Ezetimibe s Role in Cardiovascular Risk Reduction

PL Detail-Document #310101 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER January 2015 Ezetimibe s Role in Cardiovascular Risk Reduction Background The primary target of lipid-lowering therapy is LDL because there is a strong relationship between elevated LDL and coronary heart disease. 1-3 Statins are the drugs of choice for cardiac risk reduction due to their proven benefits. 1,3 Moderate doses of statins, which primarily target LDL, decrease cardiovascular morbidity and mortality by 25% to 35% with five years use. 2,4 When patients can t take a statin, or don t achieve the LDL-lowering effects seen in statin clinical trials, use of a nonstatin is usually contemplated. However, the benefit/risk ratio of these medications, especially when added to a statin, is generally marginal or even unfavorable. 1,5,6 Several studies have examined the efficacy of ezetimibe (Zetia [U.S.], Ezetrol [Canada]) or ezetimibe plus simvastatin (Vytorin [U.S.] for improving surrogate or clinical outcomes in patients with dyslipidemia or other cardiovascular risk factors. But the recent IMPROVE-IT study is the first to show that adding ezetimibe to a statin can further reduce cardiovascular risk. This article reviews these studies and discusses potential therapeutic niches for ezetimibe. Ezetimibe Imaging Studies ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) was the first large trial designed to assess the effects of combination lipid-lowering therapy compared to statin monotherapy on the progression of atherosclerosis. ENHANCE compared simvastatin 80 mg/ezetimibe 10 mg to simvastatin 80 mg. Over 700 patients were enrolled. ENHANCE included patients between the ages of 30 and 75 years (mean 46 years) with a baseline LDL >210 mg/dl (>5.4 mmol/l). The primary endpoint was change in mean carotid artery intima-media thickness (CA IMT). CA IMT is a measurement of plaque build-up, and is a surrogate marker for cardiovascular events. CA IMT was measured using ultrasound at baseline, six months, 12 months, 18 months, and 24 months. The percent change in baseline in lipid parameters was a secondary endpoint. After two years, combination therapy did not reduce atherosclerotic progression more than monotherapy, despite being more effective at lowering LDL (58% vs 41%, p<0.01). Although there did not seem to be a difference in cardiovascular events between the treatment groups, the study was underpowered to detect such as difference. Adverse effects were similar between groups. 7 ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) had a primary endpoint similar to ENHANCE. ARBITER 6-HALTS included patients with coronary heart disease or a coronary heart disease risk equivalent (e.g., diabetes, 10- year Framingham risk score of 20% or more, etc) who were on long-term statin therapy. Subjects were required to have measurements of LDL-C <100 mg/dl (<2.6 mmol/l) and HDL-C <50 mg/dl (<1.3 mmol/l) (men) or <55 mg/dl (1.4 mmol/l) (women) within three months prior to enrollment. There were 363 patients enrolled in the study. Study subjects were randomly assigned to receive either extended-release niacin at a target dose of 2000 mg per day or ezetimibe 10 mg daily. The drugs were given in an openlabel fashion. (Note that only 75% of the patients assigned to niacin reached the target dose.) The primary endpoint of the study was the difference between groups in the change in CA IMT from baseline to 14 months. There were four secondary endpoints: change in lipid values; a composite endpoint of heart attack, myocardial revascularization, hospital admission for acute coronary syndrome, and death from coronary Copyright 2015 by Therapeutic Research Center www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

heart disease; discontinuation of study drug because of adverse effects; and health-related quality of life. The study was stopped short of finishing because of a difference in efficacy. There were 14-month endpoint data available for only 208 patients, or 57% of total enrollment. Regarding the primary endpoint, niacin was better than ezetimibe at reducing CA IMT at both eightmonth and 14-month follow-up. There was a significant reduction in CA IMT from baseline with niacin, but there was not a significant change in CA IMT from baseline with ezetimibe. Ezetimibe was better than niacin at lowering LDL (p=0.01). Niacin was better than ezetimibe at increasing HDL-C (p<0.001). A significantly larger number of subjects experienced the composite outcome of cardiovascular events in the ezetimibe group in comparison with the niacin group (5% vs 1%, p=0.04). (Note that the study was not powered to show a difference in clinical outcomes.) There was no significant difference in the number of subjects who left the study because of side effects from the drugs. There was also no significant difference between groups in healthrelated quality of life at baseline or at 14 months. 