19 20 Dyslipidemia Therapeutics.docx

Dyslipidemia Therapeutics Learning Objectives Recognize appropriate lifestyle modifications for the treatment of dyslipidemia Compare and contrast each lipid-lowering agent’s impact on specific lipoproteins State the following for each lipid-lowering therapy: adverse effects, contraindications, mon...

Dyslipidemia Therapeutics Learning Objectives Recognize appropriate lifestyle modifications for the treatment of dyslipidemia Compare and contrast each lipid-lowering agent’s impact on specific lipoproteins State the following for each lipid-lowering therapy: adverse effects, contraindications, monitoring parameters, counseling points, and place in therapy Recommend a treatment plan for the primary or secondary prevention of ASCVD Describe a treatment plan for a patient with hypertriglyceridemia Clinical Presentation Clinical Presentation Symptoms (ASCVD) Chest pain Palpitations Sweating Anxiety Shortness of Breath Difficulty with speech or movement Abdominal pain Loss of consciousness Signs Abdominal pain Pancreatitis (↑ TG) Eruptive xanthomas Peripheral polyneuropathy Laboratory Tests Screening: Fasting or non-fasting lipid panel Before puberty (9-11 years) After puberty (17-20 years) 20 years or older (not on lipid—lowering therapies) Goals of Therapy Global Outcome(s) Prevent ASCVD-related morbidity & mortality Includes: Revascularization procedures Myocardial Infarction (Heart Attack) Ischemic Stroke Prevent non-ASCVD-related morbidity E.g., Acute pancreatitis due to hypertriglyceridemia Specific Outcomes Dependent on dyslipidemia and related surrogate markers (see slides 54-59) REMEMBER: The goal is not to just correct lab abnormalities! General Approach Healthy lifestyle Management of modifiable risk factors (e.g., HTN, DM) Lipid-Lowering Therapy Reduced Morbidity & Mortality Non-Pharmacologic Treatment “Healthy Lifestyle” Diet Emphasize intake of vegetables, fruits, whole grains, legumes, and non-tropical vegetable oils Choose healthy protein sources: Low-fat dairy, low-fat poultry without skin, fish/seafood, nuts Limit % of calories from saturated & trans fats Limit red meats, sweets, sugar-sweetened beverages, and red meats Physical Activity 3-4 sessions/week of aerobic physical activity Approximately 40 min/session Moderate-to-vigorous intensity Focus on Specific Dyslipidemias Lower LDL-C Increase soluble fiber intake Phytosterol (2 g/day) supplementation Increase HDL-C Increase physical activity Smoking cessation Weight loss Moderate alcohol intake Lower TGs Weight loss (5-10% of body weight) Increase physical activity Limit alcohol Reduce intake of refined carbohydrates and sugars Limit saturated and trans fats Treatment Guidelines on the Management of Blood Cholesterol Primary and Secondary ASCVD Prevention 2018 ACC/AHA Management of Blood Cholesterol: Overview KEY POINT: The greater the patient’s ASCVD risk, the greater LDL-C reduction we want to achieve. Patients with a history of ASCVD have the greatest risk for another event! They need secondary prevention to prevent a subsequent episode Other patients at high risk for ASCVD include those with very high LDL-C levels, a history of diabetes, and an elevated 10-year ASCVD risk score. They need primary prevention to prevent their first episode We always start with healthy lifestyle or statin therapy → cost-efficacy is a factor Patient Management Groups Previously referred to as “statin benefit groups” Primary Prevention Severe Hypercholesterolemia (LDL-C ≥ 190 mg/dL) Diabetes in Adults Other Patients Who Need Primary Prevention Based on Risk Secondary Prevention ‘Not Very High Risk’ Clinical ASCVD ‘Very High-Risk’ Clinical ASCVD Primary Prevention: Severe Hypercholesterolemia (LDL-C ≥ 190 mg/dL) Primary Prevention Risk Assessment Tool Pooled Cohort Equation used to calculate 10-year or lifetime ASCVD risk Used in primary prevention only! Calculates % risk of CHD death, fatal or