PCSK9 Inhibitors Praluent (Alirocumab) and Repatha (Evolocumab) For the Treatment of Familial Hypercholesterolemia

Transcription

1 PCSK9 Inhibitors Praluent (Alirocumab) and Repatha (Evolocumab) For the Treatment of Familial Hypercholesterolemia Policy Number: Original Effective Date: MM /01/2016 Line(s) of Business: HMO; PPO; QUEST Integration Section: Prescription Drugs Place of Service: Outpatient I. Description Hypercholesterolemia is defined as excessive cholesterol in the bloodstream. An elevation in lowdensity lipoprotein (LDL) cholesterol has been proven to increase risks of cardiovascular events. LDL-C accumulates in the body primarily by liver production and secondarily by food consumption. The most common treatment for hypercholesterolemia has been a combination of the use of oral statins and lifestyle modifications. If desired outcomes are not achieved, additional treatment using drugs in other classes such as fibrates, nicotinic acid, bile acid sequestrants or ezetimibe may be used. Familial hypercholesterolemia (FH) is inherited in an autosomal dominant manner; therefore, a parent who carries an altered gene has a one in two chance of passing it on to each child. One in 500 individuals carries one altered gene and is considered genetically heterozygous. More rarely, a person inherits the gene mutation from both parents, making them genetically homozygous. Individuals who are homozygous have a more severe form of hypercholesterolemia, with heart attack and death often occurring before age 30. Signs and symptoms include high levels of LDL cholesterol (LDL-C) as well as total cholesterol, a strong family history of high cholesterol and early heart attack, therapy resistant levels of LDL-C, xanthomas, xanthelasmas, corneal arcus, and sometimes angina. People diagnosed with homozygous hypercholesterol-emia have fewer treatment options and achieving target cholesterol levels is rarely attained. Evolocumab (Repatha) and alirocumab (Praluent) are human monoclonal antibodies that inhibit the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein controlled by its respective gene that reduces the liver's ability to remove LDL cholesterol before it is released into the bloodstream. Restricting this protein s ability to hinder the liver by using PCSK9-inhibiting drugs has shown to lower LDL-C as much as 52%. Studies to date have shown that adverse events are manageable. An assessment of the severity of hypercholesterolemia is determined by performing labs and documenting a complete family history, which have an impact on treatment choices and outcome of disease. Evolocumab and alirocumab do not replace current standards of care; rather, they may

2 PCSK9 Inhibitors 2 contribute to better health outcomes for those unable to achieve or maintain recommended cholesterol levels using traditional treatment only. II. Criteria/Guidelines PCSK9 Inhibitors, alirocumab (Praluent) or evolocumab (Repatha) are covered (subject to Limitations and Administrative Guidelines) when one of the following criteria is met: A. Documented diagnosis of homozygous familial hypercholesterolemia (HoFH) as defined by clinical or genetic criteria by the European Atherosclerosis Society (Table 1); OR B. Documented diagnosis of definite heterozygous familial hypercholesterolemia (HeFH) as defined by the Dutch Lipid Network (Table 2) or Simon Broome Diagnostic Criteria (Table 3) with 1. the highest cardiovascular (CV) risk as defined by the National Lipid Association Expert Panel on FH (Table 4); and 2. the inability to reach target LDL-C as defined by the National Lipid Association Guidelines (Table 5), a. Despite a meaningful trial of at least two high-intensity statins (Table 6); and b. Despite maximally tolerated dose of a high-intensity statin (Table 6) and at least one additional lipid-lowering agent, such as fibrates, nicotinic acid, bile acid sequestrants or ezetimibe; and c. Despite lifestyle modifications supporting lipid management as recommended by the 2013 AHA/ACC Guidelines to Reduce Cardiovascular Risk (Table 7); OR C. Documented diagnosis of clinical atherosclerotic cardiovascular disease (ASCVD) or a cardiovascular event (Table 8) and the inability to reach target LDL-C as defined by the National Lipid Association Guidelines (Table 5) 1. Despite a meaningful trial of at least two high-intensity statins (Table 6); and 2. Despite maximally tolerated dose of a high-intensity statin (Table 6) and at least one additional lipid-lowering agent, such as fibrates, nicotinic acid, bile acid sequestrants or ezetimibe; and 3. Despite lifestyle modifications supporting lipid management as recommended by the 2013 AHA/ACC Guidelines to Reduce Cardiovascular Risk (Table 7); OR D. Individual is determined to be statin intolerant by the following: 1. Individual has a condition that is contraindicated for statin therapy, such as: a. Chronic active liver disease greater than 3 months; and/or b. Unexplained persistent elevation of serum transaminases; OR 2. Individual is unable to tolerate at least 2 statins, with at least one started at the lowest starting daily dose; AND 3. Statin dose reduction is attempted for symptom and biomarker abnormality resolution, rather than discontinuation of statin therapy altogether; AND 4. Intolerable symptoms or abnormal biomarker changes are reversible upon statin discontinuation, but reproducible by re-challenge of statins; if clinically appropriate. Statin re-challenge may be appropriate for individuals with all of the following: a. Symptomatic; and b. Creatine kinase is less than four times (4) the upper limit of normal per laboratory reference range or creatine kinase is between four (4) and ten (10) times the upper limit of normal per laboratory reference range without evidence of rhabdomyolysis; and