8 Ezetimibe Outcome Studies Preliminary data suggested that lipid-lowering treatment might reduce progression of aortic stenosis. Based on this data, and the association between aortic stenosis and cardiovascular events, the SEAS trial compared simvastatin 40 mg plus ezetimibe 10 mg to placebo in over 1800 patients with mild-to-moderate aortic stenosis but without known coronary disease. The drugs did not affect the primary composite endpoint of major cardiovascular events (e.g., nonfatal heart attack, revascularization, ischemic stroke, aortic valve replacement). They also did not affect the need for aortic valve replacement. Fewer patients had ischemic cardiovascular events in the treatment group (HR 0.78, 95% CI 0.63 to 0.97, p=0.02), but there was a higher risk of cancer in the treatment group (11.1% vs 7.5%, p=0.01). 9 After analyzing the data, the FDA concluded, in part, that: ezetimibe did not increase cancer risk in animals in preclinical studies; cancer risk did not increase over time, as would be expected if the drug caused growth of pre-existing cancers; it is not likely that the drug would cause the myriad cancers that presented; and the study was not designed to assess cancer risk. 10 (PL Detail-Document #310101: Page 2 of 4) Chronic kidney disease is associated with cardiovascular risk. The primary prevention SHARP trial (Study of Heart and Renal Protection) was designed to assess the safety and efficacy of simvastatin plus ezetimibe in patients with moderate to severe renal disease. The primary outcome measure was first major atherosclerotic event (nonfatal heart attack, coronary death, ischemic stroke, or revascularization). Because of concern for myopathy with high-dose statins in renal disease, the study compared just 20 mg of simvastatin plus ezetimibe 10 mg to placebo. Over 9000 patients were randomized. Median follow-up was almost five years. Treatment safely reduced the risk of the primary endpoint regardless of renal disease severity. There was no indication of increased cancer risk. 11 In the as-yet unpublished IMPROVE-IT study, ezetimibe 10 mg plus simvastatin 40 mg was compared to simvastatin 40 mg alone in a very high-risk secondary prevention population: recent hospitalization for acute coronary syndrome. The combination modestly reduced cardiovascular events (a composite endpoint of cardiovascular death, heart attack, unstable angina requiring hospitalization, revascularization, or stroke) over simvastatin alone, without more side effects. The primary endpoint was reached in 32.7% of the combination group and in 34.7% of the simvastatin monotherapy group (p=0.016). Treating 50 patients with the combination for seven years will prevent one cardiovascular event compared to simvastatin alone (i.e., absolute risk reduction 2%). The parts of the composite endpoint that had the most impact on reducing it were heart attack and stroke, which were nonfatal endpoints. All-cause mortality was not affected. Combination therapy dropped LDL from a mean of 95 mg/dl (2.5 mmol/l) to 53 mg/dl (1.4 mmol/l), compared to 70 mg/dl (1.8 mmol/l) with simvastatin alone. 12 Commentary Last year s new U.S. cholesterol guidelines represented a paradigm shift in the treatment of dyslipidemia. Moderate- or high-dose statins were recommended based on cardiac risk, and LDL was no longer the therapeutic target. This was based on the fact that statin clinical outcome trials used fixed statin doses, and did not target an LDL goal. 1 But not all experts agreed, and those Copyright 2015 by Therapeutic Research Center www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

experts now cite IMPROVE-IT as support for their backing of a lower is better strategy in which LDL goals are targeted. 12 However, per the new U.S. guidelines, simvastatin 40 mg is a moderate-intensity statin, and is not commonly used for secondary prevention. 1,12 For secondary prevention in adults 75 years and younger, a highintensity statin (e.g., atorvastatin 80 mg or 40 mg [if 80 mg not tolerated] once daily or rosuvastatin 20 or 40 mg once daily) is recommended. 1 Unfortunately, IMPROVE-IT did not test the safety and efficacy of adding ezetimibe to a highintensity statin, or compare the combination to a high-intensity statin alone. 12 Others point out that IMPROVE-IT did not reduce mortality, and benefit was modest. 12 IMPROVE-IT was not designed to compare the benefits of specific LDL targets. But it does support the concept put forth in the guidelines that lower is better with proven therapy shown to provide incremental benefit that s safe. 12 Several high-quality studies support specific statin doses for reducing cardiovascular morbidity and mortalilty. 1 Conclusion Consider ezetimibe as a statin add-on for highrisk patients who can t tolerate a high-intensity statin dose, or for high-risk patients who don t get the expected 50% LDL reduction with a highintensity statin [Evidence level C; expert opinion]. 1 IMPROVE-IT shows that ezetimibe can provide modest benefit when added to a moderate dose statin in a high-risk secondary prevention population, particularly in regard to heart attack and stroke prevention. 