Non-Statin Lipid-Lowering Agents (Last modified May 2016)

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1 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER July 2015 Non- Lipid-Lowering Agents (Last modified May 2016) s are the lipid-lowering agents of choice because they have by far the most, and most robust, evidence for reducing cardiovascular events, including death. 25,49 Non-statins are no longer recommended for routine use. 25,49 When deciding to start or continue a non-statin, consider the following: The addition of a non-statin to a statin has not been proven to further reduce cardiovascular mortality. 1,25,30,49 Despite IMPROVE-IT, the FDA denied the expanded indication for morbidity and mortality benefits for ezetimibe. 65 Adding a non-statin to achieve a specific LDL goal could result in reduction of the statin to a suboptimal dose. 49 Reinforce statin adherence and lifestyle changes, and check for secondary causes before adding a non-statin. 25,49 For patients who cannot tolerate the recommended statin dose or who do not achieve the expected statin response (e.g., 50% LDL reduction with high-intensity statin) and are high-risk at baseline, consider adding a non-statin. 25,49 Consider adding ezetimibe to a moderate-intensity statin in high-risk patients, especially those with a recent ACS. 30 There s no proof that adding other non-statins (fibrates, etc) to a statin improves outcomes, and niacin worsens glycemic control. 1,32 Consider adding a PCSK9 inhibitor in high-risk patients with extremely elevated LDLs (e.g., familial hypercholesterolemia) Consider a bile acid sequestrant, gemfibrozil, or niacin for patients who cannot tolerate a statin. 1,7,21,24 Do not add gemfibrozil to a statin due to myopathy risk. 49 Consider omega-3 fatty acids, fenofibrate, or niacin if TG 500 mg/dl (about 5 mmol/l), or even approaching 1000 mg/dl (about 10 mmol/l). 38,39 However, there s no good evidence that lowering triglycerides reduces CV events or prevents pancreatitis. The chart below provides lipid effects, outcomes, and cost information for the non-statins. (Information in the chart may differ from product labeling). For specifics on lowering triglycerides see our PL Detail-Document, Strategies for Lowering Triglycerides; for more information on the lipid-lowering potential of individual statins in our PL Chart, Characteristics of the Various s. Abbreviations: ACS = acute coronary syndrome; CV = cardiovascular; CVD = cardiovascular disease; ER = extended-release; GI = gastrointestinal; HDL = highdensity lipoprotein; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; IR = immediate release; LDL = lowdensity lipoprotein; PCSK9 = proprotein convertase subtilisin/kexin type 9; SR = sustained release; SubQ = subcutaneous; TG = triglycerides Alirocumab d (Praluent [U.S.]) Continued LDL : 40% to 60%. 52,56,63 (Regardless of statin use.) See Lipid Effects column. Post-hoc analysis suggests alirocumab in combination with maximally Very expensive. Consider as monotherapy (statinintolerant patients) or added to maximally U.S.: $1120 (75 mg/two weeks).

2 (PL Detail-Document #310703: Page 2 of11) Alirocumab, continued (PCSK9 inhibitor) tolerated statin doses may reduce major CV events in high-risk patients. Further data are needed to confirm [Level B]. 55 tolerated statin (with or without ezetimibe) in patients with HeFH or clinical CVD requiring additional LDL lowering. 52 No adjustment needed with mild to moderate renal or hepatic impairment. No safety data available with severe renal or hepatic impairment. 52 Administer via SubQ injection (allow to reach room temperature before injecting). 52 No long-term safety data. Bezafibrate (Bezalip SR, generic bezafibrate SR, generic immediaterelease bezafibrate); (Canada only) (Fibric acid) LDL : 6% to 21% (400 mg). 35,36 HDL : 15% to 25% (400 mg). 35,36 TG : 25.1% to 42% (400 mg). 35,36 1.1% (400 mg) % (400 mg). 36 Further TG : 31.7% (400 mg). 36 Secondary prevention: prevents composite endpoint of MI and sudden death in a subgroup with TG 200 mg/dl or higher. No increase in non-cv death. 37 First-line option for TG >10 mmol/l. 39 Option for TG 5 to 10 mmol/l. 39 Option for low HDL. 39 Reversible increase in serum creatinine. 33 Requires renal dose adjustment. 33,b Limited data with statins. Canada: $75.43 (Bezalip SR) (400 mg/day).

