PHP327 Lipids Week 5 Fall 2024 PDF

DYSLIPIDEMIA PATHOPHYSIOLOGY & PHARMACOTHERAPY Joseph A. Nardolillo, PharmD, BCACP (he/him/his) Assistant Professor, Pharmacy Practice and Clinical Research PHP327 – CTS I, Fall 2024 Dr. Joe Nardolillo Assistant Professor of Pharmacy Practice Training and Education...

DYSLIPIDEMIA PATHOPHYSIOLOGY & PHARMACOTHERAPY Joseph A. Nardolillo, PharmD, BCACP (he/him/his) Assistant Professor, Pharmacy Practice and Clinical Research PHP327 – CTS I, Fall 2024 Dr. Joe Nardolillo Assistant Professor of Pharmacy Practice Training and Education PharmD – University of Rhode Island PGY1 – Indian Health Service PGY2 – University of Colorado Board-certified ambulatory care Mix of research and clinical practice! LIPIDS! and cardiometabolic risk LGBTQ+ health and equity HIV Pharmacy-based services in primary care Learning Objectives Pathophysiology Describe the components of lipoproteins and their functions in the body Explain the steps of lipid metabolism through the exogenous and endogenous pathways Identify risk factors for dyslipidemia and ASCVD Describe different types of dyslipidemias Learning Objectives Pharmacotherapy Utilize clinical information and calculators to assess ASCVD risk Describe the mechanism of action, side effects, and counseling points for statins and non-statin agents Apply patient characteristics to select appropriate lipid-lowering therapies to manage dyslipidemia and reduce ASCVD risk Develop monitoring and follow-up plans, including steps to further optimize therapies or manage adverse effects related to the management of dyslipidemia Readings Chapter 32 – Dipiro’s Pharmacotherapy Dixon DL, Riche DM, Kelly MS. Dyslipidemia. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed October 01, 2024. https://accesspharmacy-mhmedical-com.uri.idm.oclc.org/content.aspx? bookid=3097&sectionid=267225800 2018 AHA/ACC/Multisociety Guideline Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3168-3209. doi:10.1016/j.jacc.2018.11.002 Videos for Clarifications Cholesterol Good and Bad by the US National Library of Medicine https://tinyurl.com/yx6a5ufj Physiology of Lipoprotein Cholesterol by Armando Hasudungan https://tinyurl.com/hcy239y Physiology of Lipoprotein Metabolism by National Heart, Lung, and Blood Institute https://tinyurl.com/pwo856o Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up See Week 1 content from Dr. Cohen regarding the full overview of atherosclerosis We will briefly review key terminology relevant to dyslipidemia ASCVD and Terminology ASCVD Atherosclerotic Cardiovascular Disease (ASCVD) is the build up of Heart Brain plaque within arteries, limiting the blood flow to organs Coronary Artery Disease (CAD) Ischemic Stroke Differentconditions or terminology are used to Ischemic Heart Cerebrovascular specify ASCVD based upon Disease disease location of plaque and impacted organs Extremities Various (Legs) Locations Does not include conditions of the venous system (e.g., Peripheral venous thromboembolism) Artery Disease (PAD) Aorta, etc. Primary vs. Secondary Risk Secondary Prevention Primary Prevention Any history of diagnosis of No history of diagnosis of ASCVD, also known as an ASCVD or events “event” “Patients that have not yet had “Patient has already had an an event, but are at increased ASCVD event and are at risk of risk of an event occurring” developing another event”  Progression of ASCVD Terms Image: https://my.clevelandclinic.org/health/diseases/16753-atherosclerosis-arterial-disease  Progression of ASCVD Occlusion Fatty Complicated and Streaks Normal Lesions decreased Develop Artery Plaque + oxygen Increased supply Thrombosis risk factors ASCVD event Dyslipidemia + Additional Risk Factors + Inflammation = Risk of ASCVD c  The “Clogged Pipes” Pour things Water isn’t Water runs Call the down the draining as fine drain fast… plumber! Review Question #1 Which of the following is NOT considered to indicate a diagnosis of ASCVD? A. Heart attack B. Stroke C. Angina pectoris D. Venous thromboembolism Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up  What is a lipid? Lipids are the broad class of compounds used throughout the body to maintain critical functions Fats, wax, vitamins Organic, carbon-containing molecules Often, long-chain molecules Largely water-insoluble, but some are amphiphilic Lipophilic, hydrophobic, or “water hating amphiphilic, meaning different parts of the lipid are attracted