DYSLIPIDEMIA

Laura Waite, PharmD, BCPS, CLS, BC-ADM and Thaddeus McGiness, PharmD, BCPS

Quick Facts

Risk factors1 Complications5

00 Type 2 diabetes mellitus (T2DM): T2DM can Over time, high cholesterol levels can lead to the decrease levels of good cholesterol (HDL) following: and increase levels of bad cholesterol 00 Artery damage (LDL), which increases chance for a cardio- 00 Hardening of the arteries (atherosclerosis) vascular (CV) event, such as stroke. 00 Heart disease 00 Lifestyle choices: eating a diet high in 00 Increased risk of stroke saturated and trans fats, physical inactivity, 00 Chest pain caused by decreased lack of obesity oxygen-rich blood 00 Family history 00 Peripheral artery disease (PAD) caused by 00 Age: Risk increases with advancing age decreased blood flow to arteries in arms, 00 Gender: men typically have lower HDL stomach, legs, and feet levels than women; women typically have lower LDL levels than men (until age 55) REFERENCES 1. Centers for Disease Control. Knowing your risk: high Prevalence and incidence cholesterol. Centers for Disease Control and Prevention. https://www.cdc.gov/cholesterol/risk_factors.htm. 00 About 1 in 6 adult Americans has high Accessed November 16, 2017. cholesterol.2 2. Minino AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. National Vital Statistics Reports. 00 Anyone can develop high cholesterol, 2011;59(10). https://www.cdc.gov/nchs/data/nvsr/nvsr59/ including children. nvsr59_10.pdf. 00 42.2% of US adults are at moderate risk of 3. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha developing high cholesterol, 13.1% are at MJ, Cushman M, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart high risk, and another 6.2% are thought to Association. Circulation. 2016;133(4):e38–60. be undiagnosed.3 4. Fox KM, Wang L, Gandra SR, Quek RGW, Li L, Baser O. Clinical and economic burden associated with cardiovascular events among patients with Cost of disease burden4 hyperlipidemia: a retrospective cohort study. BMC Cardiovasc Disord. 2016;16:13. 00 Among patients in the US with hyperlip- 5. Feingold KR, Brinton EA, Grunfeld C. The effect of idemia, the direct clinical and economic endocrine disorders on lipids and lipoproteins. [Updated 2017 Feb 24]. In: De Groot LJ, Chrousos G, Dungan K, annual costs associated with new cardio- Feingold KR, Grossman A, Hershman JM, et al., eds. vascular event (including up to 3 years Endotext [Internet]. South Dartmouth, MA: MDText. post-event) are approximately US$195.6 com, Inc.; 2000. https://www.ncbi.nlm.nih.gov/books/ billion. NBK409608/.

DYSLIPIDEMIA Overview

Pathophysiology1 adipose tissue, and if in excess, depos- ited along artery walls. 00 No clear definition of dyslipidemia exists; ➤➤ HDL particles can be protective against however, there is a linear relationship this process by removing cholesterol from between lipid levels and benefits of pharma- the artery walls and returning it to the cologic and non-pharmacologic treatments. liver; this is known as reverse cholesterol 00 A diagnosis of dyslipidemia can include any transport. (or a combination) of the following: 00 Atherosclerosis occurs as a compensatory ➤ ➤ Elevated chylomicrons response to excess lipids, and this process is ➤ ➤ Elevated triglycerides (TG) the basis of most acute coronary syndromes: ➤➤ Elevated total cholesterol (TC) ➤➤ LDL particles with a cholesterol and ➤ ➤ Elevated low-density lipoproteins (LDL-C) triglyceride core enter the arterial wall. ➤ ➤ Decreased high-density lipoproteins Macrophages consume these lipids and (HDL-C) trigger inflammation. 00 Cholesterol Transport and Removal2 ➤➤ The resulting lipid core/macrophage ➤ ➤ Chylomicrons take in dietary lipids in infiltration/inflammation is clinically the intestines, travel through the blood- referred to as plaque. stream, where muscle and adipose tissue ➤➤ As the plaque grows, the arterial wall convert it into Chylomicron remnants. expands into the artery lumen. ➤➤ Chylomicron remnants travel to the liver ➤➤ Blood flow becomes progressively where they are converted into VLDL restricted and will continue to do so until particles. the artery becomes clotted off alto- ➤ ➤ VLDL particles travel through the blood- gether, causing ischemia. stream where they are broken down ➤➤ As plaques enlarge, they may burst, into a final product known as LDL parti- which allows the plaque components to cles and taken up into the muscles and enter the blood stream and cause full occlusions in smaller blood vessels. FIGURE 1: Excess lipids; Atherosclerosis

Fatty Streak Formation

Lipoprotein Oxidation Lipoproteins enter artery wall into intima Foam Cell Formation Bind to Decrease proteoglycan molecules that molecules maintain vascular Plaque Formation tome Monocytes are Increased recruited into production of intima, Maturation inflammatory differentiate into Foam cells markers (e.g., cell macrophages accumulate adhesion More oxidized Vascular wall molecules (CAM)) lipoproteins grows out into Lipid-rich core is accumulate arterial lumen formed Smooth muscle cells move from media to intima to form fibrous cap

DYSLIPIDEMIA Etiology1 Early detection and screening1

Causes Should be Fasting lipoprotein profile should performed include the following: 00 Genetic mutation of receptors or every 5 ➤➤ Total cholesterol (TC) apolipoproteins years on ➤➤ Low-density lipoprotein (LDL-C; 00 Overproduction of lipids or beta-apolipo- adults 20 calculated) proteins (LDL) years of ➤➤ High-density lipoprotein (HDL-C) 00 Underproduction of alpha-apolipoproteins age and ➤➤ Triglycerides (TG) (HDL) older Non-HDL-C can be calculated by the Medications that can elevate following formula: non-HDL-C = TC – HDL-C LDL-C or TG3

LDL-C TG Both REFERENCES Anabolic Oral estrogen Cyclosporine 1. Talbert RL. Dyslipidemia. In: DiPiro JT, Talbert RL, Yee GC, steroids Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Tamoxifen, Thiazides Pathophysiologic Approach. 10th ed. New York, NY: Mc- Danazol Raloxifene Glucocorticoids Graw-Hill, 2017. 2. Feingold KR, Grunfeld C. Introduction to Lipids and Progestins Retinoids Thiazolidinedi- Lipoproteins. [Updated 2015 Jun 10]. In: De Groot LJ, Isotretinoin Sirolimus ones Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available Amiodarone Interferon (TG = from: https://www.ncbi.nlm.nih.gov/books/NBK305896/ rosiglitazone 3. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays Beta-blockers HE, Jones PH, et al. National Lipid Association only) recommendations for patient-centered management Atypical of dyslipidemia: part 1-full report. J Clin Lipidol. antipsychotics 2015;9(2):129–169. Protease inhibitors Fibrates or omega-3 Bile acid fatty acids (if sequestrants patient has L-asparaginase severely ele- Cyclophospha- vated TG and mide atherogenic dyslipidemia)

DYSLIPIDEMIA Guidelines and Landmark Trials

Guidelines 00 Jacobson T, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand, G, et al. 00 Stone NJ, Robinson J, Lichtenstein AH, National Lipid Association recommenda- Bairey Merz CN, Blum CB, Eckel RH, et al. tion for patient-centered management 2013 ACC/AHA guideline on the treatment of dyslipidemia: part 2. J Clin Lipidol. of blood cholesterol to reduce atheroscle- 2015;9(6):S1–S122.e1. rotic cardiovascular risk in adults. Circula- 00 Lloyd-Jones DM, Morris PM, Ballantyne CM, tion. 2014;129:S1–S45. Birtcher KK, Daly Jr DD, DePalma SM, et al. 00 Jacobson TA, Ito MK, Maki KC, Orringer 2017 focused update of the 2016 ACC expert CE, Bays HE, Jones PH, et al. National consensus decision pathway on the role of Lipid Association recommendations for non-statin therapies for LDL-cholesterol low- patient-centered management of dyslip- ering in the management of atherosclerotic idemia: part 1-full report. J Clin Lipidol. cardiovascular disease risk: a report of the 2015;9(2):129–169. American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(14):1785–1822.