3 PCSK9 Inhibitors 3 c. AST and/or ALT are less than three (3) times the upper limit of normal per laboratory reference range; and d. Symptoms or biomarker abnormalities are not attributable to established predispositions or conditions recognized to increase the risk of statin intolerance, such as: i. Hypothyroidism; and/or ii. Drug interactions; and/or iii. Concurrent illness; and/or iv. Significant changes in physical activity/exercise; and/or v. Underlying muscle disease; OR 5. Individual has significant biomarker abnormalities, defined as: a. Elevation in alanine (ALT) of greater than three (3) times the upper limit of normal; or b. Elevation in aspartate aminotransferase (AST) of greater than three (3) times the upper limit of normal; or c. Elevation of creatine kinase (CK) of greater than ten (10) times the upper limit of normal per laboratory reference range; or d. Elevation of creatine kinase (CK) between four (4) to ten (10) times the upper limit of normal per laboratory reference range with evidence of rhabdomyolysis. Note: A meaningful trial for statins is at least six weeks which allows lipid levels to stabilize and when objective measures can be assessed. III. IV. Limitations A. Patients are not covered for use of PCSK9 inhibitors if they are able to achieve target LDL-C levels using other lipid-lowering interventions regardless of clinical status. B. Recommendation is a 4-week dosing regimen and quantities will be limited to an initial three month supply. Administrative Guidelines A. Precertification is required for the initial three months of therapy. To precertify, please complete CVS's Drug Review Request form and mail or fax the form as indicated. The following documentation must be submitted: 1. DNA evidence of homozygous FH and other criteria outlined in table 1; or 2. Documentation of diagnosis of heterozygous FH at highest of CHD unable to reach target or of statin intolerance including laboratory results and clinical notes that include a detailed history of previous treatments, including all relevant pharmaceutical agents including evidence of a meaningful of two high-intensity and maximally tolerated statins; and 3. Documentation showing patient is at highest risk of CHD and unable to reach target LDL- C B. Precertification is required for continuation of therapy for up to an additional six months. Clinical notes and laboratory results must be submitted showing, at minimum, a 30% reduction in patient LDL-cholesterol levels prior to starting treatment with PCSK9 inhibitors. C. Precertification is required for continuation of therapy for up to an additional 12 months.

4 PCSK9 Inhibitors 4 Clinical notes and laboratory results must be submitted showing continued benefit of treatment measured by continued decrease in LDL-C levels or maintenance of optimum levels of LDL-C. HCPCS Codes J3490/J3590 J3490/J3590 Description Praluent (Alirocumab) Repatha (Evolocumab) V. Important Reminder The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician. Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii s Patients Bill of Rights and Responsibilities Act (Hawaii Revised Statutes 432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA s determination as to medical necessity in a given case, the physician may request that CVS/caremark reconsider the application of the medical necessity criteria to the case at issue in light of any supporting documentation.