to unpolarized (fats) or polarized (water) molecules The more hydrogens, single-bonds the more “saturation” Image: https://en.wikipedia.org/wiki/Lipid  Lipids throughout the body Phospholipids are in every cell of the body (along with cholesterol) to create the cell membrane Triglycerides store and transport energy Fatty Acids are metabolized for energy Cholesterols are larger molecules that can be broken down into hormones, bile acids, and help metabolize fats Image: https://my.clevelandclinic.org/health/body/24425-lipids  Cholesterol Vitamins D, K, etc. Cholesterols are large molecules with a wide variety of metabolic Steroid functions and Hormones Atherosclerosis Aldosterone, metabolites Cortisol Cholesterol Sex Hormones Estrogen, Bile Acids Testosterone Image: https://en.wikipedia.org/wiki/Cholesterol Triglycerides Tri - - glycer - - ide What do each of these words mean? Lipoproteins LIPO Fatty acids PROTEIN Cholesterol Apoproteins Triglycerides Lipoproteins vary into multiple categories based upon their size, ratio of lipids to proteins, and specific apolipoproteins Based upon these characterizes, they have unique roles in atherosclerosis  Types of Lipoproteins Lipoproteins are used to carry cholesterol throughout the body because fatty acids are lipophilic and cannot transport through blood There are 4 main categories of lipoproteins Chylomicrons Very-low-density lipoprotein (VLDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL) The combination of each of these individual components is known as total cholesterol Solnica B, et al. Arch Med Sci. 2020 Mar 2;16(2):237-252. doi: 10.5114/aoms.2020.93253  Types of Lipoproteins As the particles INCREASE IN SIZE they are LESS DENSE, More triglycerides, less protein More triglycerides indicates, more fatty acids, and more ASCVD risk Chylomicrons are the largest, least dense molecules and contain the most fatty acids HDL is the smallest, most dense, and contain the least fatty acids “Good Cholesterol” Solnica B, et al. Arch Med Sci. 2020 Mar 2;16(2):237-252. doi: 10.5114/aoms.2020.93253 Apoproteins and ASCVD risk Eachmolecule contains unique apoproteins to guide its action in cholesterol metabolism and development of ASCVD ApoA, ApoB, ApoC, ApoD, ApoE Subtypes indicate further action – ApoB-48 vs. Apo-B-100 B (ApoB) – indicates Apolipoprotein INCREASED risk of ASCVD Lp(a) or “L-P-Little a” HDL does not contain ApoB, but rather is a genetic molecule with an ApoA, ApoE and ApoC, and therefore, does unknown mechanism. that is not increase ASCVD related to increased ASCVD when Chylomicrons, VLDL, LDL all contain ApoB, elevated, similar to LDL. It is an and are known as “non-HDL” emerging target of medications Review Question #2 Which of the following statements is true regarding lipoproteins? A. All lipoproteins increase risk of ASCVD B. HDL contains the least triglycerides of all lipoproteins C. ApoB is included on all lipoproteins except for LDL D. Lipids include a broad group of fats, including glucose The “Clogged Pipes” Lipoproteins transport fatty acids which are the “food” that get stuck in the drain! Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up Overview of Cholesterol Synthesis and Metabolism A. Exogenous Pathway B. Endogenous Pathway C. Reverse Cholesterol Transport A.) Exogenous pathway Exogenous – Cholesterol outside the body…from food! Fattyacids are eaten, digested by bile in the GI track, and are encapsulated into micelles to be carried through the lumen FattyAcids → Triglycerides and incorporated into Chylomicrons Chylomicrons are rare in “fasting” or without food Conversion through LPL or lipoprotein lipase transports triglycerides to tissues throughout the body and remnants arrive at the liver to bind to the LDL receptor B.) Endogenous pathway Endogenous – production of lipoproteins from inside the body In the liver, fatty acids from remanent chylomicrons combine with glucose to be converted into cholesterol Glucose → pyruvate → acetyl-CoA →…metabolized by HMG-CoA reductase →cholesterol Cholesterolis packaged with other TG, proteins, into VLDL in the liver. HDL is also created with minimal triglycerides B.) Endogenous Pathway VLDL is released from the liver, LPL continues to “drop off” triglycerides for energy or storage Storage results in increased adipose tissue VLDL continues to release the triglycerides, leaving an LDL particle LDL is mainly cholesterol with minimal triglycerides LDL