non-fatal MI, and stroke Initially calculated with baseline lipid panel off statin therapy Recalculate every 4-6 years in patients with LDL-C of 70-189 mg/dL without clinical ASCVD or DM Primary Prevention: Diabetes in Adults Diabetes Risk Enhancers Long duration (≥10 years for type 2 diabetes or ≥ 20 years for type 1 diabetes) Albuminuria ≥30 mcg/mg eGFR < 60 mL/min/1.73 m2 Retinopathy Neuropathy ABI < 0.9 Primary Prevention in Other Patients Assessment by Age ASCVD Risk Enhancers Family history of premature ASCVD Age ≤ 55 years in males Age ≤ 65 years in females Persistently elevated LDL-C ≥ 160 mg/dL Chronic kidney disease Metabolic syndrome Conditions specific to women Inflammatory diseases Ethnicity Lipid/biomarkers Persistently elevated triglycerides ≥ 175 mg/dL If measured: High sensitivity C-Reactive Protein ≥ 2.0 mg/dL Lipoprotein a levels ≥ 50 mg/dL Apolipoprotein B levels ≥ 130 mg/dL Ankle-brachial index < 0.9 Special Populations Primary Prevention in Older Adults > 75 Years of Age Review of recommendations for adults ≥ 75 years of age Primary prevention for adults with DM: reasonable to initiate statin Secondary prevention: initiate moderate- to high-intensity statin In adults ≥ 75 years of age with limitations to potential benefit of statin therapy. Consider stopping statin therapy I.e., functional decline, multimorbidity, frailty, reduced life-expectancy In adults 76-80 years of age with LDL-C of 70-189 mg/dL Consider measuring a CAC score to possibly reclassify patients to avoid statin therapy Secondary Prevention: Clinical ASCVD Treatment Algorithm Classification of Very High-Risk ASCVD Major ASCVD Events Recent ACS within the past 12 months History of myocardial infarction other than recent ACS event listed above History of ischemic stroke Symptomatic peripheral arterial disease (e.g., history of claudication, previous revascularization or amputation High-Risk Conditions Age ≥ 65 years Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of major ASCVD events Selected comorbidities: diabetes, hypertension, congestive heart failure, CKD Current smoker Persistently elevated LDL ≥ 100 mg/dL despite max tolerated statin and ezetimibe Special Populations Statin-Associated Muscle Symptoms (SAMS) Assess symptoms, predisposing factors, and possible non-statin causes Measure CPK levels in patients with severe symptoms and objective muscle weakness Re-challenge statin therapy or change to non-statin therapy with ASCVD benefit; Coenzyme Q10 is not recommended Re-challenge Strategies: Try lower dose of statin Change to lower potency statin (pravastatin) Use alternate dosing for long-acting statin (atorvastatin, rosuvastatin) Pharmacologic Treatment Agents that Primarily Lower Atherogenic Cholesterol (e.g., LDL-C) Statins Proven CV morbidity and mortality risk reductions in primary and secondary prevention Statins MOA Inhibition of the HMG-CoA Reductase enzyme in the cholesterol synthesis pathway Therapeutic Benefit Pleiotropic effects to: Improve endothelial cell function --> ↑ vasodilation ↑ plaque stability ↓ inflammation ↓ lipoprotein oxidation ↓ coagulation Efficacy LDL-C ↓ 18-62%; HDL-C ↑ 5-15%; TG ↓ 7-30% ADRs Common: myopathy, myalgias, LFT elevations, new-onset DM CI Pregnancy/lactation, acute liver disease, decompensated cirrhosis, unexplained persistent LFT elevation Monitoring Baseline: FLP, LFTs, A1c (if DM status unknown) Follow-Up: FLP 4-12 weeks after initiation/titration Statin Dosage Intensity Characterized by EXPECTED % LDL-C reduction High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Daily dose ↓ LDL-C by 50% or more Daily dose ↓ LDL-C by 30-49% Daily dose ↓ LDL-C by < 30% Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg Statins: Administration Generally, administer with or without food Dosing time depends on half-life of agent Shorter half-life: dose in evening – Why? Lovastatin, simvastatin, pravastatin, Fluvastatin Longer half-life: dose any time of