CV outcome data trials to date.
      • Ballantyne C.M.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
      Bempedoic acid (180 mg) and ezetimibe (10 mg combination tablet) reduces LDL-c by 35%. Additionally, it may have a significant CV impact on statin-intolerant patients.
      • Ballantyne C.M.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
      Cost is a limiting factor to prescribing bempedoic acid because a 30-day supply costs approximately $330.
      • Laufs U.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid in patients with hyper cholesterolemia and statin intolerance.
      Significant CV data and long-term adverse event profiles are needed before recommending the use of bempedoic acid to lower LDL-c and potentially benefit CV outcome end points in the statin-intolerant patient. Adverse events reported with bempedoic acid include tendon rupture and uricemia, causing a 10% risk of a gout flare in patients with gout.

       Ezetimibe

      Ezetimibe is a cholesterol absorption inhibitor that the FDA approved for cholesterol reduction in 2002. Ezetimibe results in an 18% LDL-c reduction on average.
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      The IMPROVE-IT trial
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      compared ezetimibe (10 mg) to placebo in addition to simvastatin (40 mg). Over 10 years, ezetimibe improved clinical efficiency by reducing CV primary end points by 11%, with an absolute CV risk reduction of 2% compared with simvastatin and placebo. In the IMPROVE-IT trial,
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      ezetimibe prevented 5 myocardial infarctions, 2 strokes, and 4 revascularizations over a 10-year period.
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      Despite this evidence, the FDA did not approve a CV benefit indication for ezetimibe monotherapy.
      • Murphy S.A.
      • Cannon C.P.
      • Blazing M.A.
      • et al.
      Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial.
      However, ezetimibe is recommended in clinical guidelines as a first-line add-on for patients receiving the maximum tolerated dose of a statin but who require further LDL-c reduction and CV protection. Ezetimibe has an economical 30-day cost of $20 and has been proven a safe drug with minimal adverse events.
      • Chaiyasothi T.
      • Nathisuwan S.
      • Dilokthornsakul P.
      • et al.
      Effects of non-statin lipid-modifying agents on cardiovascular morbidity and mortality among statin-treated patients: a systematic review and network meta-analysis.

       Niacin

      Niacin is primarily known for its ability to increase high-density lipoprotein-cholesterol (HDL-c) levels. However, it can reduce LDL-c by 14% to 17% by inhibiting very LDL-c production in the liver. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials failed to demonstrate any CV benefits of niacin. In fact, niacin transiently worsened glycemic metabolic parameters by increasing glycated hemoglobin (HgbA1c) by 1% and increased fasting blood glucose by 8.1 mg/dL in patients with diabetes.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      Its cost is economical at $15 for a 30-day supply. However, the negative CV outcome data, low LDL-C reduction, and impact on metabolic parameters place niacin as a medication to avoid in the statin-intolerant patient.
      • Chaiyasothi T.
      • Nathisuwan S.
      • Dilokthornsakul P.
      • et al.
      Effects of non-statin lipid-modifying agents on cardiovascular morbidity and mortality among statin-treated patients: a systematic review and network meta-analysis.

       Bile Acid Sequestrants

      BASs reduce LDL-c by trapping bile acids in the stomach causing an upregulation of LDL-c receptors, an increase in serum clearance of LDL-c, ultimately resulting in a 15% to 25% reduction of serum LDL-c.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      In 1984, the Lipid Research Clinics Coronary Primary Prevention Trial showed that over 7.4 years, the BAS cholestyramine (16 mg) reduced coronary artery disease, death, and myocardial infarction by 19% compared with placebo.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      In 1988, BASs and niacin were the drugs of choice for dyslipidemia according to the National Cholesterol Education Project.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      Colesevelam (3.8 mg) has an FDA indication for treating type 2 diabetes mellitus; on average, it reduces HgbA1c by 0.5% to 1.0% and is weight neutral.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      The cost for a 30-day supply of a BAS ranges from $100 to $190, depending on the medication prescribed. The adverse effects of BASs are significant enough to cause patients to be noncompliant with therapy. These include abdominal gas and pain, nausea, cramping, and constipation. Colesevelam is the best tolerated BAS from an adverse event standpoint.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      While BASs do have older evidence of CV outcomes, their cost, limited LDL-c reduction, adverse event profile, and lack of current evidence demonstrating primary CV outcomes limits their use as a first-line choice for the statin-intolerant patient.