provides tissues with cholesterol for hormones and cell membranes. Excess cholesterol is placed in arteries resulting in plaque formation and atherosclerosis LDL is returned to the liver through the LDL-receptor and repackaged into VLDL or excreted through bile HDL, as the “good cholesterol” picks up the excess cholesterol to be transported back to the liver, rather than leaving it to form plaques C. Reverse cholesterol transport HDL from the liver and Apo A from the gut transport cholesterol back to the liver “scavengers” Cholesterolthat is not needed in the periphery is brought to the surface, harvested by HDL HDL gives the cholesterol back to the ApoB-containing molecules, which will turn to LDL and returns to the liver at the LDL receptor (back to step B) HDL subtypes are then further recycled and the process continues Summary of Cholesterol Synthesis and Metabolism The three processes work in harmony to maintain cholesterol levels Homeostasis Risk factors, such as a high-fat diet, lead to more triglycerides transported to the liver from chylomicrons and subsequently more cholesterol...and so it continues Cholesterol deposited by LDL leads interacts with the endothelial wall of the vasculature leading to anthogenesis  Result of LDL depositing cholesterol Anthogenesis – plaque formation via cholesterol + inflammatory processes LDL (and other lipoproteins) that deposit remnant cholesterol enter the vessel walls. LDL undergoes oxidation,, are taken up by macrophages without order (unregulated), leading to endothelial dysfunction. ↓ Nitric Oxid, producing vasoconstriction Oxidation and macrophages are an inflammatory process  Result of LDL depositing cholesterol Foam cells are formed, developing small plaques known as “fatty streaks” Over many years, macrophages will destabilize the plaques as they accumulate by deregulating the collagen matrix of a plaque, making them unstable Unstable plaques lead with a thrombus to produce an ASCVD event Review Question #3 Which of the following definitions best describes the components' role within the cholesterol synthesis pathway A. Chylomicrons – maintains the exogenous pathway B. HDL – deposits cholesterol to the vasculature C. LDL - returns to the liver to be recycled D. VLDL – released by the liver to deposit triglycedies and cholesterol The “Clogged Pipes” The food builds up in the pipes, even with the help of some occasional unclogging Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up Dyslipidemia Conditions and Classifications Dyslipidemia - The broad terminology for lipid abnormalities Step 1 – What is causing the dyslipidemia? Primary or Familial – Significant elevations in cholesterol likely leading to premature ASCVD (occurring at a young age) Dyslipidemias Caused abnormalities in the presence and expression of certain genes occur due to a Heterozygous (one gene abnormal, one gene normal) mix of genetic Homozygous (both genes abnormal) and environmental factors Secondary or Acquired – Abnormalities (mainly elevation) due to environmental factors or exposures Caused by the “4 Ds Classification” – diet, drugs, disorders, diseases Dyslipidemia Conditions and Classifications Step 2 – What lipoproteins are impacted? Hypercholesterolemia elevated cholesterol above their goal based upon ASCVD** Hypertriglyceridemia Dyslipidemias occur due to a Elevated triglycerides > 150 mg/dL (severe >500 mg/dL) mix of genetic Hypocholesterolemia and low cholesterol** (less common) environmental Low HDL – low HDL cholesterol factors Common, often accompanying other metabolic conditions Familial or Primary Hypercholesterolemia Heterozygous (one gene abnormal, one gene normal) 1 in 250 individuals. LDL-C >190 mg/dL Homozygous (both genes abnormal) 1 in 1,000,000 individuals. LDL-C >500 mg/dL Suspicious of familial 160 mg/dL 20 years or older: LDL-C >190 mg/dL Family member’s total cholesterol >240 mg/dL Xanthoma (fatty deposits) at any age Cascade Screening – Test family members if genetic abnormalities are identified in a patient Clinical Presentation - Dyslipidemia Most patients with dyslipidemia are asymptomatic Dyslipidemia is often accompanied by other risk factors for ASCVD Abdominal obesity** Atherogenic dyslipidemia Increased blood pressure** Insulin resistance and/or glucose intolerance** Prothrombotic or proinflammatory state Patients with three or more of these abnormalities are considered to have the metabolic syndrome