Dyslipidemia Pathophysiology & Pharmacotherapy Part 2 PDF

DYSLIPIDEMIA PATHOPHYSIOLOGY & PHARMACOTHERAPY PART 2 Joseph A. Nardolillo, PharmD, BCACP (he/him/his) Assistant Professor, Pharmacy Practice and Clinical Research PHP327 – CTS I, Fall 2024 Learning Objectives Pathophysiology: Describe the components of lipoprote...

DYSLIPIDEMIA PATHOPHYSIOLOGY & PHARMACOTHERAPY PART 2 Joseph A. Nardolillo, PharmD, BCACP (he/him/his) Assistant Professor, Pharmacy Practice and Clinical Research PHP327 – CTS I, Fall 2024 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 Review Question #5 John(he/him/his) is a 58-year-old patient in your clinic. He selected “white” when completing is intake form. He denies a history of smoking. He currently takes losartan 50 mg once daily for his hypertension. Lipid Panel: TC – 230 mg/dL, HDL - 38 mg/dL, 175 mg/dL Blood Pressure: 138/88 mmHg 1.) What is his calculated LDL-C? 2.) Classify each component of the lipid panel 3.)According to the Pooled Cohort Equation, calculate his 10-year ASCVD risk 4.) How would you classify this patient? https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/ estimate/ Review Question #5 5.) How would his ASCVD risk change in the following scenarios? A.) 68 years old B.) Female C.) Smoker D.) SBP of 152 mmHg E.) SBP of 118 mmHg F.) TC – 180 mg/dL, HDL-C 50 mg/dL G.) Smoker + 68 + SBP 152 mmHg Limitations of PCE Severity of other conditions are not accounted for in calculation PCE asks “yes/no” for diabetes PREVENT is more specific with A1C Race – social construct vs. clinical predictor. Also, only black, white, and other. PREVENT uses social vulnerability index (SVI) based off of zip code instead of race Age limitations Only for PRIMARY prevention Lots of conditions that are known to increase ASCVD risk are not included (e.g., HIV) Roadmap for Dyslipidemia Cholesterol ASCVD Lipoproteins Synthesis and Dyslipidemias Metabolism Medications Monitoring Assessing Treatment for and Follow- ASCVD risk Pathways Dyslipidemia Up Medications to Treat Dyslipidemias Omega-3 Statins! Ezetimibe Inclisiran** fatty acids PCKS9 Bempedoic Niacin Fibrates mABs Acid Vascepa Bile acid (TG)? sequestrants Unclear CVD benefits** CVD benefits alone No clear CVD benefits - but may CVD benefits w/ statins have other benefits  Statins – HMG CoA Reductase Inhibitors First step in almost all dyslipidemia management after lifestyle interventions Mechanism of Action (MOA): inhibit the rate-limiting enzyme, HMG CoA reductase, in the cholesterol synthesis pathway ↓ TC, Non-HDL, LDL-C, TG & ↑ HDL-C Many unique properties based upon specific agent which impact adverse effects, dosing, administration, and concurrent medications Drug-drug interaction (metabolism) Half-Life (metabolism) Active metabolites (metabolism) Lipophilicity (distribution) Image: https://app.pulsenotes.com/clinical/pharmacology/notes/statins  Statins – Doses and Intensities High-intensity Moderate-intensity Low-intensity LDL-C ↓ ≥ 50% LDL-C ↓ ≥ 30-49% LDL-C ↓ < 30% Atorvastatin 10 mg-20 mg daily Rosuvastatin 5 mg-10 mg daily Simvastatin 20 mg-40 mg daily Simvastatin 10 mg daily Atorvastatin 40 mg-80 mg daily Pravastatin 40 mg-80 mg daily Pravastatin 10 mg-20 mg daily Rosuvastatin 20 mg-40 mg daily Lovastatin 40 mg daily Lovastatin 20 mg daily Fluvastatin XL 80 mg daily Fluvastatin 20 mg-40 mg daily Fluvastatin 40 mg twice daily Pitavastatin 1 mg daily Pitavastatin 2 mg-4 mg daily Doses & Average LDL-C/Non-HDL Lowering Statins - Properties Drug-Drug Interactions – Metabolized by CYP450 and UGT 3A4 (most common interactions)– simvastatin**, lovastatin, atorvastatin 2C9 – fluvastatin, rosuvastatin Potentially hold or adjust dose of statin with 2C19 – rosuvastatin CYP inhibitors UGT – pitavastatin Common CYP3A4 interaction: CCBs, None – pravastatin antifungals, HIV therapies, Paxlovid Lipophilic– more distribution to the periphery (muscles) where HGM-coA is also present Lovastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin Rosuvastatin and pravastatin are hydrophilic Statins - Properties Activemetabolites – when metabolized, continue to have pharmacological action throughout the body Lovastatin, simvastatin, atorvastatin, rosuvastatin Half-Life Long – atorvastatin (7-14 hours), rosuvastatin (13-20 hours), pitavastatin (12 hours) Short – lovastatin, simvastatin, pravastatin, fluvastatin (1-3 hours) Statins - Counseling Common Adverse Effects Statin associated muscle symptoms (SAMS) – myalgias/myopathy New-onset diabetes (benefits typically outweigh risks) Transient, mild elevations in LFTs Severe/Rare SAMS - Rhabdomyolysis Severe hepatotoxicity - very large increase in LFTs Contraindications Breastfeeding Pregnancy? – risk vs. benefit but most people should avoid (FDA 2021) Severe liver disease – cirrhosis or acute liver failure Statins - Counseling Additional Counseling Points One of the clear ways to avoid heart attack, strokes, or dying from one! Live a longer, healthier life VERY well studied – one of the oldest classes of drugs Most people do not have side effects Avoid the Nocebo Effect (opposite of placebo effect) – 90% of people do not experience a side effect vs. 10 % of people do experience a side effect Which statins should be taken at night? Why? Which statins are most likely to be impacted by grapefruit juice? Why? Review Question #6 Which of the following are considered high intensity statins? A. Atorvastatin 40 mg once daily B. Pravastatin 20 mg once daily C. Rosuvastatin 5 mg once daily D. Simvastatin 80 mg once daily  Ezetimibe MOA: ↓ cholesterol absorption in small intestine Indication(s): ↓ cholesterol in patients w/ primary hyperlipidemia, either alone or w/ statins Efficacy: ↓ LDL-C 18% ↓ cholesterol in patients w/ mixed (monotherapy), ↓ LCL-C 25% hyperlipidemia in combination with fenofibrate (incremental w/statin) ↓ cholesterol in patients w/ HoFH, in Pearls: combination with atorvastatin or simvastatin Generally well tolerated Affordable Dosing: Take 1 tablet (10 mg) by DDI w/ mouth once daily CV Outcomes - YES IMPROVE-IT Sizar O, Nassereddin A, Talati R. Ezetimibe. [Updated 2023 Feb 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532879  Ezetimibe – RACING Open-label trial in South Korea among patients with ASCVD receiving 1.) high-intensity statin or 2.) moderate-intensity statin + ezetimibe Non-inferior rate of MACE Results remained consistent in More patients achieved LDL-C