5 PCSK9 Inhibitors 5 VI. Appendices Table 1 - Criteria for the diagnosis of homozygous familial hypercholesterolemia European Heart J Genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9, or LDLRAP1 gene locus; or An untreated LDL-C >13 mmol/l (500 mg/dl) or treated LDL-C 8 mmol/l (300 mg/dl)* together with either: Cutaneous or tendon xanthoma before age 10 years; or Untreated elevated LDL-C levels consistent with heterozygous FH in both parents * These LDL-C levels are only indicative, and lower levels, especially in children or in treated patients, do not exclude HoFH

6 PCSK9 Inhibitors 6 Table 2 - World Health Organization aka Dutch Lipid Clinic Network - Diagnostic criteria for the clinical diagnosis of heterozygous familial hypercholesterolemia Family History Clinical History Criteria First-degree relative with known premature coronary or vascular disease; or first-degree relative with known LDL-C >95th percentile First-degree relative with tendon xanthomata and/or arcus cornealis, or children <18 y with LDL-C >95th percentile Patient has premature CAD Patient has premature cerebral/peripheral vascular disease 1 Physical Tendon xanthomata 6 Examination Arcus cornealis age <45 y 4 LDL-C >8.5 mmol/l (> 330 mg/dl) mmol/l (> mg/dl) mmol/l (> mg/dl) mmol/l (> mg/dl) 1 Score Definite FH Score >8 Probable FH Score 6-8 Possible FH Score 3-5 No diagnosis Score <3 CAD: coronary artery disease; FH: familial hypercholesterolemia; HeFH: heterozygous familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; Premature CAD: male before age 55, women before age

7 PCSK9 Inhibitors 7 Table 3 - Simon-Broome criteria for diagnosis of familial hypercholesterolemia FH Definite Possible Criteria TC >6.7 mmol/l or LDL-C >4.0 mmol/l in a child aged <16 y OR TC >7.5 mmol/l or LDL-C >4.9 mmol/l in an adult (levels either pretreatment or highest on-treatment) PLUS Tendon xanthomas in patient, or in first-degree relative (parent, sibling or child), or in second-degree relative (grandparent, uncle, or aunt) OR DNA-based evidence of an LDL-R mutation, familial defective apo B100, or a PCSK9 mutation. TC >6.7 mmol/l or LDL-C >4.0 mmol/l in a child aged <16 y OR TC >7.5 mmol/l or LDL-C >4.9 mmol/l in an adult (levels either pretreatment or highest on-treatment) AND AT LEAST ONE OF THE FOLLOWING: o Family history of myocardial infarction: <50 y of age in second-degree relative or <60 y of age in first-degree relative o Family history of raised TC: >7.5 mmol/l in adult first-or second-degree relative or >6.7 mmol/l in child or sibling aged <16 y Apo: apolipoprotein; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; LDL-R: lowdensity lipoprotein receptor; PCSK9: proprotein convertase subtilisin/kexin type 9; TC: total cholesterol. Table 4 - Characteristics place FH patient at the highest Cardiovascular Disease Risk Intensification of treatment and an LDL-C goal < 100 mg/dl (non-hdl-c < 130mg/dL) is recommended for FH patients with any of these high risk characteristics Established CHD or other CVD History of acute myocardial infarction, stroke, peripheral arterial disease, resuscitated cardiac arrest, cardiovascular revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis, >50%, aortic abdominal aneurysm Smokers Male current smokers have > 2 fold higher risk than female smokers Encourage smoking cessation to reduce risk Diabetes mellitus Lifestyle or drug treated diabetes Family history of very premature onset CHD First or second degree male relative onset before age 45 First or second degree female relative onset before age 55 2 or more risk factors See below Cardiovascular risk factors in individuals with FH Cut-points for risk factors Risk Factor If > 2 risk factors present intensification of therapy is recommended Increasing age Men > 30 years of age Women > 40 years of age

8 PCSK9 Inhibitors 8 Baseline LDL-C level Male sex Smoking >250 mg/dl Male sex Current smoker Family history of premature onset CHD First degree male relative onset before age 55 Metabolic syndrome First degree female relative onset before age 65 3 of 5 characteristics: Increased waist circumference: o Men > 40 (>37 in some populations) and women>35 Blood pressure > 130 mmhg or > 80 mmhg or drug treatment Triglycerides > 150 mm/dl or drug treatment Low DL-C: o Men < 40 mm/dl and women < 50 mm/dl Elevated glucose > 100 mg/dl or drug treatment Low HDL-C level HDL-C < 40 mm/dl Hypertension Blood pressure > 140 or > 90 mmhg or drug treatment High lipoprotein (a) > 50 mm/dl using an isoform insensitive assay Physical findings Tendon xanthoma CHD coronary heart disease; FH familial hypercholesterolemia; HDL-C high density lipoprotein cholesterol; LDL-C low density lipoprotein cholesterol