12 Less benefit might be expected in a lower-risk population. U.S. subscribers can get our PL Chart, Lipid Treatment FAQ, for practical pointers on helping patients manage their cholesterol. Canadian subscribers, see our PL Chart, Canadian Cardiovascular Society Dyslipidemia Recommendations, for a summary of the 2012 guidelines. 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. (PL Detail-Document #310101: Page 3 of 4) 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;65:251-8. Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. Stone 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. Circulation 2014;129(25 Suppl 2):S1-45. 2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 3. Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29:151-67. 4. The AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J 2011;161:471-77. 5. FDA statement on the AIM-HIGH trial. May 26, 2011. http://www.fda.gov/drugs/drugsafety/post marketdrugsafetyinformationforpatientsandprovid ers/ucm256841.htm. (Accessed December 1, 2014). 6. Anderson TJ, Boden WE, Desvigne-Nickens P, et al. Safety profile of extended-release niacin in the AIM-HIGH trial. N Engl J Med 2014;371:288-90. Copyright 2015 by Therapeutic Research Center www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

(PL Detail-Document #310101: Page 4 of 4) 7. PL Detail-Document, Does Ezetimibe ENHANCE Lipid Therapy? More Information from the ENHANCE Trial. Pharmacist s Letter/Prescriber s Letter. May 2008. 8. PL Detail-Document, Ezetimibe vs. Niacin for Atherosclerosis: the ARBITER 6-HALTS study. Pharmacist s Letter/Prescriber s Letter. December 2009. 9. Rossebo AB, Pedersen TR, Borman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56. 10. FDA. Follow-up to the August 2008 early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia)-FDA investigates a report from the SEAS trial. December 22, 2009. http://www.fda.gov/drugs/drugsafety/postmarketd rugsafetyinformationforpatientsandproviders/drug SafetyInformationforHeathcareProfessionals/ucm1 94964.htm. (Accessed December 1, 2014). 11. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92. 12. O Riordan M. IMPROVE-IT: Modest benefit when adding ezetimibe to statins in post-acs patients. November 21, 2014. http://www.medscape.com/viewarticle/835030?nlid =70146_2562&src=wnl_edit_medp_card&spon=2. (Accessed December 1, 2014). Cite this document as follows: PL Detail-Document, Ezetimibe s Role in Cardiovascular Risk Reduction. Pharmacist s Letter/Prescriber s Letter. January 2015. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 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 www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com

This Clinical Resource gives subscribers additional insight related to the Recommendations published in March 2017 ~ Resource #330309 Lipid Treatment FAQs The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines represented a paradigm shift in the treatment of dyslipidemia. The 2017 American Diabetes Association Standards of Medical Care in Diabetes make similar recommendations. The guidelines focus on reducing cardiovascular risk using moderate- or high-intensity statins. (See our chart, 2013 ACC/AHA Cholesterol Guidelines, for a list of high- and moderate-intensity statins.) Familiar tools such as LDL targets, non-statin lipid medications, and the Framingham risk calculator have fallen by the wayside for the most part. The chart below addresses common questions that arise in practice concerning the new thinking about treatment of lipids. Clinical Question Should I still screen patients for high cholesterol? How do I assess cardiovascular risk to help decide if a patient needs a statin for primary prevention? Can I still use Framingham? Continued Suggested Approach Assess traditional cardiovascular risk factors (e.g., lipids, blood pressure, diabetes) every four to six years in patients 20 to 79 years of age without atherosclerotic cardiovascular disease. 2,6 Patients will be treated based on cardiovascular risk (see next box), not just lipid levels. 1 For estimation of 10-year cardiovascular disease risk in patients 40 to 75 years of age without cardiovascular disease, not receiving cholesterol-lowering therapy, with LDL 70 to 189 mg/dl, use the Pooled Cohort Equations Cardiovascular Risk Calculator, available at http://my.americanheart.org/cvriskcalculator. 1,2 This new calculator was introduced in the 2013 guidelines. Evidence suggests that predicted risk with the new calculator and observed risk are similar. 8 Obtain the patient s age, sex, race, total and HDL cholesterol, systolic blood pressure, antihypertensive use, presence of diabetes, and smoking status. 2 Plug this information into the calculator. The 10-year cardiovascular risk can be used to help you determine whether the patient needs a statin (see first box on next page). Not all experts agree with its use. For example, the new calculator may overestimate risk in women. 