Hyperlipidemia Management_Statins_ 2024 STUDENT PDF

Mark Stephens, PharmD, BCPS Professor of Pharmacy Practice Union University College of Pharmacy At the conclusion of this discussion the student should be able to: 1. Calculate an LDL, using the Friedewald Equation, and Non-HDL 2. Calculate the 10-yr risk of ASCVD 3. Compare the ASCVD Risk Calcu...

Mark Stephens, PharmD, BCPS Professor of Pharmacy Practice Union University College of Pharmacy At the conclusion of this discussion the student should be able to: 1. Calculate an LDL, using the Friedewald Equation, and Non-HDL 2. Calculate the 10-yr risk of ASCVD 3. Compare the ASCVD Risk Calculator and PREVENT 4. Identify the 4 statin benefit groups described in the 2018 ACC/AHA Cholesterol Guidelines 5. Identify or recognize low-, moderate-, and high-intensity statins At the conclusion of this discussion the student should be able to: 6. Given a patient case, recommend appropriate drug therapy for hyperlipidemia 7. Recognize significant adverse drug reactions associated with statins 8. Given a patient case, recommend appropriate treatment for statin-associated adverse effects 9. Define statin intolerance 10. Identify important pharmacokinetic properties of statins 11. Recommend lifestyle modifications for patients with hyperlipidemia  ASCVD: atherosclerotic cardiovascular disease  IDL: intermediate density lipoprotein  FmHx: family history  ApoB: apolipoprotein B  HeFH: heterozygous familial hyperlipidemia  BAS: bile acid sequestrant  Cholesterol ▪ Sources: liver and diet ▪ Functions:  Triglycerides ▪ Sources: liver and diet ▪ Function: energy   Lipoproteins ▪ LDL: primary carrier of cholesterol Together considered Non-HDL ▪ VLDL: primary carrier of TG Very atherogenic ▪ HDL: not atherogenic  Apolipoprotein B (ApoB) ▪ Primary protein embedded in LDL and VLDL ▪ Strong predictor of atherogenicity 2018 Cholesterol Clinical Practice Guidelines. Circulation 2018;139:e1082-1143. Feingold KR. Introduction to Lipids and Lipoproteins. [Updated 2021 Jan 19]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. 86 million US adults ≥ 20 yo have TC > 200 mg/dl 33-36% of US adults 25 million above 240 mg/dl https://www.cdc.gov/cholesterol/data-research/facts-stats/index.html Hyperlipidemia Atherosclerosis ASCVD   Dyslipidemia/Hyperlipidemia ▪ ↑ LDL ▪ ↑ VLDL (TG) ▪ ↓ HDL  Cigarette smoking  Hypertension  Diabetes  ↑ Age 2018 Cholesterol Clinical Practice Guidelines https://www.cdc.gov/heartdisease/facts.htm. Accessed September 2022   Leading cause of morbidity and mortality for men, women, people of most racial and ethnic groups in the US  1 in 4 deaths  Key risk factors for CVD: Other risk factors: ▪ HTN Overweight and obesity Unhealthy diet ▪ Cigarette smoking Physical inactivity ▪ Hyperlipidemia Excessive alcohol use ▪ Diabetes Heart Disease Facts | Heart Disease | CDC Accessed September 2024 JAMA 2022;328(8):746-53. Circulation 2019;139:31082-e1143 J Am Coll Cardiol 2018;doi://doi.org/10.1016/j.jack.2018.11.003. Class (Strength) of Recommendation (COR) Level (Quality) of Evidence (LOE) Class I (strong) Benefit >>> Risk Level A: high quality from > 1 RCT Class IIa (moderate) Benefit >> Risk Level B-R: moderate quality from 1 or more RCT Class IIb (weak) Benefit ≥ Risk Level B-NR: moderate quality from non- randomized trials, observations Class III (no benefit) Level C-LD: limited data due to limitations in study design Harm Level C-EO: expert opinion  Lipid profile  10-year risk of ASCVD ▪ Risk Enhancing Factors  Secondary causes Fasting or non-fasting blood  Total cholesterol  LDL* Friedewald Equation: LDL = Total cholesterol – HDL – (TG/5)  HDL Non-HDL Equations:  Triglycerides Non-HDL = Total