3 (PL Detail-Document #310703: Page 3 of11) Cholestyramine (Questran, Questran Light [U.S.; brands no longer available], Olestyr [Canada] (Bile acid sequestrant) LDL : 9% (4 g to 8 g/day); 1 21% (16 g to 20 g/day); 1 23% to 28% (>20 g/day). 1 HDL : 4% to 8% (16 to 24 g/day). 1 TG : 11% to 28% (4 g to 24 g/day). 1 about 10% (8 g) to about 20% (24 g). 4,5 0% to 10%. 3,4 Primary prevention, men: reduces need for bypass, and combined endpoint of coronary heart disease, death, and nonfatal MI (NNT = 59 for 7 years) [Level A]. 6,14 Secondary prevention, men: with diet, reduces cardiac events vs usual care (not placebo-controlled; events not a primary outcome)[level B]. 7 Slows progression and increases regression of atherosclerosis. 7,34 Can be difficult to tolerate due to GI side effects such as constipation and gas. 1 U.S.: $ (generic packets) (16 g/day). Canada: $ (Olestyr) (16 g/day). Colesevelam (WelChol [U.S.], Lodalis [Canada]) (Bile acid sequestrant) (FDA-approved for glycemic control in type 2 diabetes). 2 LDL : 15% to 19.1% (3.8 g/day). 2,8 HDL : 3% to 8.1% (3.8 g/day). 2,8 TG : 10% (3.8 g/day; about 20% when used with insulin or sulfonylureas). 2 10% to 16% (3.8 g/day). 2 3% to 7% (3.8 g/day). 2 None. Limited data with statins. Studied in combination with atorvastatin, lovastatin, pravastatin, and simvastatin. 2,10 Potential lower risk of GI side effects compared to cholestyramine and colestipol. 8,64 U.S.: $ (3.8 g/day). Canada: $ (3.8 g/day).

4 (PL Detail-Document #310703: Page 4 of11) Colestipol (Colestid, generic [U.S.]) (Bile acid sequestrant) LDL : 5% (2 g/day) to 26% (16 g/day). 1 HDL: no effect. 1 TG : 10% to 15% (2 to 16 g/day). 1 10% (5 g/day) to 12% (10 g/day). 11 Reduces progression of atherosclerosis and events when combined with niacin or lovastatin (events not a primary outcome). 50 Can be difficult to tolerate due to GI side effects such as constipation and gas. 8 U.S.: $ (10 g/day). Canada: $71.52 (10 g/day). Evolocumab d (Repatha) (PCSK9 inhibitor) LDL : 42% to 65%. 58,59,61,63 (Regardless of statin use.) See Lipid Effects column. Lowered LDL 34% to 38.5% more compared to ezetimibe. 58,60 The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study (NCT ) is ongoing and is intended to provide an assessment of the cardiovascular benefit of evolocumab. 61 Very expensive. Consider with statins for HeFH and HoFH or clinical CVD requiring additional LDL lowering. 53,54 Administer by SubQ injection (allow to reach room temperature before injecting). 53,54 No dosage adjustment needed with mild to moderate renal or hepatic impairment. No safety data available for patients with severe renal or hepatic impairment. 53,54 No long-term safety data. U.S.: $ (140 mg every two weeks). Canada: $ (140 mg every two weeks).

5 (PL Detail-Document #310703: Page 5 of11) Ezetimibe (Zetia [U.S.], Ezetrol, generics [Canada]) (Cholesterol absorption inhibitor) (In U.S., available in combination with simvastatin [Vytorin] and atorvastatin [Liptruzet]). LDL : 18% (10 mg/day). 12,13 HDL : 1% (10 mg/day). 12,13 TG : 8%. 12,13 25%. 13 3%. 13 Further TG : 14%. 13 With simvastatin 20 mg, reduces first major atherosclerotic event in chronic renal disease [Level A]. 29 Adding ezetimibe to simvastatin 40 mg post-acs prevents one CV event for every 50 patients treated for 7 yrs vs simvastatin alone [Level A]. 30 Consider ezetimibe as a moderate-dose statin add-on for high-risk secondary prevention patients who can t tolerate a highintensity statin, or who don t get the expected 50% LDL reduction with a high-intensity statin. 49 U.S.: $ (10 mg/day). Canada: $50.81 (10 mg/day). (Vytorin [U.S.]: $ [10 mg/ 20 mg/day]). (Liptruzet [U.S.]: $ [10mg/20mg/day]). Fenofibrate (Tricor, Lofibra, Trilipix, Antara [U.S.], Lipidil EZ [Canada], others, generics) (Fibric acid) Continued LDL : 20.6% (145 mg). 15 HDL : 11% (145 mg). 15 TG : 23.5% to 54.5% (greatest drop in patients with highest triglycerides) (145 mg). 15 0% to 6% (200 mg) % to 17% (200 mg) Further TG : 20% to 32% (200 mg) Prevention of CV events in type 2 diabetes: did not reduce primary composite outcome (non-fatal MI or CV death). Improved outcomes included non-fatal MI (24% ), coronary revascularization (21% ), progression to albuminuria, and reduced laser treatments for First-line option for TG >10 mmol/l 39 (about 1000 mg/dl). Option for TG >500 mg/dl 38 or 5 to 10 mmol/l. 39 Option for low HDL. 39 Requires renal dose adjustment. 33,b Associated with reversible increase in serum creatinine. 33 Unclear risk of cholelithiasis. 51 In the U.S., FDA U.S.: $27.92 (48 mg/day). U.S.: $15.29 (145 mg/day). Canada: $29.53 (145 mg/day). Canada: $8.82 (200 mg/day).