Signs of dyslipidemia, often only when very-high levels occur (primary), if present at all, often include the following: Abdominal pain Pancreatitis – especially triglycerides** Xanthomas Peripheral polyneuropathy  Clinical Presentation - Xanthomas https://en.wikipedia.org/wiki/Familial_hypercholesterolemia#:~:text=FH%20is%20classified%20as%20a,receptor%20defect)%20is%20type%202 http://www.chicagofootcareclinic.com/foot-problems/achilles-problems/xanthomas-achilles-tendon/. https://www.researchgate.net/publication/380462560_Examining_treatment_strategies_for_xanthelasma_palpebrarum_a_comprehensive_literature_review_of_contemporary_modalities/figures?lo=1&utm_s ource=google&utm_medium=organic Clinical Presentation - ASCVD Varies based upon specific ASCVD condition Coronary heart disease (Myocardial infarction), ischemic stroke, peripheral artery disease Death General symptoms of ASCVD Chest pain, Palpitations, Sweating, Anxiety, Shortness of breath, Loss of consciousness Difficulty with speech or movement, Abdominal pain Severe leg pain or cramping Secondary Causes – Diseases & Disorders Decreased metabolic function Hypothyroidism, diabetes, chronic kidney disease, obesity Lipodystrophy – abnormal adipose tissue distribution Liver dysfunction Hepatitis, alcohol use disorder Other Pregnancy Hypocholesterolemia only: malnutrition, malabsorption Patients often present with a mixed presentation of symptoms due to a blend of different causes Secondary Causes - Drugs Dyslipidemia Subtype Medications Hypercholesterolemia *progestins, thiazide diuretics, glucocorticoids, beta blockers, isotretinoin, protease inhibitors, cyclosporine, Others: mirtazapine, sirolimus Hypertriglyceridemia *Alcohol, estrogens, isotretinoin, beta blockers, glucocorticoids, bile acid resins, thiazides, -azole antifungals, anabolic steroids Others: asparaginase, interferons,, mirtazapine,, sirolimus, bexarotene Patients often present with a mixed presentation of symptoms due to a blend of different causes Secondary Causes - Diet Alcohol Saturated and Trans Fats Examples: Are all oils bad? Low Fiber Additional Lifestyle Smoking Sedentary lifestyle – lack of physical activity Uncontrolled diabetes* Epidemiology Cholesterol increases throughout the life for all patients 49%of Americans have total cholesterol > 200 mg/dL LDL-C is the 8th highest risk factor for death! 1 in 7 deaths in the U.S. is due to coronary heart disease Fewer than 20% of patients with heart disease achieve their LDL-C goal Epidemiology Oncepatients have one ASCVD event, they are extremely likely to have another 50% of all MI and 70% of all deaths from MI are due to people with a history of coronary heart related conditions SECONDARY prevention Risk factors for ASCVD are additive for both primary and secondary patients Dyslipidemia, smoking, obesity, diabetes Familial dyslipidemias are more rare, but we are diagnosing more often  Social Determinants of Health Environment - access to health foods Economic – afford treatment, time off work Education – navigate healthcare Social and Community – support, cultural norms Healthcare Access – different treatment based upon bias, access, etc Review Question #4 Which of the following describes combinations best describes the relationship levels and ASCVD risk A. Testosterone use – increased ASCVD risk B. Increased HDL – increased ASCVD risk C. Increased obesity – decreased ASCVD risk D. Increased TG – decreased ASCVD risk Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up Biomarkers 101 What is a biomarker? Whydo we care about lipid levels, blood pressure, or other measurements of ASCVD risk? What do we actually want to know? Lab Tests - Lipid Panels Components: Total Cholesterol (TC) High Density Lipoprotein Cholesterol (HDL-C) Triglycerides (TG) Low Density Lipoprotein Cholesterol (LDL-C) calculated or direct Non-HDL is often reported TC – HDL = Non-HDL Used to both screening and to guide treatment Annual screenings for patients with concurrent high-risk conditions (e.g., diabetes) Consider every 3 years for borderline elevated and ever 5 years for normal levels Unclear evidence of when to discontinue lipid screening Consider 65 – 79 based on previous results Calculating LDL-C The Martin Equation The Friedewald Equation LDL-C = TC – HDL – (TG/factor) LDL-C = TC – HDL – (TG/5) Adjustable factor better accounts for Not accurate in TG >400 mg/dL VLDL-C – 3.1-11.9 Underestimates LDL-C