cholesterol – HDL, OR * Measured or calculated Non-HDL = LDL + TG/5 LDL Non-HDL < 100 Desirable < 130 Desirable 100-129 Above desirable 130-159 Above desirable 130-159 Borderline high 160-189 Borderline high 160-189 High 190-219 High ≥ 190 Very High ≥ 220 Very High Triglycerides HDL < 150 Normal ≥ 40 (men) Desirable 150-199 Borderline high ≥ 50 (women) Desirable 200-499 High ≥ 500 Very High Optimal Total Cholesterol: 150 mg/dl  COR LOE Adults ≥ 20 yo, and not on lipid- Check fasting or non-fasting I B-NR lowering therapy lipid levels Check every 4-6 years TG > 400 mg/dl, if non-fasting Check fasting lipid levels I B-NR Friedewald Equation less accurate LDL < 70 mg/dl Measure direct LDL. IIa C-LD Friedewald Equation less accurate FmHx of premature ASCVD or genetic Check fasting lipid levels IIa C-LD hyperlipidemia Circulation 2018 J Am Coll Cardiol 2018;doi://doi.org/10.1016/j.jack.2018.11.003. Criteria Recommendations for Screening 2019 AHA/ACC Guideline on the Primary Prevention of CVD Age 20-39 yrs Assess ASCVD risk factors every 4-6 years Age 40-75 yrs Assess ASCVD risk factors and calculate 10-year risk of ASCVD using the ASCVD Risk Calculator Adults with 10-yr Consider assessment of “Risk Enhancing Factors” to guide risk of 5% to < 20% decisions about preventative interventions Circulation 2019;140:e596-e646  Factors: Age Gender Race Pooled Cohort Risk Assessment BP “ASCVD Risk Calculator” TC  ASCVD Risk Estimator (acc.org) HDL  Mobile app: ASCVD Plus LDL Hx of diabetes, smoker   Calculates risk of CVD, ASCVD, heart failure  Uses cardiovascular-kidney-metabolic health  10-year risk for patients 30-79 years  30-year risk for patients 30-59 years  Differs from ASCVD Risk Estimator ▪ BMI, eGFR, no LDL, no race ▪ Optional info: UACR, HbA1c, zip code https://professional.heart.org/en/guidelines-and-statements/prevent-calculator Accessed September 2024  High Risk (≥ 20%) Intermediate (7.5% to 19.9%) Borderline % of patients with risk (5% to 7.4%) factors who will likely develop ASCVD within Low (< 5%) 10 years  Diet Drugs Diseases  Cause Elevated LDL Elevated TG Drugs Diuretics, cyclosporine, Oral estrogens, glucocorticoids, glucocorticoids, anabolic steroids, BAS, protease amiodarone, SGLT2 inhibitors, raloxifene, tamoxifen, inhibitors beta blockers (not carvedilol), thiazides, antipsychotics Diseases, disorders Biliary obstruction, Nephrotic syndrome, chronic renal nephrotic syndrome, failure, diabetes (poorly controlled), hypothyroidism, obesity, hypothyroidism, obesity, pregnancy pregnancy JACC 2014;63:2889-934. A 46 yo AAM presents to your pharmacy. His father just died of a heart attack at age 70. He is concerned about his risk of heart disease.  PMHx: HTN (146/86 on HCTZ), diabetes  TC=240, LDL=170, TG=200, HDL=30  BMI=25, eGFR=60 ml/min What is the 10-yr risk of ASCVD? Classify their 10-yr risk of ASCVD. Secondary causes of hyperlipidemia?  Adults ≤ 75 yo Adults 20-75 yo, with clinical ASCVD LDL ≥ 190 mg/dl Need Statins Adults 40-75 yo, Adults 40-75 yo, diabetes, LDL > 70 < 189 mg/dl, LDL > 70 mg/dl 10-yr ASCVD risk ≥5.0%  Adults ≤ 75 yo Adults 20-75 yo, with clinical ASCVD LDL ≥ 190 mg/dl High Intensity Statin High Intensity Statin Need Statins Adults 40-75 yo, Adults 40-75 yo, diabetes, LDL > 70 < 189 mg/dl, LDL > 70 mg/dl 10-yr ASCVD risk ≥5.0% Moderate – High Intensity Statin Moderate – High Intensity Statin A. 60 yo with hx of MI B. 25 yo with diabetes C. 40 yo with LDL=180 D. 35 yo with HTN  High-Intensity Moderate-Intensity Low-Intensity Statin Statin Statin (LDL 50%) (LDL 30-50%) Rosuvastatin 20-40 mg Rosuvastatin 5-10 mg Atorvastatin 40-80 mg Atorvastatin 10-20 mg Simvastatin 20-40 mg Simvastatin 10 mg Each 1% LDL reduction