6 (PL Detail-Document #310703: Page 6 of11) Fenofibrate, continued retinopathy. Nonsignificant increase in CV death. 31 As statin add-on, did not lower risk of non-fatal MI, non-fatal stroke, or CV death more than statin alone in patients with type 2 diabetes at high risk for CV disease. 32 indication for fenofibric acid (Trilipix) use with statins revoked in April 2016 due to lack of CV benefit. 57 Fenofibrate is still indicated as monotherapy for lipid lowering. 66 Preferred over gemfibrozil for use with statins for safety. 33 Gemfibrozil (Lopid [U.S.], generics) (Fibric acid) LDL: No effect. 21 HDL : 6% (1200 mg/day). 21 TG : 33% to 50% (greatest drop in patients with highest triglycerides) (1200 mg/day). 21,41 Further TG : 41%. 19 9%. 19 Primary prevention, men: reduced sudden cardiac death plus fatal/nonfatal MI (NNT = 71 over 5 years)[level A]. 20 Secondary prevention of nonfatal MI plus cardiac death in men with low HDL (NNT = 23 over 5 years)[level A]. 21 First-line option for TG >10 mmol/l 39 (about 1000 mg/dl). Option for TG >500 mg/dl 38 or 5 to 10 mmol/l. 39 Option for low HDL. 39 Requires renal dose adjustment. 33,b Avoid with statin. 33,39 No mortality benefit. 20,21 Unclear risk of cholelithiasis. 51 U.S.: $6.85 (1200 mg/day). Canada: $33.42 (1200 mg/day).

7 (PL Detail-Document #310703: Page 7 of11) Icosapent ethyl (Vascepa) (U.S. only) (EPA; about 1 g omega-3s/capsule) LDL: No effect. 46 HDL: No effect. 46 TG : 27%. 46 Further TG : 21.5% (4 g/day), 10.1% (2 g/day) % (4 g/day). 47 A study is underway to look at reduction in cardiovascular events with icosapent in patients taking a statin. 48 Option for TG ³500 mg/dl. 46 Safe for use with statin. 47 Use caution with fish or shellfish allergy. 46 U.S.: $ (4 g/day). Niacin (Niacor [IR; U.S. only], Niaspan [ER], Niaspan FCT [Canada]) In the U.S., niacin was available as a combo with lovastatin (Advicor) and simvastatin (Simcor). Both products voluntarily withdrawn from the market in December Continued LDL : 14% to 17% 2 g/day); % (niacin IR 1.5 g/day and Niaspan 1.5 g/day). 28 HDL : 22% to 26% (2 g/day Niaspan); % (niacin IR 1.5 g/day); 28 20% to 22% 1.5 g/day) TG : 20% to 50%. 25 8% 1 g/day); 31% 2 g/day). 9 23% 1 g/day); 27% 2 g/day). 9 Further TG : 24% 1 g/day); 27% 2 g/day). 9 As statin add-on, reduces carotid intima-media thickness (surrogate marker) as compared to ezetimibe as statin add-on in patients with lower HDL. 29 Secondary MI prevention: one less MI for every 30 patients treated for five years (Coronary Drug Project)[Level B]. 24 No CV event benefit from combo of niacin + statin vs statin alone in patients with wellcontrolled LDL, low HDL, and high TG. 40 Option for TG >500 mg/dl 38 (about 5 mmol/l). Raises HDL more than any other agent. Dose-dependent risk of hyperglycemia (especially in patients with type 2 diabetes) and liver toxicity. 24 No mortality benefit. 24 May increase risk of statin myopathy. 24 FDA indication for niacin ER use with statins revoked in April 2016 due to lack of CV benefit/safety. 57 In Canada, niacin is still indicated as monotherapy for dyslipidemia. 22,23 In the U.S., niacin IR U.S.: $19.48 (Niacor 1 g/day). U.S.: $ g/day). Canada: $ g/day). Canada: $43.53 FCT 1 g/day).