Table 1: Guidelines for Hyperlipidemia

Category Recommendation

2013 American Initiation of ➤➤ Focus on prevention of atherosclerotic cardiovascular disease (ASCVD; eg, MI, angina, College of statin therapy stroke, PAD, revascularization). Cardiology/ ➤➤ Recommend primary and secondary intervention in individuals without New York Heart American Association (NYHA) class II–IV heart failure and/or not receiving hemodialysis. Heart ➤➤ Guideline organized by statin benefit groups. Association ➤➤ Risk assessment conducted using Pooled Cohort Equations, which predicts a 10-year blood risk of ASCVD. cholesterol ➤➤ No specific numeric goals of treatment, but rather proportional benefit is seen as com- guideline pared to the patient baseline. ➤➤ In patients without clear indications, risk and benefit should be weighed for statin therapy. ➤➤ Statin therapy is the only therapy recommended by this guideline owing to a lack of randomized controlled trials supporting other medications for reducing atherosclerotic cardiovascular disease and mortality. ➤➤ Guideline recommends moderate- to high-intensity statins for most patients.

Statin benefit ➤➤ Patients ≥ 21 years of age for whom the ASCVD risk reduction clearly outweighs the risk groups of adverse events ➤➤ Secondary prevention in individuals with clinical ASCVD ➤➤ Primary prevention in individuals with LDL-C ≥ 190 mg/dL ➤➤ Primary prevention in individuals with diabetes (but no ASCVD), 40 to 75 years of age, with LDL-C 70 to 189 mg/dL ➤➤ Primary prevention in individuals 40 to 75 years of age with LDL-C 70 to 189 mg/dL without diabetes or ASCVD but with estimated 10-year ASCVD risk ≥ 7.5%

Statin benefit ➤➤ Primary prevention in individuals with 5–7.5% 10-year ASCVD risk and 40–75 years of group for age with LDL-C 70–89 mg/dL whom ➤➤ < 5% 10-year ASCVD risk, or < 40 years old or > 75 years old moderate ➤➤ Patients and providers should discuss ASCVD risk reduction benefits, adverse effects of evidence statin therapy, drug interactions, drug-disease interactions and patient preference. supports the use of statins

DYSLIPIDEMIA Category Recommendation

2015 National Importance ➤➤ Historically useful for both health care providers and patients to monitor progress. Lipid of numeric ➤➤ Ensure that aggressive lowering of atherogenic cholesterol is matched to absolute risk Association treatment of an event. (NLA) goals ➤➤ Avoid undertreatment. Part 1 Risk Risk category Criteria Guidelines assessment Low ➤➤ 0 or 1 major ASCVD risk factors ➤➤ Equates to < 5% 10-year risk of an ASCVD event using any available risk assessment calculator

Moderate ➤➤ 2 major ASCVD risk factors in the absence of conditions that place individuals in higher risk categories ➤➤ Is approximately equated to 5–10% 10-year risk for an ASCVD event using any available risk assessment calculator

High ➤➤ T1DM or T2DM and ≤ 1 major ASCVD risk factor ➤➤ CKD stage 4 ➤➤ LDL-C ≥ 190 mg/dL ➤➤ Presence of ≥ 3 major ASCVD risk factors

Very high ➤➤ Clinical evidence of ASCVD ➤➤ T1DM or T2DM and ≥ 2 major ASCVD risk factors ➤➤ Evidence of end-organ damage ➤➤ End stage chronic kidney disease (CKD; however, data have consis- tently not shown benefit)

Major ASCVD risk factors ➤➤ Age (male 45 years or older, female 55 years or older) ➤➤ Family history of early heart disease (male < 55 years, female < 65 years) ➤➤ Cigarette smoking ➤➤ High blood pressure (on medication or at least 140/90mmHg) ➤➤ Low HDL-C (male < 40 mg/dL, female < 50 mg/dL)

Statin initiation ➤➤ Initiate treatment with statin at the dose required to reach goal. ➤➤ Each doubling of statin dose is estimated to result in an additional 6% of LDL-C lowering. ➤➤ If treatment goals are not met, especially in high- and very high-risk individuals, a second or third agent can be considered. ➤➤ Therapies to be considered include ezetimibe, niacin, gemfibrozil, and cholestyramine.

Non-statin ➤➤ Bile acid sequestrants: 15–30% therapy ➤➤ Nicotinic acid: 5–25% projected ➤➤ Fibric acids: 5–20% LDL-C ➤➤ Cholesterol absorption inhibitors: 13–20% lowering ➤➤ Long chain omega-3 fatty acid drugs: 6–25%

2015 NLA Addition to ➤➤ Primary emphases of these guidelines include lifestyle therapies and special Part 2 NLA Part 1 populations. Guidelines and ACC/AHA ➤➤ Mirror recommendations in NLA Part 1 including risk assessment and goals of therapy, Guidelines but include guidance for patient populations not included in NLA Part 1 (or ACC/AHA). ➤➤ Provide additional guidance for use of non-statin therapies. ➤➤ Stresses the importance of team-based care (including pharmacists).

DYSLIPIDEMIA Category Recommendation

2017 Update Statin benefit ➤➤ Addresses the concern that the 2013 ACC/AHA guidelines did not include any on ACC Expert groups non-statin recommendations. Consensus ➤➤ Statins remain cornerstone of dyslipidemia management. Decision ➤➤ Recommendations organized by statin benefit groups as in the 2013 ACC/AHA Pathway guideline: on Use of ♦♦ Group 1: Adults ≥ 21 years of age with clinical ASCVD on statin for secondary Non-Statins prevention ♦♦ Group 2: Adults ≥ 21 years of age with baseline LDL-C > 190 mg/dL (not caused by secondary modifiable causes) on statin for primary prevention ♦♦ Group 3: Adults 40–75 years of age without clinical ASVD but with diabetes and baseline LDL-C 70–189 mg/dL, on statin for primary prevention ♦♦ Group 4: Adults 40–75 years of age without clinical ASCVD or diabetes with base- line LDL-C 70–189 mg/dL with an estimated 10-year risk of an ASCVD event ≥ 7.5% and on statin for primary prevention

Risk Other factors should be considered when deciding whether to add on additional therapy assessment to a statin: ➤➤ Adherence to medication and lifestyle ➤➤ Statin intolerance ➤➤ Control of other risk factors ➤➤ Clinical-patient discussion on potential benefits and risks and patient preference ➤➤ Projected percentage of LDL-C reduction with add-on therapy ➤➤ Monitoring of response to therapy, adherence, and lifestyle ➤➤ Additional therapies to be considered only if a ≥ 50% LDL-C reduction is not achieved with maximally tolerated high-intensity statin

Interventions ➤➤ Referral to lipid specialist/registered dietitian to consider ➤➤ Ezetimibe ➤➤ Bile-acid sequestrants in ezetimibe-intolerant patients (cholestyramine) ➤➤ PCSK9 inhibitors (evolocumab or alirocumab) ➤➤ Mipomersen, lomitapide, LDL apheresis may be considered by lipid specialist for familial hypercholesterolemia

Guideline comparisons

ACC/AHA guidelines NLA parts 1 and 2 ACC non-statin consensus pathway

➤➤ Intended for general practitioners ➤➤ Intended for medical specialists ➤➤ Addresses barriers to appropri- ➤➤ Designed for easy use seeing higher-risk patients (e.g., ate use of statin therapy ➤➤ Focus on ASCVD risk reduction cardiologists, lipid specialists) ➤➤ Gives specific and hierarchical ➤➤ Does not include specific goals ➤➤ Designed for more individualized recommendations for additional for lipid lowering, but rather in- risk assessment and treatment therapies for patients in need of cludes approximate proportion- targets additional lipid lowering that are al decrease in lipid levels that ➤➤ Includes specific numeric lipid receiving maximally tolerated might be expected goals based on comorbidities or dosing of high-intensity statins ➤➤ Only recommends statins be- the condition of the patient cause no randomized controlled ➤➤ Has co-primary targets of LDL-C trial data exists that shows addi- and non-HDL-C tional ASCVD risk lowering with ➤➤ Part 2 recommendations for spe- further therapies cial populations not addressed ➤➤ Introduces the concept of “statin by ACC/AHA benefit groups” ➤➤ Includes recommendations for non-statins

DYSLIPIDEMIA Landmark trials

PROVE-IT TIMI 221 Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.

Summary Examined the effects of intensive vs. moderate statin therapy after acute coronary syndromes (ACS).

Importance This trial heavily influenced subsequent guidelines to recommend higher-intensity statin therapy in high-risk patients.