13 See Can I still use Framingham? below for information about alternative calculators. Use the Pooled Cohort Equations Cardiovascular Risk Calculator (the new calculator) for most patients. The Pooled Cohort Equations Cardiovascular Risk Calculator was developed to be more clinically useful and generalizable than Framingham. 3 Framingham was based on data from whites, and was less precise in patients with diabetes. 4 For development of the new calculator, large, diverse, contemporary, community-based, primary prevention cohorts were used. 3 Some of the Framingham cohorts were included. 3 While Framingham Copyright 2017 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Clinical Resource #330309: Page 2 of 6) Clinical Question Can I still use Framingham, continued Who do I treat, and how? What if a patient doesn t fit into one of the four benefit groups (see above)? Should patients 21 to <40 years of age receive a statin? Continued Suggested Approach calculated the risk of coronary heart disease, the risk determined with the new calculator is the risk of hard cardiovascular outcomes: coronary death, nonfatal MI, and fatal and nonfatal stroke. 3 These are clinically relevant outcomes. 3 Risk estimated with the new calculator does not include risk of coronary heart disease alone, risk of revascularization, or risk of heart failure. 3 The new calculator is intended for use in both black and white men and women, with and without diabetes. 3 Consider other risk calculators if they were developed in a patient population that more closely matches the patient in question. 5 For example, risk in a healthy, non-diabetic female nurse might be best represented by the Reynolds Risk Score. 5 See our chart, Common Cardiovascular Risk Calculators, to help you choose the most appropriate calculator for a given patient. First, determine which of the four statin benefit groups the patient fits into. This determines whether the patient should be considered for high- or moderate-intensity statin therapy. The benefit groups and statin dosing are delineated in our chart, 2013 ACC/AHA Cholesterol Guidelines. Briefly, a statin is recommended for patients with clinical atherosclerotic heart disease, LDL 190 mg/dl or higher, or diabetes and age 40 to 75 years. For other patients age 40 to 75 years with an LDL of 70 to 189 mg/dl, 10-year cardiovascular risk determines if a statin is appropriate. In these patients, a 10-year risk of 7.5% is the point where the benefit of statins appears to exceed the risk. 1 Discuss the benefits and risks of statin therapy with the patient BEFORE starting a statin, especially for primary prevention. 1 Start with the target dose in most patients; there is no proof that up-titrating improves tolerability. It is prudent to use cautious dosing in patients more prone to statin side effects: those over 75 years of age, those with a history of statin intolerance, and those taking interacting medications. 7 If there is clinical suspicion that such a patient may benefit from a statin, additional factors can be taken into consideration. 1 These are listed in footnote a at the end of the chart. See discussions below on patients <40 years of age and those >75 years of age. A high-intensity statin (e.g., atorvastatin 80 mg) is recommended for patients with cardiovascular disease. 1 A high-intensity statin is recommended for patients with LDL 190 mg/dl or higher. 1 If a patient has diabetes, but no cardiovascular disease and LDL <190 mg/dl, individualize. Consider additional factors (see footnote a ). Discuss statin risks and benefits, lifestyle changes, and risk factor management. 1 The American Diabetes Association recommends considering a high- or moderate-intensity statin for diabetes patients with additional risk factors (see footnote b). 10 Copyright 2017 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Clinical Resource #330309: Page 3 of 6) Clinical Question Should patients 21 to <40 years of age receive a statin, continued Which patients with diabetes should receive a statin? How should patients over 75 years of age be managed? Continued Suggested Approach Discuss lifestyle changes (e.g., smoking cessation) and manage risk factors (e.g., control hypertension, diabetes). 1,7 Patients with multiple risk factors or a single strong risk factor (see footnote a at the end of the chart) may opt to try at least a moderate-intensity statin for primary prevention based on statin risks/benefits, and patient preferences. 1 Use the Pooled Cohort Equations Cardiovascular Risk Calculator as a tool when discussing risk with patients. The calculator provides lifetime risk calculation for 20 to 59-year-olds; 10-year risk may underestimate lifetime risk in young patients. 1,2 Ensure women taking a statin do not become pregnant. For patients with cardiovascular disease, use high-intensity statin for most patients who can tolerate it. 1,10 See discussion below about patients over 75 years of age. 1 For patients 40 to 75 years of age, with LDL 70 to 189 mg/dl (1.8 to 4.9 mmol/l) and an estimated 10-year risk of atherosclerotic cardiovascular disease of less than 7.5%, use a moderate-intensity statin. 