       Fibrates

      Fibrates reduce LDL-c by 20% by accelerating the clearance of triglyceride-enriched lipoproteins meditated by cholesteryl esterase transfer proteins. Fibrates have additional positive effects on the cholesterol panel by increasing HDL-c levels and decreasing triglycerides.
      • Goyal P.
      • Igel L.I.
      • LaScalea K.
      • Borden W.B.
      Cardiometabolic impact of non-statin lipid lowering therapies.
      Several older studies have shown promise of positive CV outcomes with fibrates as monotherapy; however, these trials were focused on patients with metabolic syndrome and did not demonstrate positive CV outcomes for the general population.
      • Sando K.R.
      • Knight M.
      Nonstatin therapies for management of dyslipidemia: a review.
      Recent trials with fibrates used in addition to statins have not shown CV benefit.
      • Sando K.R.
      • Knight M.
      Nonstatin therapies for management of dyslipidemia: a review.
      A recent meta-analysis of 18 trials found no evidence of all-cause mortality or CV benefit with fibrates.
      • Jun M.
      • Foote C.
      • Lv J.
      • et al.
      Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.
      The average 30-day cost of fibrates is $20. Adverse events of fibrates include a permanent increase in serum creatinine, risk of cholelithiasis, and an increase in serum transaminases. Fibrates need renal dosing if the patient’s creatinine clearance is < 60 mL/min and may require dose adjustments if used in combination with statins due to the potential effects on liver enzymes.
      • Sando K.R.
      • Knight M.
      Nonstatin therapies for management of dyslipidemia: a review.
      Fibrates are not recommended for use in the statin-intolerant patient due to the lack of positive CV outcome data, adverse event profile, and overall LDL-c reduction (Figure 2).
      Figure thumbnail gr2
      Figure 2Secondary therapy algorithm for the statin-intolerant patient. ACS = acute coronary syndrome; CrCl = creatinine clearance; CV = cardiovascular; DM = diabetes mellitus; GI = gastrointestinal; LDL-c = low-density lipoprotein cholesterol; MI = myocardial infarction; PAD = peripheral artery disease; PCSK9 = proprotein convertase subtilisin/kexin; PO = oral; SQ = subcutaneous; TBD = to be determined.

      Conclusion

      Only 1% of patients have a true statin intolerance, defined as the inability to tolerate at least 2 different statins, 1 statin at the recommended average daily dose and the other statin at any dose or frequency.
      • Banach M.
      • Jankowski P.
      • Jóźwiak J.
      • et al.
      PoLA/CFPiP/PCS guidelines for the management of dyslipidemias for family physicians 2016.
      Because statins reduce LDL-c and CV risk, they continue to be the gold standard for treating the patient with dyslipidemia. This is why rechallenging the statin-intolerant patient and identifying potential secondary causes of myalgias and myopathy is the most critical step in treating dyslipidemia in the statin-intolerant patient.
      Secondary nonstatin therapy remains an option for patients who cannot tolerate statin rechallenging. PCSK9 inhibitors and ezetimibe, when used with statin therapy, have positive CV results in outcome trials; however, these results may not be generalizable to patients with statin intolerance. Currently, none of the nonstatin medications have positive CV outcomes associated with their use as monotherapy. As a result, these medication classes do not have an FDA indication for CV risk reduction. Bempedoic acid is a promising medication for the treatment of statin intolerance because it currently has a CV outcome trial without the addition of statin therapy underway.
      • Laufs U.
      • Banach M.
      • Mancini G.B.J.
      • et al.
      Efficacy and safety of bempedoic acid in patients with hyper cholesterolemia and statin intolerance.
      In future research, trials evaluating PCSK9 inhibitors, bempedoic acid, and ezetimibe without the addition of statins on CV outcomes are needed.
      Dissemination of this evidence-based guideline to frontline primary care providers is paramount to direct therapy and improve CV outcomes in the statin-intolerant patient. Providers should use the provided algorithms in conjunction with shared decision making with their patients to optimize their CV outcome risk.

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      Biography

      Dylan Lempp, DNP, FNP-C, is a graduate of Texas Christian University, Fort Worth and a nurse practitioner at Baylor Scott and White Health, Dallas, TX and can be contacted at [email protected] .