9 PCSK9 Inhibitors 9 Table 5 - Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol and levels at which to consider drug therapy: National Lipid Association Guidelines Risk Criteria Treatment Goal Consider Drug Category Therapy ASCVD Very high diabetes mellitus (type 1 or 2) AND 2 other major ASCVD risk factor(s )a <100 non-hdl-c, mg/dl 100 non-hdl-c, mg/dl 70 <70 LDL-C, mg/dl LDL-C, mg/dl or Evidence of end-organ damage b High 3 major ASCVD risk factors a Diabetes mellitus (type 1 or 2) c 0 or 1 other major ASCVD risk factors, and No evidence of end-organ damage Chronic kidney disease stage 3B or 4 d LDL-C 190 mg/dl (severe hypercholesterolemia) e 10% 10-y hard CHD event risk f <130 non-hdl-c, mg/dl <100 LDL-C, mg/dl 130 non-hdl-c, mg/dl 100 LDL-C, mg/dl Moderate Low 2 major ASCVD risk factors a Consider other risk indicators g 0 or 1 major ASCVD risk factors Consider other risk indicators g <130 non-hdl-c, mg/dl <100 LDL-C, mg/dl <130 non-hdl-c, mg/dl <100 LDL-C, mg/dl 160 non-hdl-c, mg/dl 130 LDL-C, mg/dl 190 non-hdl-c, mg/dl 160 LDL-C, mg/dl ASCVD: atherosclerotic cardiovascular disease; CHD: coronary heart disease; CKD: chronic kidney disease; egfr: Estimated glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. a. Major risk factors for ASCVD: (1) Age (male 45 y or female 55 y). (2) Family history of early CHD (55 years of age in a male firstdegree relative or 65 y of age in a female first-degree relative). (3) Current cigarette smoking. (4) High blood pressure ( 140/ 90 mm Hg, or on blood pressure medication). (5) Low HDL-C (male <40 mg/dl; female <50 mg/dl). b. End-organ damage indicated by increased albumin-to-creatine ratio ( 30 mg/g), CKD (egfr, <60 ml/min/1.73 m 2) or retinopathy. c. For patients with diabetes plus 1 major ASCVD risk factor, treating to a non-hdl-c goal of <100 mg/dl (LDL-C of <70 mg/dl) is considered a therapeutic option. d. For patients with CKD stage 3B (egfr, ml/min/1.73 m2) or stage 4 (egfr, ml/min/1.73 m2), risk calculators should not be used because they may underestimate risk. Stage 5 CKD (or on hemodialysis) is a very high-risk condition, but results from randomized controlled trials of lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD. e. If LDL-C is 190 mg/dl, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and pharmacotherapy are recommended for adults with the severe hypercholesterolemia phenotype. If it is not possible to attain desirable levels of atherogenic cholesterol, a reduction of at least 50% is recommended. For familial hypercholesterol-emia patients with multiple or poorly controlled other major ASCVD risk factors, clinicians may consider attaining even lower levels of atherogenic cholesterol. Risk calculators should not be used in such patients. f. High-risk threshold is defined as 10% using Adult Treatment Panel III Framingham Risk Score for hard CHD (myocardial infarction or CHD death), 15% using the 2013 Pooled Cohort Equations for hard ASCVD (myocardial infarction, stroke, or death from CHD or stroke), or 45% using the Framingham long-term cardiovascular disease (myocardial infarction, CHD death, or stroke) risk calculation. Clinicians may prefer to use other risk calculators, but should be aware that quantitative risk calculators vary in the clinical outcomes predicted (e.g., CHD events, ASCVD events, cardiovascular mortality); the risk factors included in their calculation; and the timeframe for their prediction (e.g., 5 y, 10 y, or long-term or lifetime). Such calculators may omit certain risk indicators that can be very important in individual patients, provide only an approximate risk estimate, and require clinical judgment for