JUPITER2 Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

Summary Analyzed the benefits of statins in patients without hyperlipidemia but with elevated inflammatory markers.

Importance This trial demonstrated the efficacy of statins in reducing clinical outcomes even when used in primary prevention.

HPS2-THRIVE3 Effects of extended-release niacin with laropiprant in high-risk patients.

Summary Define the role of niacin therapy (in combination with a statin) in reducing cardiovascular events. Importance Niacin therapy does not add additional benefit to a statin in regard to clinical outcomes, despite beneficial effects on lipids. IMPROVE-IT4 Ezetimibe added to statin therapy after acute coronary syndromes

Summary Define the role of ezetimibe therapy (in combination with a statin) in reducing cardiovascular events.

Importance This trial formed the basis of current recommendations to prioritize ezetimibe as the first- line non-statin therapy when further lipid lowering is desired.

FOURIER5 Evolocumab and clinical outcomes in patients with cardiovascular disease.

Objective Examine the effect of PCSK9 inhibitors on cardiovascular outcomes.

Importance PCSK9 inhibitors have positive benefits on clinical outcomes in high-risk patients even when added to a statin.

REFERENCES 3. The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk 1. Ray KK, Cannon CP, McCabe CH, Cairns R, Ronkin AM, patients. N Engl J Med. 2014;371(3):203–212. Sacks FM, et al. Early and late benefits of high-dose 4. Cannon CP, Blazin MA, Gugliano RP, McCagg, A, atorvastatin in patients with acute coronary syndromes: White, JA, Theroux P, et al. Ezetimibe added to statin results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. therapy after acute coronary syndromes. N Engl J Med. 2005;46(8):1405–1410. 2015;372(25):2387–2397. 2. Ridker PM, Danielson E, Fonseca F, Genest J, Gotto AM, 5. Sabatine MS, Gugliano RP, Keech AC, Honarpour N, Kastelein JJP, et al. Rosuvastatin to prevent vascular Wiviott SD, Murphy SA, et al. Evolocumab and clinical events in men and women with elevated C-reactive outcomes in patients with cardiovascular disease. N Engl J protein. N Engl J Med. 2008;359(21):2195–2207. Med. 2017;376(18):1713–1722.

DYSLIPIDEMIA Patient Presentation

Symptoms1 Clinical evaluation

00 Usually patients present symptom-free. 00 Family history 00 Certain modifiable and non-modifiable fac- ➤➤ Early family ASCVD increases patient tors can increase risk for high cholesterol.2 risk 00 Rule out secondary causes of dyslipidemia Risk factor Effect on cholesterol ➤➤ Diet (malabsorption) Diabetes ➤➤ Lowers HDL-C and raises ➤➤ Hypothyroidism LDL-C ➤➤ Obstructive liver disease

Diet ➤➤ High trans and saturated fat ➤➤ Medication-related causes diets (high TC) 00 ASCVD risk factors ➤➤ Low physical activity ➤➤ Age (male 45 years or older, female ➤➤ Obesity (high TG, high LDL-C, 55 years old) low HDL-C) ➤➤ Family history of early heart disease

Age ➤➤ Increased risk with age (male < 55 years, female < 65 years) ➤➤ Inability to clear cholesterol ➤➤ Cigarette smoking from our blood as we get ➤➤ High blood pressure (on medication or older at least 140/90 mmHg) ➤➤ Gender ➤➤ Women (< 55 years of age) Low HDL-C (male < 40 mg/dL, female have lower LDL-C than men. < 50 mg/dL) ➤➤ Women tend to have higher HDL-C than men at any age. Risks of uncontrolled dyslipidemia Family ➤➤ Family history of high cho- history lesterol combined with poor 00 ASCVD events lifestyle choices increases risk ➤➤ Acute coronary syndrome for high cholesterol. ➤➤ Myocardial infarction ➤➤ Inherited genetic high cho- ➤➤ Stable or unstable angina lesterol “familial hypercholes- ➤➤ Transient ischemic attack terolemia” starts young and ➤➤ Peripheral arterial disease worsens with age. 00 Cardiovascular mortality ➤➤ Familial hypercholesterol- emia often cannot be treated or controlled with lifestyle changes alone.

00 All patients should be screened regardless of symptoms (age ≥ 20 years old). ➤➤ Repeat screening should be done every 5 years. ➤➤ Rescreen earlier than 5 years if clinically indicated. ♦♦ Changes in ASCVD risk factors ♦♦ ASCVD event in close relative ♦♦ Secondary cause of dyslipidemia ➤➤ Screen patients early with family history of ASCVD.

DYSLIPIDEMIA Diagnostic tests 00 Lipoprotein lipid levels should be used in conjunction with ASCVD risk assessment to 00 Fasting lipid panel (9 to 12 houvrs without determine treatment goals and therapies. food) should be obtained at baseline. 00 Test, at minimum, total cholesterol and Total < 200 mg/dL Desirable HDL. cholesterol ➤➤ Non–HDL-C = total cholesterol minus 200–239 mg/dL Borderline (TC) HDL-C ≥ 240 mg/dL High LDL < 100 mg/dL Optimal REFERENCES cholesterol 1. Feingold KR, Grunfeld C. Approach to the patient with 100–129 mg/dL Near optimal (LDL-C) dyslipidemia. [Updated 2015 Jun 12]. In: De Groot LJ, 130–159 mg/dL Borderline Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext [Internet]. South 160–189 mg/dL High Dartmouth, MA: MDText.com, Inc.; 2000. https://www. ncbi.nlm.nih.gov/books/NBK326736/. 190 mg/dL Very high ≥ 2. Knowing your risk: high cholesterol. Centers for Disease HDL < 40 mg/dL Low Control and Prevention website. https://www.cdc.gov/ cholesterol cholesterol/risk_factors.htm. Accessed November 16, 2017. ≥ 60 mg/dL High (HDL-C)

Triglycerides < 150 mg/dL Normal (TG) 150–199 mg/dL Borderline

200–499 mg/dL High

≥ 500 mg/dL Very high

Treatment Goals

Treatment goals for dyslipidemia vary between National Lipid Association the available guidelines. Overall, the American Treatment Goals1 College of Cardiology and the American Heart Association aim for ASCVD prevention instead Consider drug of numeric treatment targets; the National Lipid Treatment goal therapy Association guidelines provide specific numeric Risk Non-HDL-C (mg/dL) Non-HDL-C (mg/dL) goals based on risk stratification.1-3 The 2017 category LDL-C (mg/dL) LDL-C (mg/dL) ACC/AHA Non-Statin Expert Consensus Path- Low < 130 ≥ 190 way recommends treatment thresholds above < 100 ≥ 160 which non-statin therapy should be considered, Moderate < 130 160 which does include an absolute LDL-C reduction ≥ < 100 ≥ 130 percentage that varies by statin benefit group.2 Therefore, the ultimate treatment goal for each High < 130 ≥ 130 patient should be individualized and dependent < 100 ≥ 100 upon an in-depth and ongoing assessment of Very < 100 ≥ 100 risks vs. benefits, drug interactions, drug-disease high < 70 ≥ 70 interactions, and patient preference.

DYSLIPIDEMIA The ACC does not provide numeric goals of consider the use of non-statins in addition therapy for dyslipidemia, but in its Expert to maximally tolerated statin therapy.2 These Consensus Decision Pathway on the Role of thresholds are based on statin benefit group Non-Statin Therapies, treatment thresholds as described in the 2013 ACC/AHA Blood are recommended above which providers can Cholesterol Guidelines.3

Threshold for considering non-statin

Statin benefit group LDL-C (mg/dL) Non-HDL-C (mg/dL)

Group 1 (secondary prevention in patients with ASCVD) < 70 < 100

Group 2 (primary prevention in patients with LDL-C ≥ 190 mg/dL) < 100 < 130 Group 3 (primary prevention in individuals with diabetes [but no < 100 < 130 ASCVD], 40 to 75 years of age, with LDL-C 70 to 189 mg/dL)

Group 4 (primary prevention in individuals 40 to 75 years of age < 100 < 130 with LDL-C 70 to 189 mg/dL without diabetes or ASCVD but with estimated 10-year ASCVD risk ≥ 7.5%)

REFERENCES of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease 1. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, risk: a report of the American College of Cardiology task Jones PH, et al. National Lipid Association recommenda- force on expert consensus decision pathways. tions for patient-centered management of dyslipidemia: J Am Coll Cardiol. 2017;70(14):1785–1822. epub 2017 Sep 5. part 1-full report. J Clin Lipidol. 2015;9(2):129–169. 3. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, 2. Lloyd-Jones DM, Morris PM, Ballantyne CM, Birtcher KK, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the Daly Jr DD, DePalma SM, et al. 2017 focused update of the treatment of blood cholesterol to reduce atherosclerotic 2016 ACC expert consensus decision pathway on the role cardiovascular risk in adults. Circulation. 2014;129:S1–S45.