1 American Diabetes Association guidelines recommend considering a moderate-intensity statin for patients 40 to 75 years of age without additional risk factors (see footnote b). 10 American Diabetes Association guidelines recommend considering a high-intensity statin for patients ages 40 to 75 years with additional risk factors (see footnote b). 10 The American Diabetes Association guidelines recommend considering a high- or moderate-intensity statin for patients <40 years with additional risk factors (see foot note b). 10 The American Diabetes Association guidelines recommend considering a moderate-intensity statin in diabetes patients >75 years of age without additional risk factors (see footnote b). 10 If additional risk factors are present, a high-intensity statin may also be considered. 10 For secondary prevention, use a moderate-intensity statin. 1 If the patient is already taking a high-intensity statin and tolerating it well, it can be continued. 1 American Diabetes Association guidelines recommend a high-intensity statin for diabetes patients of all ages with cardiovascular disease. 10 For primary prevention, consider comorbidities, potential for harm, patient preferences and priorities, and 10-year cardiovascular risk. 1 The Pooled Cohort Equations Cardiovascular Risk Calculator can be used in patients 75 to 79 years of age. 1 See footnote a for a list of factors to consider. The American Diabetes Association guidelines recommend considering a moderate-intensity statin in diabetes patients >75 years of age without additional risk factors (see footnote b). 10 If additional risk factors are present, a high-intensity statin may also be considered. 10 Discuss lifestyle changes (e.g., smoking cessation) and manage risk factors (e.g., control hypertension and Copyright 2017 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Clinical Resource #330309: Page 4 of 6) Clinical Question How should patients over 75 years of age be managed, continued How should patients already on a statin be managed? How do I explain the new thinking about lipids to patients? How should statin patients be monitored? What is the role of nonstatins? Continued Suggested Approach diabetes). 1,7 If a statin is chosen, a high- or moderate-intensity statin is preferred. 1 Consider stopping statins in patients with life expectancy <1 year, or advanced dementia. 9,12 Ensure most patients with atherosclerotic cardiovascular disease or LDL 190 mg/dl or higher are getting a highintensity statin. For primary prevention patients, do not use the patient s on-treatment lipid values in the calculator. If a patient is already taking a cholesterol medication, use their pretreatment lipid values. 4 Lipid treatment was not common in the cohorts used to develop the equation. 3 If pretreatment lipids are not available, keep in mind that the risk calculator is only one piece of information used in the decision to start a statin for primary prevention. 5 Consider patient preferences, potential for harm, and potential for benefit. 5 Factors to consider besides those included in the risk calculator are listed in footnote a. If baseline levels are unavailable, aim for an LDL <100 mg/dl in most patients, and possibly <70 mg/dl in very high-risk patients with cardiovascular disease and comorbidities such as diabetes, based on levels reached in statin outcome trials. 1,14 Explain that studies looking at statin benefits used specific doses, and did not adjust therapy to meet specific cholesterol goals. Check fasting (preferred) lipid panel four to 12 weeks after statin initiation, then every three to 12 months. 1 If the LDL drop is less than expected, check adherence to the statin and lifestyle interventions. Expected LDL reductions for each statin dose are delineated in our chart, 2013 ACC/AHA Cholesterol Guidelines. Statin dose reduction may be considered if two consecutive LDL measurements are less than 40 mg/dl. 1 Check ALT (alanine aminotransferase) at baseline. Repeat only if symptoms of hepatotoxicity occur. 1 Document any pre-existing muscle symptoms before starting a statin to establish a baseline. 1 Consider checking creatine kinase at baseline in patients at increased risk for myopathy (e.g., drug interactions, etc). Repeat only if symptomatic. 1 If severe muscle symptoms or fatigue of unknown cause develops, hold the statin and check creatine kinase, creatinine, and urinalysis to rule out rhabdomyolysis. 1 Do not routinely use non-statins. Re-evaluate need in patients already on them. The addition of a non-statin to a statin has not been proven to further reduce cardiovascular mortality; therefore, non-statins are no longer routinely recommended. 