8 (PL Detail-Document #310703: Page 8 of11) Niacin, continued and ER are approved for monotherapy or for use with bile acid sequestrants. 24 Omega-3 ethyl esters (Lovaza) (U.S. only) (EPA/DHA; about 1 g omega-3s/capsule). LDL : 44.5% (4 g/day). 27 HDL : 9.1% (4 g/day). 27 TG : 45% (4 g/day). 27 LDL : 0.7% (4 g/day) % (4 g/day). 27 Further TG : 29.5% (4 g/day). 27 Secondary prevention: reduces cardiovascular death, sudden death, and combined endpoint of death, non-fatal MI, and non-fatal stroke [Level B]. 26 Secondary prevention in patients with, or at risk for, type 2 diabetes: did not reduce CV events. About half of patients were taking a statin. 42 Option for TG >500 mg/dl (about 5 mmol/l). 38 Safe for use with statin. 39 Associated with an increase in risk for recurrence of symptomatic atrial fibrillation or flutter within first three months of therapy. 27 Use with caution with fish or shellfish allergy. 27 U.S.: $ (4 g/day). a. U.S. cost is wholesale acquisition cost (WAC) b. Maximum daily dose if CrCl <60 ml/min: bezafibrate 200 mg, gemfibrozil 600 mg, and fenofibrate 67 mg. Avoid if CrCl <15 ml/min. 33 c. TG-lowering effects of niacin, omega-3-ethyl esters, and fibrates is greatest in patients with higher baseline TG levels d. Lipid levels off statin therapy may be required for prior authorization.

9 (PL Detail-Document #310703: Page 9 of 11) Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Project Leaders in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS (Original July 2015), Beth Bryant, Pharm.D., BCPS, Assistant Editor (May 2016 update) References 1. PL Detail Document, Ezetimibe s Role in Cardiovascular Risk Reduction. Pharmacist s Letter/Prescriber s Letter. January Product information for WelChol. Daiichi Sankyo. Parsippany, NJ January Pravastatin Multicenter Study Group II. Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Arch Intern Med 1993;153: Pan HY, DeVault HR, Swites BJ, et al. Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia. Clin Pharmacol Ther 1990;48: Sprecher DL, Abrams J, Allen JW, et al. Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients. Ann Intern Med 1994;120: Rifkind BM. Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. Am J Cardiol 1984;54:30C-34C. 7. Watts GF, Lewis B, Brunt JN, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St. Thomas Atherosclerosis Regression Study (STARS). Lancet 1992;339: Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med 1999;159: Wolfe ML, Vartanian SF, Ross JL, et al. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol 2001;87: Bays HE, Davidson M, Jones MR, Abby SL. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol 2006;97: Simons LA, Simons J, Parfitt A. Successful management of primary hypercholesterolaemia with simvastatin and low-dose colestipol. Med J Aust 1992;157: Product monograph for Ezetrol. Merck Canada Inc. Kirkland, QC H9H 4M7. March Product information for Zetia. Merck/Schering- Plough Pharmaceuticals. North Wales, PA August Probstfield JL, Rifkind BM. The Lipid Research Clinics Coronary Primary Prevention Trial: design, results, and implications. Eur J Clin Pharmacol 1991;40(Suppl 1):S Product information for Tricor. AbbVie Inc. North Chicago, IL February Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005;45: Vega GL, Ma PT, Cater NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91: Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002;25: Murdock DK, Murdock AK, Murdock RW, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999;138: Product information for Lopid. Pfizer, Inc. New York, NY November Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-

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11 (PL Detail-Document #310703: Page 11 of 11) 51. Brown WV. Expert commentary: the safety of fibrates in lipid-lowering therapy. Am J Cardiol 2007;99(6A):19C-21C. 52. Product information for Praluent. Sanofi-Aventis U.S. Bridgewater, NJ October Product monograph for Repatha. Amgen Canada Inc. Mississauga, ON L5N 0A4. September Product information for Repatha. Amgen Inc. Thousand Oaks, CA September Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372: Navarese SP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163: U.S. Government Publishing Office. Withdrawal of approval of indications related to coadministration with statins in applications for niacin extendedrelease tablets and fenofibric acid delayed-release capsules. April 18, Federal Register;81(74): /pdf/ pdf. (Accessed April 29, 2016). 58. Koren MJ, Lundqvist P, Bolognese M, et al. Anti- PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63: Stroes E, Colquhoun D, Sullivan D, et al. Anti- PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63: Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo controlled, phase 2 study. Lancet 2012;380: Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372: OptumRx. Advicor, Simcor product discontinuations. %20Withdrawal_Advicor_Simcor_ v2.pdf. (Accessed May 11, 2016). 63. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. New Engl J Med 2014;370: Brunetti L, DeSantis EH. Patient tolerance and acceptance of colesevelam hydrochloride: focus on type-2 diabetes mellitus. P T 2015;40: Merck. Merck statement on FDA advisory committee meeting on IMPROVE-IT study with Vytorin. December 14, (Accessed May 11, 2016). 66. Product information for Trilipix. AbbVie Inc. North Chicago, IL April Cite this document as follows: PL Detail-Document, Non- Lipid-Lowering Agents. Pharmacist s Letter/Prescriber s Letter. July Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright Ó 2015 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or