Disease State Management

Nonpharmacologic Management of 00 ≥ 150 minutes/week of moderate or higher Dyslipidemia1,2 intensity exercise 00 Plant sterols/stanols (2 g/day) 00 Results in an expected total cholesterol 00 Dietary viscous soluble fiber (10–25 g/day) reduction of 3–7% 00 Weight reduction (5–10% of body weight) 00 Heart-healthy diet 00 Smoking cessation ➤➤ Emphasizes intake of vegetables, fruits, 00 VERY low-fat diet for high TG (to prevent whole grains, low-fat dairy products, pancreatitis) poultry, fish, legumes, nontropical vege- 00 Per NLA, individuals in low and moderate table oils, and nuts risk groups should be given a 3-month trial ➤ ➤ Limits intake of sweets, sugar-sweetened to implement lifestyle modifications before beverages, and red meats (as culturally initiation of drug therapy accepted) ➤➤ Dietary cholesterol < 200 mg/day ➤➤ 5–6% of calories from saturated fat and minimal to no calories from trans fat ➤➤ Options include DASH diet, USDA Food Pattern, or AHA Diet

DYSLIPIDEMIA Pharmacologic Management of Predicted LDL-C 2-5 Dyslipidemia lowering (% from Drug baseline) All guidelines recommend initiating a statin as first-line therapy for dyslipidemia, with intensity Bile acid sequestrants 15–30 of therapy based on degree of LDL-C reduction. Nicotinic acid 5–25

Fibrates 5–20 Dose (in mg/day) Cholesterol absorption 13–20 High intensity Moderate inhibitors Drug (lowers LDL-C intensity (lowers ≥ 50% from LDL-C 30–50% Long chain omega-3 6–25 baseline) from baseline) fatty acids

Atorvastatin 40–80 10–20

Fluvastatin – 80 American College of Cardiology/ American Heart Association Lovastatin – 40

Pitavastatin – 2–4 The 2013 ACC/AHA Blood Cholesterol Guidelines recommend statin therapy as the first-line therapy Pravastatin – 40–80 (the only medication therapy recommended by Rosuvastatin 20–40 5–10 these guidelines) based on statin benefit group.2 Simvastatin – 20–40 The 2017 ACC Non-Statin Expert Consensus Deci- sion Pathway provides additional considerations for If non-statin therapies are considered, the LDL-C what agents are appropriate when maximally tol- lowering varies by drug class. erated statin therapy does not decrease LDL-C by ≥ 50% from baseline or when treatment thresholds are not met (see treatment goals section above).5 A compilation of both sets of recommendations is depicted in the following algorithm in figure 2.

FIGURE 2: Adapted from 2013 ACC/AHA Blood Cholesterol Guidelines and 2017 ACC Non-Statin Expert Consensus Decision Pathway.2,5

Patient in a statin benefit group?

Statin Benefit Group 1 Statin Benefit Group 2 Statin Benefit Group 3 Statin Benefit Group 4

Moderate intensity statin Moderate-to-high High intensity statin High intensity statin (high intensity if 10-yr intensity statin based on (moderate if > 75 yrs) ASCVD risk ≥ 7.5% risk-benefit analysis

Increase to LDL-C NOT decreased Increase to Increase to high-intensity statin if by 50% with maximally high-intensity statin if high-intensity statin if not previously done tolerated statin? not previously done not previously done

LDL-C NOT decreased Ezetimibe OR PCSK9i LDL-C NOT decreased LDL-C NOT decreased by 50% with maximally (add the other agent by 50% with maximally by 50% with maximally tolerated statin? second) tolerated statin? tolerated statin?

If no comorbidities, ezetimibe first, then Ezetimibe Ezetimibe PCSK9i second

If no comorbidities, ezetimibe OR PCSK9i (add the other agent second) DYSLIPIDEMIA Statin benefit groups (patients ≥ 21 years of High-risk markers influencing use of 5 age for whom the ASCVD risk reduction clearly ezetimibe in statin benefit group 4 outweighs the risk of adverse events)2,5 00 10-yr ASCVD risk ≥ 20% Group 1 Secondary prevention in individuals with 00 LDL-C ≥ 160 mg/dL at baseline clinical ASCVD 00 Poorly controlled ASCVD risk factors Group 2 Primary prevention in individuals with 00 Family history of premature ASCVD LDL-C ≥ 190 mg/dL 00 Evidence of subclinical atherosclerosis 00 Elevated hsCRP Group 3 Primary prevention in individuals with 00 Inflammatory comorbidities (chronic kidney diabetes (but no ASCVD), 40 to 75 years of age, with LDL-C 70 to 189 mg/dL disease, HIV, rheumatoid arthritis)

Group 4 Primary prevention in individuals 40 to 75 years of age with LDL-C 70 to 189 mg/ Considerations dL without diabetes or ASCVD but with 00 Adherence to medication and lifestyle mod- estimated 10-year ASCVD risk ≥ 7.5% ifications, along with control of ASCVD risk factors, should be assessed at every visit. Comorbidities influencing use of 00 Bile acid sequestrants can be used as non-statin in statin benefit group 15 alternative to ezetimibe if patient is eze- timibe-intolerant and triglycerides < 300 00 Diabetes mg/dL. 00 ASCVD event within 3 months 00 Mipomersen and lomitapide can be used 00 ASCVD event while taking statin in coordination with a lipid specialist for 00 Poorly controlled ASCVD risk factors patients with familial hypercholesterolemia. 00 Elevated Lp(a) 00 Chronic kidney disease +/- hemodialysis National Lipid Association 00 Heart failure 00 Baseline LDL-C ≥ 190 mg/dL without sec- The National Lipid Association Guidelines Parts 1 ondary causes and 2 also recommend statin therapy as first-line 00 Age ≥ 65 years treatment, with intensity based on LDL-C reduc- 00 Prior myocardial infarction (MI) or tion needed to achieve numeric lipid targets. If non-hemorrhagic stroke treatment goals are not met, especially in high- 00 Current smoking risk and very-high-risk patients, a second or third 00 Symptomatic peripheral artery disease with agent can be considered.3,4 prior MI or stroke 00 Revascularization 00 Residual coronary artery disease after revascularization 00 Low HDL-C 00 Elevated hsCRP 00 Metabolic syndrome

DYSLIPIDEMIA Table adapted from the 2015 National Lipid Association Recommendations for Patient- Centered Management of Dyslipidemia Parts 1 and 2.3,4

Treatment Consider goal drug therapy

Non-HDL-C Non-HDL-C Non-statin therapy LDL-C LDL-C (if goal not Risk category (mg/dL) (mg/dL) Statin intensity achieved)

Low 0–1 major ASCVD < 130 ≥ 190 Drug and dose First-line: ezetimibe risk factors < 100 ≥ 160 selected based on Second-line: reduction needed Moderate 2 major ASCVD risk < 130 ≥ 160 colesevelam to achieve goal. factors < 100 ≥ 130 Third-line: Use high-intensity High T1DM or T2DM and extended-release statin as required. ≤ 1 major ASCVD risk niacin factor Titrate patient to Consider PCSK9i maximally tolerated CKD stage 4 < 130 130 for ASCVD + ≥ statin. LDL-C ≥ 100; HeFH LDL-C ≥ 190 mg/dL < 100 ≥ 100 without ASCVD Presence of ≥ 3 but LDL-C ≥ 130; major ASCVD risk statin-intolerance factors (off-label) Very high Clinical evidence of ASCVD

T1DM or T2DM and ≥ 2 major ASCVD risk factors < 100 ≥ 100 < 70 ≥ 70 Evidence of end- organ damage

End stage chronic kidney disease

Major ASCVD risk factors3 Considerations4

00 Age (male 45 years or older, female 55 00 Elderly patients with one major ASCVD risk years or older) factor should receive formal risk stratifica- 00 Family history of early heart disease (male tion using the Framingham Risk Score or < 55 years, female < 65 years) the Pooled Cohort Equations. 00 Cigarette smoking 00 Patients ≥ 80 years old should be initiated 00 High blood pressure (on medication or at on a moderate-intensity statin for second- least 140/90 mmHg) ary prevention regardless of LDL-C reduc- 00 Low HDL-C (male < 40 mg/dL, female < 50 tion needed based on increased risk of mg/dL) adverse effects. 00 HIV and rheumatoid arthritis can be consid- ered major ASCVD risk factors.

