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; ➤0 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 ➤ 0 Elevated chylomicrons response to excess lipids, and this process is ➤ 0 Elevated triglycerides (TG) the basis of most acute coronary syndromes: ➤0 Elevated total cholesterol (TC) ➤0 LDL particles with a cholesterol and ➤ 0 Elevated low-density lipoproteins (LDL-C) triglyceride core enter the arterial wall. ➤ 0 Decreased high-density lipoproteins Macrophages consume these lipids and (HDL-C) trigger inflammation. 00 Cholesterol Transport and Removal2 ➤0 The resulting lipid core/macrophage ➤ 0 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 ➤0 As the plaque grows, the arterial wall convert it into Chylomicron remnants. expands into the artery lumen. ➤0 Chylomicron remnants travel to the liver ➤0 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- ➤ 0 VLDL particles travel through the blood- gether, causing ischemia. stream where they are broken down ➤0 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 ➤0 Total cholesterol (TC) apolipoproteins years on ➤0 Low-density lipoprotein (LDL-C; 00 Overproduction of lipids or beta-apolipo- adults 20 calculated) proteins (LDL) years of ➤0 High-density lipoprotein (HDL-C) 00 Underproduction of alpha-apolipoproteins age and ➤0 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 ➤0 Focus on prevention of atherosclerotic cardiovascular disease (ASCVD; eg, MI, angina, College of statin therapy stroke, PAD, revascularization). Cardiology/ ➤0 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 ➤0 Guideline organized by statin benefit groups. Association ➤0 Risk assessment conducted using Pooled Cohort Equations, which predicts a 10-year blood risk of ASCVD. cholesterol ➤0 No specific numeric goals of treatment, but rather proportional benefit is seen as com- guideline pared to the patient baseline. ➤0 In patients without clear indications, risk and benefit should be weighed for statin therapy. ➤0 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. ➤0 Guideline recommends moderate- to high-intensity statins for most patients. Statin benefit ➤0 Patients ≥ 21 years of age for whom the ASCVD risk reduction clearly outweighs the risk groups of adverse events ➤0 Secondary prevention in individuals with clinical ASCVD ➤0 Primary prevention in individuals with LDL-C ≥ 190 mg/dL ➤0 Primary prevention in individuals with diabetes (but no ASCVD), 40 to 75 years of age, with LDL-C 70 to 189 mg/dL ➤0 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 ➤0 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 ➤0 < 5% 10-year ASCVD risk, or < 40 years old or > 75 years old moderate ➤0 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 ➤0 Historically useful for both health care providers and patients to monitor progress.