Pravastatin 40-80 mg Pravastatin 10-20 mg reduces risk of ASCVD by 1% Lovastatin 40 mg Lovastatin 20 mg Fluvastatin XL 80 mg Fluvastatin 20-40 mg Pitavastatin 2-4 mg Pitavastatin 1 mg  Medication Equivalent Dose F Fluvastatin 80 mg L Lovastatin 40 mg P Pravastatin 40 mg S Simvastatin 20 mg A Atorvastatin 10 mg R Rosuvastatin 5 mg P Pitavastatin 2 mg A. 25% B. 30% C. 50% D. 70% A. Low B. Moderate C. High A. Low B. Moderate C. High D. Very high Patient Recommendation COR LOE Adults ≤ 75 yo with clinical ASCVD High-intensity statin to I A reduce LDL ≥ 50% High-intensity statin contraindicated or not Moderate-intensity statin I A tolerated to reduce LDL 30-50% Patients with ASCVD, maximum tolerated statins, ADD ezetimibe IIb B-R AND LDL ≥ 70 mg/dl or non-HDL ≥ 100 mg/dl Patients with HFrEF, reasonable life expectancy Consider initiation of IIa B-R (3-5 years), not already on statin for ASCVD moderate-intensity statin to reduce ASCVD risk Patient Recommendation COR LOE Adults > 75 yo, with clinical ASCVD Initiate moderate or high- IIa B-R intensity statin therapy Adults > 75 yo, with clinical ASCVD, already Continue high-intensity IIa C-LD tolerating high-intensity statin statin Multiple major ASCVD events OR One major ASCVD event WITH multiple high-risk condition MAJOR ASCVD EVENTS HIGH-RISK CONDITIONS  Recent ACS (past 12 months)  ≥ 65 yo  Hx of MI  HeFH  Hx of CABG or PCI outside of major ASCVD  Ischemic CVA event  Symptomatic PAD  DM ▪ claudication w/ ABI < 0.85, or  HTN ▪ revascularization, or  CKD (eGFR 15-59 ml/min) ▪ amputation  Current smoking  LDL ≥ 100 mg/dl despite max tolerated statin + ezetimibe  CHF Patient Recommendation COR LOE Adults ≤ 75 yo with very high-risk ASCVD Add ezetimibe IIa B-R On maximum tolerated statin LDL ≥ 70 mg/dl or non-HDL ≥ 100 mg/dl Patients with very high-risk ASCVD Add PCSK9 inhibitor IIa A On maximum tolerated LDL-lowering therapy following a clinician-patient (statin + ezetimibe) AND discussion LDL ≥ 70 mg/dl or non-HDL ≥ 100 mg/dl A. MI B. CVA C. PAD D. Heart failure E. Hypertension A. < 130 mg/dl B. < 100 mg/dl C. < 70 mg/dl D. < 50 mg/dl A. Niacin B. Fenofibrate C. Ezetimibe D. Evolocumab Patient Recommendation COR LOE Adults 20-75 yo, LDL ≥ 190 mg/dl High-intensity statin I B-R (maximum-intensity tolerated) Adults 20-75 yo, LDL ≥ 190 mg/dl, Add ezetimibe IIa B-R Less then 50% LDL reduction on max statins, AND/OR LDL > 100 mg/dl Adults 20-75 yo, LDL ≥ 190 mg/dl, Add BAS IIb B-R Less then 50% LDL reduction, On max tolerated statin and ezetimibe AND TG ≤ 300 mg/dl Adults 30-75 yo, HeFH Add PCSK9 inhibitor IIb B-R LDL > 100 mg/dl (PCSK9 mAB) On max tolerated statin and ezetimibe Adults 40-75 yo, baseline LDL ≥ 220 mg/dl, Add PCSK9 inhibitor IIb C-LD LDL ≥ 130 mg/dl (PCSK9 mAB) On max tolerated statin and ezetimibe Patient Recommendation COR LOE Adults 40-75 yo, diabetes, regardless of 10-year Moderate-intensity statin I A ASCVD risk Adults with diabetes with: High-intensity statin IIa B-R Multiple ASCVD risk factors, OR 10-year risk ≥ 20% Adults with diabetes and Add ezetimibe to IIb C-LD 10-year risk ≥ 20% lower LDL > 50% On maximally tolerated statin dose No specific LDL target Adults 20-39 yo, and Consider moderate- IIb C-LD Diabetes-specific risk enhancers intensity statin  Long duration of diabetes ▪ T2DM ≥ 10 yrs Assess in patients 20-39 yo ▪ T1DM ≥ 20 yrs with DM  Albuminuria (> 30 mcg)  eGFR < 60 ml/min  Retinopathy Microvascular complications of diabetes  Neuropathy  ABI 10% B. A1C > 7.5 C. With diabetes-specific risk factors D. 10-yr risk > 20%  SUMMARY 40-75 yo, moderate intensity statin 40-75 yo Higher CV risk (≥ 1 ASCVD risk factors) high-intensity statin to reduce LDL ≥ 50% AND target and LDL < 70 mg/dl ASCVD Risk Factors: 40-75 yo with multiple ASCVD Duration of diabetes risk factors and LDL ≥ 70 mg/dl, Obesity/overweight add ezetimibe or PCSK9 HTN inhibitor to max tolerated Hyperlipidemia statin Smoking 20-39 yo FmHx of premature CHD Reasonable to start statin CKD Diabetes Care 2024;47(Suppl. 