DYSLIPIDEMIA Hypertriglyceridemia REFERENCES (TG ≥ 500 mg/dL)3 1. Eckel RH, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk. Circulation. 00 Intensive lifestyle interventions, including 2014;129:S76–S99. a very low-fat diet, are the mainstay of 2. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the therapy. treatment of blood cholesterol to reduce atherosclerotic 00 ASCVD risk reduction is secondary to pre- cardiovascular risk in adults. Circulation. 2014;129:S1–S45. venting pancreatitis until TG is lowered. 3. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association 00 Goal of therapy is TG < 500 mg/dL. recommendations for patient-centered management 00 Blood glucose control must be achieved. of dyslipidemia: part 1-full report. J Clin Lipidol. 00 Pharmacologic therapy is indicated with 2015;9(2):129–169. potent TG lowering effects (no preference), 4. Jacobson T, Maki KC, Orringer CE, Jones PH, Kris- Etherton P, Sikand, G, et al. National Lipid Association including fibrates, niacin, and omega-3 fatty recommendation for patient-centered management of acids: dyslipidemia: part 2. J Clin Lipidol. 2015;9(6):S1–S122.e1. ➤➤ Add second (and third) non-statin TG 5. Lloyd-Jones DM, Morris PM, Ballantyne CM, Birtcher KK, lowering agent until target achieved. Daly Jr DD, DePalma SM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(14):1785–1822. epub 2017 Sep 5.

Medications and Clinical Pearls

HMG CoA reductase inhibitors

Lovastatin Because of differing half-lives, some statins may be taken at different times of the day to Pravastatin increase efficacy. Simvastatin ➤➤ Simvastatin and fluvastatin should be taken at bedtime. Atorvastatin ➤➤ Lovastatin should be taken with the evening meal. Rosuvastatin ♦♦ Altoprev® (extended-release lovastatin) should be taken at bedtime. Pitavastatin ➤➤ Atorvastatin (Lipitor®), rosuvastatin (Crestor®), pitavastatin (Livalo®), and pravastatin Fluvastatin (Pravachol®) can be taken at any time of day. Atorvastatin/ Myopathy is a common adverse event in the use of statin therapy.1 amlodipine ➤➤ It is often overlooked in the elderly because of comorbid conditions (such as osteoar- Simvastatin/ thritis) and polypharmacy. sitagliptin ➤➤ Myopathy can progress to rhabdomyolysis if left unrecognized in patients. ➤➤ Chances of developing myopathy can be increased owing to drug-drug interactions or duplicate therapies that may increase statin levels. ➤➤ Myopathy is a dose-dependent adverse statin event.2 Percent LDL-C reduction listed in the package insert for each statin dose applies to sta- tin-naïve patients only; once a patient is already receiving a statin, each doubling of the dose results in an incremental 6% LDL-C reduction.

Bile acid resins3

Cholestyramine ➤➤ Is less potent than other classes and not always well-tolerated because of increased GI Colestipol side effects (flatulence, bloating, diarrhea, or constipation). Colesevelam ➤➤ Can increase triglycerides. ➤➤ Can bind to vitamins, hormones, or other medications in the intestines and result in subtherapeutic levels.

DYSLIPIDEMIA Cholesterol absorption inhibitor4

Ezetimibe ➤➤ When used as monotherapy or in addition to statin therapy, significantly decreases TG, Ezetimibe/ LDL-C, and non-HDL-C cholesterol and favorably affects HDL-C levels. atorvastatin ➤➤ Does not interfere with the absorption of TG, fatty acids, bile acids, or fat-soluble Ezetimibe/ vitamins (unlike bile acid resins). simvastatin ➤➤ Is well tolerated, with safety profiles similar to placebo.

Fibrates5

Choline fenofibrate ➤➤ Concomitant use of fibrates may significantly reduce CV risk in patients whose LDL-C is (fenofibric acid) controlled by statin therapy. Fenofibrate ➤➤ Most effective at decreasing plasma triglyceride-rich lipoproteins (TRLs). Gemfibrozil ➤➤ Considered to be well tolerated with an excellent safety profile. ➤➤ Increases tubular secretion of creatinine but does not affect renal function. ➤➤ Can interact with other medications: ♦♦ Rhabdomyolysis with HMG-CoA reductase inhibitors ♦♦ Decreased anticoagulant effect of warfarin derivatives may cause increased bleeding.

Omega-3 acids (fish oils)6

Omega-3 acid ➤➤ Considered as treatment for severe hypertriglyceridemia and high-risk patients with ethyl esters atherogenic dyslipidemia. Icosapent ethyl ➤➤ Prescription-strength omega-3 fatty acids (4 grams per day) have been shown to lower TG levels. ➤➤ Adding omega-3 fatty acids to statin therapy has been shown to help patients reach non-HDL cholesterol goals. ♦♦ Concomitant use has been shown to decrease the risk of major coronary events by 19% when compared to treatment with statin plus a placebo. ➤➤ Unfavorable GI side-effect profile, including belching, bad (fish) breath, heartburn, nausea, and loose stools ♦♦ Freezing capsules before administration and taking with meals can decrease GI side effects.

PCSK9 inhibitors7

Alirocumab ➤➤ Fully human monoclonal antibodies used to lower LDL-cholesterol levels. Evolocumab ➤➤ Given by injection only. ♦♦ Side-effect profile: swelling or rash at injection site, limb pain, and fatigue ➤➤ Long-term side effects are unknown. ♦♦ Target patient populations are adults with primary nonfamilial or heterozygous familial hypercholesterolemia; patients with mixed dyslipidemia, including patients with T2DM; and patients unable to tolerate statins.

Niacin (IR/SR/ER)8

Has been proven to lower total cholesterol, LDL-C, and TG and increase HDL-C. ER Niacin is associated with increased lowering effect on LDL-C and TG, whereas immedi- ate release has shown greater increases in HDL-C. Both ER and immediate release have unattractive side-effect profiles, including flushing and palpitations. Has also been associated with decreased control of diabetes and exacerbations of PUD, gout, and hepatitis.

DYSLIPIDEMIA REFERENCES 5. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart J-C. Mechanism of action of 1. Leaf D. Class act: do statins always have to be taken in fibrates on lipid and lipoprotein metabolism. Circulation. the evening? Clinical Correlations, The NYU Langone On- 1998;98:2088–2093. line Journal of Medicine. 2008 Jan 10. http://www.clinical- 6. Goldberg RB, Sabharwal AK. Fish oil in the treatment of correlations.org/?p=600. Accessed November 16, 2017. dyslipidemia. Curr Opin Endocrinol Diabetes Obes. 2008 2. Hu M. Safety of statins: an update. Ther Adv Drug Saf. Apr;15(2):167–174. 2012 Jun;3(3):133–144. doi: 10.1177/2042098612439884. 7. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with 3. Bersot TP. Drug therapy for hypercholesterolemia and PCSK9 inhibitors—the clinical benefit of lipid drugs. dyslipidemia. In: Brunton LL, Chabner BA, Knollman BC, N Engl J Med. 2015;373:1588–1591. eds. Goodman & Gilman’s The Pharmacological Basis of 8. Cruose JR. New developments in the use of niacin for Therapeutics. 12th ed. New York: McGraw-Hill, 2011 treatment of hyperlipidemia: new considerations in the 4. Shetkar SS, Singh S. Cholesterol absorption inhibitors. In: use of an old drug. Coron Artery Dis. 1996;7(4):321–326. Ghose T, ed. Handbook of Lipidology. New Dehli: JayPee Brothers Medical Ltd. 2016:152–160.

Complementary and Integrative Health Approaches (CIHA)

Many therapies have been studied for treatment There are several studies ongoing in current ani- of hyperlipidemia.1 Given the complex disease mal models for the treatment of hyperlipidemia. state that is greatly affected by lifestyle (diet and Gastrodia elata blume (EGB), acupuncture, and physical activity), it is difficult for many studies traditional Chinese herbs (Chaihu-Shugan-San) using complementary and integrative health have shown favorable results in animal models but approaches to have strong external validity. Many have been limited to no standardized testing in current therapies considered CIHA options are humans.2 Listed next are a variety of CIHA therapy understudied or have variable results. options with current human evidence for their use.