10 PCSK9 Inhibitors 10 interpretation. g. For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk stratification. Table 6 - Statin treatment categorized by intensity using 2013 AHA/ACC cholesterol guidelines Table 8. High Moderate Low Daily dose lowers LDL-C, on average, by approximately 50% Daily dose lowers LDL-C, on average, by approximately 30% to <50% Daily dose lowers LDL-C, on average, by <30% Specific statins and doses noted below were evaluated in RCTs and demonstrated a reduction in major cardiovascular events Atorvastatin 80 mg Atorvastatin 10 mg Pravastatin mg Atorvastatin 40 mg Rosuvastatin 10 mg Lovastatin 20 mg Rosuvastatin 20 mg Simvastatin mg Pravastatin 40 mg Lovastatin 40 mg Fluvastatin 40 mg bid Statins and doses listed below are approved by FDA, but not tested in reviewed RCTs Rosuvastatin 40 mg Atorvastatin 20 mg Simvastatin 10 mg Rosuvastatin 5 mg Fluvastatin mg Pravastatin 80 mg Pitavastatin 1 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg ACC: American College of Cardiology; AHA: American Heart Association; FDA: Food and Drug Administration; LDL- C: lowdensity lipoprotein-cholesterol; RCT: randomized controlled trial. a. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL trial. b. Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by FDA due to the increased risk of myopathy, including rhabdomyolisis. Table 7 - Summary of Recommendations for Lifestyle Management using 2013AHA/ACC Guidelines on Lifestyle Management to reduce Cardiovascular Risk

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12 PCSK9 Inhibitors 12 Table 8 Clinical ASCVD or Cardiovascular Event Acute coronary syndromes Myocardial infarction Stable or unstable angina Coronary or other arterial revascularization procedure (e.g./percutaneous coronary angioplasty [PTCA], coronary artery bypass graft [CABG] surgery) Transient ischemic attack (TIA) Peripheral arterial disease presumed to be of atherosclerotic origin Findings from CT angiogram or catheterization consistent with clinical ASCVD Table 9 - Statin treatment categorized by intensity using 2013 AHA/ACC cholesterol guidelines Table 8. High Moderate Low Daily dose lowers LDL-C, on average, by approximately 50% Daily dose lowers LDL-C, on average, by approximately 30% to <50% Daily dose lowers LDL-C, on average, by <30% Specific statins and doses noted below were evaluated in RCTs and demonstrated a reduction in major cardiovascular events Atorvastatin 80 mg Atorvastatin 10 mg Pravastatin mg Atorvastatin 40 mg Rosuvastatin 10 mg Lovastatin 20 mg Rosuvastatin 20 mg Simvastatin mg Pravastatin 40 mg Lovastatin 40 mg Fluvastatin 40 mg bid Statins and doses listed below are approved by FDA, but not tested in reviewed RCTs Rosuvastatin 40 mg Atorvastatin 20 mg Simvastatin 10 mg Rosuvastatin 5 mg Fluvastatin mg Pravastatin 80 mg Pitavastatin 1 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg ACC: American College of Cardiology; AHA: American Heart Association; FDA: Food and Drug Administration; LDL- C: lowdensity lipoprotein-cholesterol; RCT: randomized controlled trial. a. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL trial. b. Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by FDA due to the increased risk of myopathy, including rhabdomyolisis. VI. References 1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Specialty Pharmacy Report. Generic Name: Alirocumab, Brand Name: Praluent. TEC Specialty Pharmacy Report April 2015; Report Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Specialty Pharmacy Report. Generic Name: Evolocumab, Brand Name: Repatha (proposed). TEC Specialty Pharmacy Report April 2015; Report 7.

13 PCSK9 Inhibitors Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et. al., Homozygous familial hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolemia of the European Atherosclerosis Society. European Heart Journal , First published online: 22 July 2014 (Table 1). 4. European Association for Cardiovascular P, Rehabilitation, Reiner Z, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atheroscler-osis Society (EAS). Eur Heart J. Jul 2011;32(14): Guyton JR, Bays HE, Grundy SM, Jacobson TA. The National Lipid Association Statin Intolerance, An assessment by the Statin Intolerance Panel: 2014 update. Journal of Clinical Lipidology May- Jun;8 (3 Suppl): S O'Riordan M. IMPROVE-IT: 'Modest' Benefit When Adding Ezetimibe to Statins in Post-ACS Patients. Nov 17, Available from: 7. Robinson, JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm. 2013; 19: Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and evidence for treatment: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of Clinical Lipidology : S19-S Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New England Journal of Medicine April 16; 372 (16): Sabatine MS, Giugliano RP Wiviott, SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New England Journal of Medicine April 16; 372 (16): Stein EA, Mellis, S Yancopoulos, GD et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. The New England Journal of Medicine Mar 22; 366 (12): Stone NJ, Robinson JG, Lichtenstein AH, et al 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. Circulation. 2014; 129: S1-S Stroes 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. European Heart Journal Feb Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. Journal of Clinical Lipidology Jan-Feb; 8 (1):18-28.