1):S179–S218 Albuminuria  SUMMARY Secondary prevention: High-intensity statin Goal LDL ≤ 55 mg/dl Add ezetimibe or PCSK9 inh to max tolerated statin If statin tolerant: PCSK9 inhibitor Bempedoic acid Inclisiran Elevated TG (135-499 mg/dl) despite statin therapy, add Icosapent ethyl Diabetes Care 2024;47(Suppl. 1):S179–S218  FmHx of premature ASCVD (male < 55 yo, female < 65 yo)  LDL ≥ 160-189 mg/dl, non-HDL 190-220 mg/dl  Metabolic syndrome (waist circumference, TG, BP, BG, HDL)  CKD not on dialysis  Chronic inflammatory diseases (RA, psoriasis, HIV/AIDS)  Premature menopause (< 40 yo) or pre-eclampsia  South Asia race  Lipid biomarkers ▪ TG ≥ 175 mg/dl, persistently elevated ▪ ApoB ≥ 130 mg/dl (esp. w/ ↑ TG) ▪ Lp(a) ≥ 50 mg/dl ▪ hsCRP ≥ 2 mg/L ▪ ABI < 0.9  Adults 40-75 yo, LDL > 70 < 189 mg/dl Recommendations COR LOE Adults at high risk (≥ 20%) High-intensity statin I A Adults at intermediate risk (≥7.5% 30; FBG > 100, A1C ≥ 6%, metabolic syndrome  Benefits of statins in ASCVD reduction outweigh risk. Do not stop the statin.  Causes small but clinically insignificant ↑ A1c 2019 AHA Statin safety and associated adverse effects. Arterioscler Thromb Vasc Biol 2019;39:e38-e81.   Asymptomatic transaminase (> 3X ULN) in 1% of patients ▪ Dose related ▪ Statins increase ALT > AST  Severe liver injury very rare (0.001%)  Routine monitoring NOT recommended by the FDA ▪ Baseline, then as “clinically warranted” ▪ Remain alert to signs or symptoms hepatotoxicity 2019 AHA Statin safety and associated adverse effects. Arterioscler Thromb Vasc Biol 2019;39:e38-e81.   Rosuvastatin 40 mg → transient proteinuria, hematuria  Statins are not linked to AKI or worsening renal function, except with rhabdomyolysis 2019 AHA Statin safety and associated adverse effects. Arterioscler Thromb Vasc Biol 2019;39:e38-e81.  Mechanism of DDI: Inhibit CYP3A4 Inhibit OAT1B1 Inhibit P-gp OAT1B1/3 moves drug from portal circulation to hepatocyte P-gp moves drug from blood to Arterioscler Thromb Vasc Biol 2019;39:e38-81. intestine  Inhibition of P-gp, CYP3A4, OATP1B1 G  Grapefruit juice inhibits 3A4  Gemfibrozil inhibits OATP1b1. Avoid with all statins. P  Avoid or reduce simvastatin or lovastatin dose A with P-gp and 3A4 inhibitors: protease C inhibitors, fungal azoles, cyclosporine, macrolides, amiodarone, amlodipine, Non-DHP M CCBs (verapamil, diltiazem), etc. A N   Diet  Physical activity  Weight reduction  Smoking cessation AACE Guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract 2012; 18:1-78.  Increase vegetables, fruits, legumes, nuts, whole grain, fish Mono- and polyunsaturated fats Reduce cholesterol and sodium Minimize processed meat, refined carbs, sweetened beverages Avoid trans fats 2019 SCC/AHA Guideline on the primary prevention of cardiovascular disease. Circulation 2019;140:e596-e646 GOAL 150 min/wk of moderate- intensity, OR 75 min/wk of vigorous- intensity aerobic physical activity Recommendation “some moderate- or vigorous-intensity physical activity… can be beneficial” 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease. Circulation 2019;140:e596-e646 2019 SCC/AHA Guideline on the primary prevention of cardiovascular disease. Circulation 2019;140:e596-e646 A. 120 minutes/day B. 75 minutes/day C. 150 minutes/week D. 240 minutes/week Mark Stephens, PharmD, BCPS Professor of Pharmacy Practice Union University College of Pharmacy