CIHA Efficacy Evidence for Efficacy

Plant stanols Safe ➤➤ Guidelines recommend 2–3 g/day. and sterols ➤➤ Doses > 2g showed no additional benefit. ➤➤ 8.7% greater reduction in LDL-C vs placebo. ➤➤ Competitively inhibits absorption of dietary and biliary cholesterol by competing for space in micelles

Fibers Safe ➤➤ Guidelines recommend 2–10 g/day. ➤➤ Reduction 1.7 mg/dl per gram of fiber. ➤➤ 7.2 g of fiber showed reduction in TG of 4% and LDL-C of 7% compared to placebo. ➤➤ Affect hepatic cholesterol, lipoprotein metabolism, and increase bile acid loss resulting in decreased hepatic cholesterol concentrations and upregulation of LDL-C receptors

Soy protein Safe ➤➤ Upregulate LDL-C receptors; Variable range of doses used in studies. ➤➤ Study 1: 47 g/day average resulted in TC reduction of 9.3%, LDL-C 12.9%, and TG 10.5%. ➤➤ Study 2: meta-analysis reduction in TC of 3.8%, LDL-C 5.3%, TG 5.3%, and increase HDL-C of 3.0% vs placebo. ➤➤ Recent studies showed mixed results inconsistent with previous studies.

Garlic Safe Unclear mechanism of action, theorized to contain sulfur constituents, which inhibit hepatic cholesterol synthesis

DYSLIPIDEMIA CIHA Efficacy Evidence for Efficacy

Guggul Inadequately Contains guggulsterones E/Z, which antagonize bile acid receptors. studied, but Study 1: RCT with 1000-2000 mg guggul extract TID for 8 weeks showed safe no LDL-C reduction vs placebo. ➤➤ Study contradicts smaller studies, which showed benefit.

Red yeast rice Effective, but ➤➤ Fermented rice produces monacolin K. with some ➤➤ Monacolin K contains lovastatin, sterols, and monounsaturated fatty danger acids. ➤➤ Inhibits endogenous synthesis of cholesterol. ➤➤ Lovastatin dose per capsule of red yeast rice is variable and manufactur- ing underregulated.

Policosanol Inadequately ➤➤ Cuban product from sugarcane; is not available in the US. studied, but ➤➤ 10 mg/day showed LDL-C reduction of 23.7%, TC 16.2%, and HDL-C safe increase of 10.6% in Cuban studies. ➤➤ Inhibit hepatic cholesterol synthesis with theorized effect on LDL binding, uptake, and degradation

Vacciniam Inadequately ➤➤ 52 patients randomized to fruit extract (45 mg BID) vs placebo for 4 arctostaphylos3 studied, but weeks showed reduction in TC, LDL-C, and TG and no change in HDL-C. safe

Co-enzyme Q10 Safe ➤➤ Current phase 3 study under investigation: Co-Q10 + Vitamin E vs Co-Q10 vs placebo examining effects on lipid profiles.4 ➤➤ Addition of Co-Q10 (200 mg/day) to statin therapy reduced the intensity of statin adverse effects.5 ➤➤ Improve cholesterol efflux from macrophages. ➤➤ Antioxidant helps prevent statin- induced adverse events (myopathy).

REFERENCES levels and oxidative stress in adult patients with hyperlipidemia: a randomized, double-blind, placebo- 1. Nies LK, Cymbala AA, Kasten SL, Lamprecht DG, Ol- controlled clinical trial. son KL. Complementary and alternative therapies for Evid Based Complement Alternat Med. 2014;Article ID 217451:1–6. the management of dyslipidemia. Ann Pharmacother. 4. Zhangpeiwen. The effects of dietary supplement of 2006;40:1984–1992. coenzyme Q10 (CoQ10) on dyslipidemia (TEDSCD). 2. Qidwai W, Jahan F, Nanji K. Role of complementary https://clinicaltrials.gov/ct2/show/ and alternative medicine in controlling dyslipidemia. ClinicalTrials.gov. 2015. NCT02407548. Evid Based Complement Alternat Med. 2014;Article ID 5. Toth S, Sajty M, Pekarova T, Mughees A, Stefanic P, Katz M, 215731:1–2. et al. Addition of omega-3 fatty acid and coenzyme Q10 3. Soltani R, Hakimi M, Asgary S, Ghanadian SM, Keshvari M, to statin therapy in patients with combined dyslipidemia. Sarrafzadegan N. Evaluation of the effects of vaccinium . 2017 Jul 26;28(4):327–336. arctostaphylos l. fruit extract on serum lipids and hs-CRP J Basic Clin Physiol Pharmacol

DYSLIPIDEMIA Monitoring and Follow Up

At every visit, health care providers should rein- Refer to lipid specialist4 force adherence to therapeutic lifestyle changes and pharmacologic therapy for dyslipidemia. 00 Patients with LDL-C ≥ 190 mg/dL 00 Children and adolescents 00 Pregnancy Monitoring 00 Heterozygous or homozygous familial hypercholesterolemia 1,2,3 Efficacy 00 Statin intolerance (after rigorous assessment)

00 Fasting lipid panel (including total choles- terol, HDL-C, triglycerides, and calculated Assessing Adherence4 LDL-C) at baseline 00 Evaluate health literacy. 00 Repeat 4–12 weeks after initiation of drug therapy, then every 3–12 months as clinically 00 Establish a comfortable relationship indicated. between the patient and provider. 00 Monitor prescription refill data (eg, elec- 00 If numeric lipid targets included as part of treatment plan, monitor frequently until tronic medical record, pharmacy records, goal achieved, then every 4–12 months to insurance billing). assess maintenance of goal lipid levels and 00 Conduct direct discussion with patient. ➤ adherence. ➤ How many missed doses in the last month? ➤ Safety1 ➤ What adverse effects have you experi- enced from your medication? Timeline for Monitoring ➤➤ What are some of the reasons you do not take your medication? (Address cost 3 months after Every if necessary.) Drug class Baseline initiation 6 months 00 Administer validated questionnaire, such as the 8-item Morisky Medication Adherence Statins* LFT Scale (MMAS-8).5 Ezetimibe LFT Niacin LFT LFT LFT Strategies to Improve Adherence4 Blood Blood Blood glucose glucose glucose 00 A multidisciplinary health care team, includ- Uric acid Uric acid Uric acid ing pharmacists, is optimal for maximizing

Fibrates Renal Renal Renal medication adherence through identification function function function of and solutions to barriers to adherence. 00 SIMPLE6: Bile acid Lipid Lipid Lipid ➤➤ Simplify the regimen. sequestrants panel panel (TG) panel (TG) ➤➤ Impart knowledge. (TG) ➤➤ Modify patient beliefs and behavior. Abbreviations: LFT = liver function tests (hepatic transaminases); TG = ➤➤ Provide communication and trust. triglycerides *Check creatine kinase if muscle symptoms develop. ➤➤ Leave the bias. ➤➤ Evaluate adherence (bring all medica- tions to each visit, ask direct questions, technological intervention).

DYSLIPIDEMIA REFERENCES 1. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the SIMPLE6 treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2014;129:S1–S45. 2. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association S Simplify the regimen. recommendations for patient-centered management of dyslipidemia: part 1-full report. J Clin Lipidol. 2015;9(2):129–169. I Impart knowledge. 3. Lloyd-Jones DM, Morris PM, Ballantyne CM, Birtcher KK, Daly Jr DD, DePalma SM, et al. 2017 focused update of the Modify patient beliefs and 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the M behavior. management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task Provide communication and trust. force on expert consensus decision pathways. J Am Coll P Cardiol. 2017;70(14):1785–1822. epub 2017 Sep 5. 4. Jacobson T, Maki KC, Orringer CE, Jones PH, Kris- Leave the bias. Etherton P, Sikand, G, et al. National Lipid Association L recommendation for patient-centered management of Evaluate adherence (bring all dyslipidemia: part 2. J Clin Lipidol. 2015;9(6):S1–S122.e1. 5. Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive medications to each visit, ask E validity of a medication adherence measure for direct questions, technological hypertension control. J Clin Hypertens. 2008;10(5):348– intervention). 354. 6. Atreja A, Bellam N, Levy SR. Strategies to enhance patient adherence: making it simple. MedGenMed. 2005;7(1):4.