1,11,15 Adding fibrate or niacin to achieve a specific LDL goal could result in reduction in the statin to a suboptimal dose. 1 Copyright 2017 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Clinical Resource #330309: Page 5 of 6) Clinical Question What is the role of nonstatins, continued Suggested Approach Reinforce statin adherence and lifestyle changes and check for secondary causes of LDL elevation before adding a non-statin. 1 For patients who cannot tolerate the recommended statin dose or who do not achieve the expected statin response and are high-risk at baseline (i.e., LDL 190 mg/dl or higher, diabetes, clinical atherosclerotic or cardiovascular disease), consider a non-statin [Evidence level C; expert opinion]. 1 For high-risk patients who can t tolerate a high-intensity statin, or who don t get the expected 50% LDL reduction, suggest adding ezetimibe to a statin. There s no proof that adding other oral non-statins (fibrates, etc) to a statin improves outcomes, and niacin worsens glycemic control. 11 Consider PCSK9 inhibitors as add-on therapy for HoFH (evolocumab); with maximally tolerated statin for HeFH or clinical CVD requiring additional LDL lowering (evolocumab, alirocumab); and for statin-treated CVD patients with a CV event or multiple risk factors (evolocumab). 15-17 For triglycerides of 500 mg/dl or higher, an omega-3 fatty acid, niacin, or fenofibrate can be used. 1 Do not add gemfibrozil to a statin. 1 For information to help guide decisions regarding non-statins, see our chart, Non-Statin Lipid-Lowering Agents. Abbreviations: CV=cardiovascular; CVD=cardiovascular disease; HeFH=heterozygous familial hypercholesterolemia; HoFH=homozygous familial hypercholesterolemia; IR=immediate release; LDL=Low-density lipoprotein; PCSK9=proprotein convertase subtilisin/kexin type 9. a. Additional factors to consider: 1 LDL 160 mg/dl or higher or other evidence of genetic hyperlipidemia. Cardiovascular disease onset in a first-degree male relative before age 55, or in a first-degree female relative before age 65. High-sensitivity C-reactive protein 2 mg/l or higher. Ankle-brachial index <0.9. Elevated lifetime risk of atherosclerotic cardiovascular disease. Coronary artery calcium (CAC) score 300 Agatston units or higher, or 75 th percentile or higher for age, gender, and ethnicity. Statin adverse effects. Statin drug interactions. Patient preferences. b. American Diabetes Association risk factors: LDL >100 mg/dl, hypertension, smoking, chronic kidney disease, albuminuria, family history of premature atherosclerotic cardiovascular disease. Users of this resource 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. Copyright 2017 by Therapeutic Research Center PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Clinical Resource #330309: Page 6 of 6) 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 A B C D Definition High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study Consensus Expert opinion 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;65:251-8. Project Leader in preparation of this clinical resource (330309): Melanie Cupp, Pharm.D., BCPS References 1. Stone 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. Circulation 2014;129(25 Suppl 2):S1-45. 2. American Heart Association. 2013 Prevention Guidelines Tools. CV Risk Calculator. http://my.americanheart.org/cvriskcalculator. (Accessed January 31, 2017). 3. Goff DC Jr, 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. Circulation 2014;129(25 Suppl 2):S49-73. 4. Clinical Resource, Common Cardiovascular Risk Calculators. Pharmacist s Letter/Prescriber s Letter. January 2014. 5. Yancy CW, Harrington RA, Robinson JG. New cholesterol guidelines and CV risk calculator: controversy clarified. Medscape. January 29, 2014. http://www.medscape.com/viewarticle/819542_3. (Accessed January 31, 2017). 6. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S76-99. 7. Stone NJ, Robinson JG, Lichtenstein AH, et al. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med 2014;160:339-43. 8. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA 2014;311:1406-15. 9. Tjia J, Briesacher BA, Peterson D, et al. Use of medications of questionable benefit in advanced dementia. JAMA Intern Med 2014;174:1763-71. 10. Standards of medical care in diabetes 2017. Diabetes Care 2017;40 (Suppl 1):S1-135. 11. Clinical Resource, Ezetimibe s Role in Cardiovascular Risk Reduction. Pharmacist s Letter/Prescriber s Letter. January 2015. 12. Kutner JS, Blatchford PJ, Taylor DH, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med 2015;175:691-700. 13. Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women s Health Study. JAMA Intern Med 2014;174:1964-71. 14. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 15. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017 Mar 17. 16. Product information for Praluent. Sanofi-Aventis U.S. Bridgewater, NJ 08807. October 2015. 17. Product information for Repatha. Amgen Inc. Thousand Oaks, CA 91320. July 2016. Cite this document as follows: Clinical Resource, Lipid Treatment FAQs. Pharmacist s Letter/Prescriber s Letter. March 2017. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com