Practical Clinical Management Tips

Statin intolerance1 those with differing metabolic path- ways and half-lives. Dosing regimens 00 Muscle-related side effects are common that have been studied include every with statin therapy, but true statin intoler- other day and twice weekly (with ance is uncommon. statins that have long half-lives such as 00 Rule out other causes of myalgia (recent rosuvastatin). exercise, hypothyroidism, and vitamin D defi- 00 The American College of Cardiology Sta- ciency) to determine true statin intolerance. tin Intolerance App is available for free for 00 Drug-drug interactions that can increase both Apple and Android devices, along statin levels in the body must also be with a web-based version.2 evaluated. ➤➤ The app is based on 2013 ACC/AHA 00 Women, patients of Asian descent, and the Blood Cholesterol Guidelines3 and eval- elderly may be at increased risk for sta- uates statin intolerance to work through tin-related myalgias. steps to manage and treat the patient, 00 Testing for true tolerance: and to complete basic risk assessment. ➤➤ discontinue the offending statin therapy ➤➤ Non-statin medications should not be until muscle-related side effects have considered for therapy until statin intol- subsided erance has been thoroughly evaluated ➤ ➤ rechallenge with at least two to three and documented. alternate statin medications, preferably

DYSLIPIDEMIA Guideline changes2 REFERENCES 1. Lloyd-Jones DM, Morris PM, Ballantyne CM, Birtcher KK, 00 Recent changes in hyperlipidemia treat- Daly Jr DD, DePalma SM, et al. 2017 focused update of the ment guidelines have shifted from a treat- 2016 ACC expert consensus decision pathway on the role to-target approach to new treatment goals of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease based on a percentage decrease from risk: a report of the American College of Cardiology task baseline readings. force on expert consensus decision pathways. J Am Coll 00 Guidelines now separate patients into Cardiol. 2017;70(14):1785–1822. epub 2017 Sep 5. four groups for primary and secondary 2. American College of Cardiology tools and practice support: ACC statin intolerance app. http://www.acc.org/ prevention of hyperlipidemia, with each statinintoleranceapp. group having a recommendation for statin 3. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, intensity. Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic Current treatment guideline recommendations cardiovascular risk in adults. Circulation. 2014;129:S1–S45. include the following: 4. Zanni GR. Hyperlipidemia: updated guidelines impact counseling. Pharmacy Times. Updated: December 10, 2014. 00 Statin therapy is considered first-line treat- http://www.pharmacytimes.com/publications/issue/2014/ december2014/hyperlipidemia-updated-guidelines- ment for lowering cholesterol. impact-counseling. Accessed November 18, 2017. 00 Other agents, such as niacin, bile acid res- ins, and fibrates, are reserved for statin-in- tolerant patients or for those not reaching their target goals on statins alone.

Pharmacogenomics Implications

Drug: Simvastatin; Gene: SLCO1B1 Informative PGx CPIC Guideline

➤➤ Individuals with 1 copy of the variant SLCO1B1 gene where cytosine replaces thymine at position 521 of the coding region of the gene (c.521T>C) are considered to have an “intermediate function” phenotype, and individuals with 2 copies of this variant form are considered to have a “low function” phenotype.1 ➤➤ As compared with individuals with a “normal function” SLCO1B1 phenotype, intermediate function and poor function phenotype individuals are at intermediate and high risk of simvastatin-induced myopathy, respectively.1,2

SLCO1B1 Phenotype and related recommendation

Low function Intermediate function Normal function

Potential toxicity: Potential toxicity: Drug use as described in package labeling. Use lower dose of drug or Use lower dose of drug or choose choose an alternative. an alternative.

REFERENCES 2. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 1. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical 2014 update. Supplemental Material. https://cpicpgx.org/ Pharmacogenetics Implementation Consortium guideline content/guideline/publication/simvastatin/2014/ for SLCO1B1 and simvastatin-induced myopathy: 2014 24918167-supplement.pdf. Accessed June 13, 2018. update. Clin Pharmacol Ther. 2014;96(4):423-428.

DYSLIPIDEMIA Cultural Sensitivities and Health Disparities

Impact on specific populations 00 Black and Hispanic adolescent females tend to have lower rates of physical 00 Racial and ethnic minority populations in activity compared with their white the United States, excepting blacks, have counterparts.6 been found to have a higher incidence 00 Blacks and Hispanics have been shown to of elevated triglycerides compared with receive vascular care at health care facili- non-Hispanic whites. Additionally, most ties that perform a lower volume of proce- minority groups, except for blacks and dures and have higher mortality rates after Japanese Americans, have a higher coronary bypass surgery and myocardial incidence of low HDL cholesterol, and the infarcation.7 incidence of elevated LDL is increased 00 Mexican Americans tend to be less likely among Asian Indians, Filipinos, Japanese, to be aware of or treated for dyslipidemia, and Vietnamese individuals when while blacks have lower rates of medication 1 compared with non-Hispanic whites. adherence compared with non-Hispanic 00 Among minority populations, Hispanics, whites.7 Asian Indians and Filipinos are at the highest risk for dyslipidemia and have higher coronary heart disease mortality rates.2 Cultural Considerations 00 Older adults have a higher incidence of 00 Food choices and physical activity are dyslipidemia versus younger age groups greatly influenced by culture (beliefs, values, and premenopausal women tend to have and attitudes).7 lower rates of elevated LDL cholesterol ➤➤ Economic factors are closely linked to 3 versus their male counterparts. food availability. ➤➤ Recent immigrants and individuals of Barriers to care lower socioeconomic position may not have easy access to healthy foods. 00 In households of lower socioeconomic ➤➤ Low-cost foods can often be high in fat position, diets tend to be higher in and oils. saturated fats, which can lead to increased ➤➤ Cultures with diets high in saturated 4 cholesterol levels. fat can have an increased risk of 00 Lack of education can hinder understand- dyslipidemia. ing of the relationship between food and ♦♦ The Seven Countries Study compared cholesterol. food habits in the US, Japan, Northern ➤ ➤ One survey of black teens and young Europe, and Southern Europe. The adults in Phoenix Arizona showed that study confirmed that high blood 70% had knowledge of the relationship cholesterol increased risk for heart between cholesterol and heart disease, disease. In this study, patients who but only 49% had awareness that ate a Mediterranean diet had reduced reducing intake of animal products risk of coronary heart disease.8 could lower CHD risk.5

DYSLIPIDEMIA 00 Traditional Hispanic diets have been shown REFERENCES to include high levels of fiber. 1. Frank AT, Zhao B, Jose PO, Azar KM, Fortmann SP, ➤➤ Studies show that the diets of US-born Palaniappan LP. Racial/Ethnic Differences in Dyslipidemia Patterns. Circulation. 2014;129(5):570–579. doi:10.1161/ Hispanics include higher levels of fat CIRCULATIONAHA.113.005757. and sugar when compared to traditional 2. Pu J, Romanelli R, Zhao B, Azar KMJ, Hastings KG, Nibal V, diets because of less access to good et al. Dyslipidemia in special ethnic populations. Cardiol quality, nutritious foods.2 Clin. 2015 May;33(2):325–333. 3. Stratton MA, Jordan AH, Harrison DL, Jacobs EW, Skaggs ➤➤ Latin American immigrants often adopt VJ. Disparities in the prevalence of medication therapy poor eating habits in the United States, for hyperlipidemia in the elderly. Consult Pharm. 2007 consuming higher fat meals, larger Oct;22(10):847–854. portions, and fewer fruits and 4. Institutes of Health. High blood cholesterol: what you need to know. NIH Publication No. 05-3290. 7 vegetables. Originally printed May 2001. Revised June 2005. 00 Traditional East Asian diets are lower in https://catalog.nhlbi.nih.gov/sites/default/files/ total and saturated fats when compared publicationfiles/05-3290.pdf. 5. Winham DM, Jones KM. Knowledge of young African to traditional western and Asian Indian American adults about heart disease: a cross-sectional 2 diets. survey. BMC Public Health. 2011;11:248. doi:10.1186/ ➤➤ Chinese immigrants living in the United 1471-2458-11-248. States for prolonged periods of time 6. Kimm SY, Glynn NW, Kriska AM, Barton, BA, Kronsberg SS, Daniels SR, et al. Decline in physical activity in black girls have been shown to consume diets con- and white girls during adolescence. N Engl J Med. 2002 taining unhealthy foods and to have less Sep 5;347(10):709–715. physical activity in their daily routines.2 7. Davis AM, Vinci LM, Okwuosa TM, Chase AR, Huang ES. Cardiovascular health disparities: a systematic review of health care interventions. Med Care Res Rev. 2007 Oct;64(5 Suppl):29S–100S. 8. Winham, DM. Culturally tailored foods and CVD prevention. Am J Lifestyle Med. 2009;3(1):64S–68S. 9. Kromhout D. Serum cholesterol in cross-cultural perspective. The Seven Countries Study. Acta Cardiol. 1999Jun;54(3):155–158.

Special Populations

Part 2 of the 2015 National Lipid Association 00 Discontinue all lipid-lowering therapies (NLA) Guidelines focuses on several major patient (except bile acid sequestrants) when populations that were omitted from the 2013 a woman becomes pregnant or during ACC/AHA Guidelines and only briefly addressed attempts to become pregnant. (if at all) in Part 1 of the NLA Guidelines.1,2 00 Hypercholesterolemia during pregnancy and lactation may be treated with bile acid sequestrants. Pregnancy2

00 Screen for dyslipidemia before pregnancy Pediatrics2 or as soon as possible once pregnancy is 00 Diet, increased physical activity, and other determined. lifestyle modifications should be recom- 00 Avoid pregnancy if possible while taking mended in children and adolescents when lipid-lowering therapies (except bile acid overweight or obese; diet should be guided sequestrants). by a dietitian or nutritionist when possible.

DYSLIPIDEMIA 00 Consider screening children 2 years of age ➤➤ Caution should be used when assessing and older for dyslipidemia if one or both non-lipid risk factors such as HTN, over- biological parents have hypercholester- weight or obesity, and physical inactivity olemia or are taking cholesterol-lowering when determining ASCVD risk. medications, the child has an expanded ➤➤ African Americans have a lower inci- first-degree relative with a premature dence of metabolic syndrome and lower ASCVD event, or family history is unknown. TG and higher HDL-C. 00 Consider regular screening for children ➤➤ Incidence of T2DM is higher in African with ASCVD risk factors and conditions Americans. associated with increased ASCVD risk ➤➤ African American individuals should gen- (no valid screening methods in patients erally be treated according to NLA Part 1 < 20 years of age). guidelines. 00 Children ≥ 8 years of age should be con- 00 South Asian patients sidered for pharmacologic lipid-lowering ➤➤ Patients of South Asian descent have a therapy if LCL-C is ≥ 190 mg/dL and/ higher incidence of insulin resistance and or non-HDL-C is ≥ 220 mg/dL. accompanying metabolic disturbances. 00 Moderate evidence of efficacy and safety ➤➤ South Asians have an increased incidence exists for statins and bile acid sequestrants of metabolic syndrome and have different in children and adolescents; minimal waist circumference for defining obesity. evidence exists to support use of ➤➤ In general, South Asian patients should be cholesterol absorption inhibitors. treated according to NLA Part 1 guidelines. 00 Potential side effects of all pharmacologic ➤➤ Monitoring for statin-induced diabetes lipid-lowering therapy should be closely is indicated because South Asians are at monitored. increased risk. 00 American Indian and Alaska Native patients ➤ Ethnic groups2 ➤ American Indians and Alaska Natives have higher prevalence and incidence of 00 ASCVD risk burden varies greatly depend- ASCVD and some risk factors including ing on country of origin or descent. obesity, metabolic syndrome, diabetes 00 Overall, treatment is largely the same with mellitus, and cigarette smoking. additional considerations for risk assessment ➤➤ Clinicians should screen for and manage (incidence and risk for each ethnic group is in dyslipidemia according to NLA Part 1 comparison to non-Hispanic white patients). guidelines with strong emphasis on life- 00 Hispanic/Latino patients style therapy. ➤➤ Hispanics/Latinos have a greater preva- lence of high TG and low HDL-C. High-risk patients2 ➤➤ LDL-C levels tend to be higher in Hispanic men. 00 Human immunodeficiency virus (HIV) ➤➤ Hispanics/Latinos have a higher preva- ➤➤ HIV-infected individuals are at increased lence of T2DM, obesity, and metabolic risk for ASCVD. syndrome. ➤➤ Fasting lipid panel should be obtained in ➤➤ Some risk assessment tools may all newly diagnosed individuals with HIV over­estimate risk in Hispanic/Latino before and after starting antiretroviral individuals. therapy (ART). ➤➤ Hispanics/Latinos should be treated ➤➤ For primary ASCVD prevention, HIV according to the NLA part 1 guidelines should be considered an additional risk with special considerations. factor for risk assessment. 00 African American patients ➤➤ Non-HDL-C and LDL goals per the NLA ➤➤ African Americans are at increased risk Part 1 guidelines should be followed for of ASCVD; however, ASCVD risk is less HIV-infected patients. driven by dyslipidemia.

DYSLIPIDEMIA ➤➤ Statin therapy is first-line therapy for 00 Residual risk (patients who need additional lipid lowering in patients with HIV. lipid lowering after maximally tolerated ➤➤ Caution with drug-drug interactions statin)2 between lipid-lowering therapy and ART. ➤➤ First-line adjunctive therapy: ezetimibe 00 Rheumatoid arthritis (RA) ➤➤ Second-line adjunctive therapy: ➤➤ Patients with rheumatoid arthritis are at colesevelam increased risk for ASCVD. ➤➤ Third-line adjunctive therapy: extended ➤➤ For primary prevention of ASCVD, RA release niacin may be counted as a separate risk factor for risk assessment. REFERENCES ➤➤ Statins are generally the first-line treat- 1. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, ment for lipid lowering in patients with RA. Jones PH, et al. National Lipid Association recommenda- ➤➤ Lipid panels may not be reliable if tions for patient-centered management of dyslipidemia: part 1-full report. J Clin Lipidol. 2015;9(2):129–169. obtained during a flare and should be 2. Jacobson T, Maki KC, Orringer CE, Jones PH, Kris- re-checked once patient is stable. Etherton P, Sikand, G, et al. National Lipid Association ➤➤ Patients with RA should generally be recommendation for patient-centered management of treated according to NLA Part 1 guidelines. dyslipidemia: part 2. J Clin Lipidol. 2015;9(6):S1–S122.e1.

Interprofessional Collaborative Practice

Pharmacist counseling can play a significant role 00 Patients working with pharmacists have in managing patients with hyperlipidemia. Import- been shown to achieve greater reductions ant counseling points include the following: in LDL compared with patients treated by teams without clinical pharmacists. 00 Initial evaluation and explanation of hyper- 00 Reduction in LDL for patients managed lipidemia, including assessment of LDL-C, by multidisciplinary teams including clini- HDL-C, triglycerides, and overall cholesterol cal pharmacists was shown to be between levels 5% and 22% greater than those teams 00 Explanation and patient understanding of without, even for inpatient populations the importance of modifiable factors such as diet and exercise, discussing issues such who presented with higher risk factors for as the following: hyperlipidemia. 00 ➤➤ Difference between good and bad fats These short-term outcomes can likely be ➤➤ Motivation to read product labels and extrapolated to show fewer CV events, limit the intake of saturated fats improved quality of life and lower health- ➤➤ Importance of healthy diet and exercise care related costs for patients with dyslip- to aid in reaching cholesterol goals idemias, showing again the importance of ➤➤ Importance of maintaining a healthy weight interprofessional collaborative practice. ➤➤ Tobacco cessation 00 Review of baseline readings and percent- REFERENCES age targets, as well as consequences of 1. Interprofessional Education Collaborative. Core compe- high cholesterol such as: tencies for interprofessional collaborative practice: 2016 update. Washington, DC: Interprofessional Education Col- ➤➤ Heart attack laborative; 2016. https://www.tamhsc.edu/ipe/research/ ➤➤ Stroke ipec-2016-core-competencies.pdf. ➤➤ Vascular disease 2. Till TL, Voris JC, Horst JB. Assessment of clinical pharmacist management of lipid-lowering therapy in a ➤➤ Atherosclerosis primary care setting. J Manag Care Spec Pharm. 2003 00 Recommend and emphasize regular choles- May;9(3):269–273. terol level evaluation, starting at age 35 for men and age 45 for women

DYSLIPIDEMIA