the day Rosuvastatin, Atorvastatin, and Pitavastatin Statins: Common Adverse Effects Myopathy Sore, achy, weak muscles Typically occurs in large proximal muscle groups May present as “flu-like” symptoms in some patients May lead to rhabdomyolysis LFT elevations Must examine in context of other diseases ≥ 3x upper limit of normal (ULN) should be further evaluated Statins: Warnings Statin-Associated Muscle Symptoms (SAMS) Myopathy, rhabdomyolysis Hepatotoxicity or hepatic impairment Renal impairment No adjustment necessary for atorvastatin Diabetes – may cause new-onset DM or worsen DM Asian population – need to reduce rosuvastatin dosing Elderly – increased risk for myopathy Cognitive impairment – reverses with statin discontinuation Statins: Drug Interactions CYP3A4 inhibitors Macrolides, azole antifungals, cyclosporine, protease inhibitors, nefazodone Grapefruit juice? Warfarin Bile acid sequestrants Fibrates Niacin Highest risk = simvastatin, lovastatin Lowest risk = pravastatin (not metabolized by CYP450) Statins: Contraindications Use with strong CYP3A4 inhibitors (see drug Interactions slide) Applies to simvastatin, lovastatin Concomitant use with gemfibrozil due to increased adverse effects PREGNANCY and lactation Hypersensitivity Acute liver disease Decompensated cirrhosis Unexplained persistent elevation in serum transaminases (e.g., AST, ALT) Statins: Monitoring Parameters Lipid Panel Baseline 4-12 weeks to evaluate adherence or efficacy when changing treatment LFTs – Routine/periodic monitoring is NOT RECOMMENDED Baseline As clinically indicated - baseline is abnormal, known liver disease, risk factors for liver disease, concomitant hepatotoxic drugs CPK – Cannot rely to diagnose statin-associated myopathy Baseline if history of myopathy When symptomatic for muscle aches/weakness Ezetimibe (Zetia) Ezetimibe (Zetia) MOA​ A cholesterol absorption inhibitor that blocks the absorption of cholesterol at the brush border of the small intestine Efficacy ↓ LDL by 18%;  ↑ HDL by 0-5%; ↓ HDL by 5-11% ADRs​ LFT elevation and myopathy (in combo w/ statin); diarrhea, URT symptoms CI​ Hypersensitivities; moderate-to-severe hepatic impairment, pregnancy/breastfeeding Monitoring​ No different than statins except do not need to check for DM Ezetimibe: Drug Interactions and Monitoring Drug Interactions Increased levels of ezetimibe Cyclosporine Fibrates (minor interaction) Decreased levels of ezetimibe Bile acid sequestrants Monitoring Parameters Lipid Panel Baseline for everyone 4-12 weeks after start or therapy change LFTs – may increase with concomitant statins Baseline and as clinically indicated CPK Baseline if history of myopathy When symptomatic for muscle aches/weakness PCSK9 mAbs Evolocumab (Repatha)* or Alirocumab (Praluent)* MOA​ Inhibits the binding of PCSK9 to LDLRs to increase the number of LDLRs available to clear LDL from the blood Efficacy ↓ LDL by 30-60%;  Modest improvements in HDL and TGs ADRs​ Nasopharyngitis, injection site reactions, influenza, allergic reactions CI​ Hypersensitivities; moderate-to-severe hepatic impairment Monitoring​ FLP at baseline and 4-12 weeks; 3 to 12 months thereafter *Administered as subcut injections every 2 weeks or every month Small Interfering RNA (siRNA) Agent PCSK9 inhibitor No known effect on CV morbidity and mortality Inclisiran (Leqvio) MOA​ Taken up by the hepatocytes and utilizes RNA interference to direct catalytic breakdown of mRNA for PCSK9 ↑ LDL-C receptor recycling and expression on the hepatocyte cell surface, which ↑ LDL-C uptake and ↓ LDL-C levels in the circulation. Efficacy ↓ LDL by 50% when added to high-intensity statin ADRs​ injection site reactions, arthralgia, bronchitis CI​ Pregnancy/breastfeeding Monitoring​ Lipid panel at baseline and 4-12 weeks to assess adherence and efficacy; 3 to 12 months thereafter Adenosine Triphosphate-Citrate Lyase (ACL) Inhibitor Bempedoic Acid (Nexletol) MOA​ Inhibits ACL enzyme to decrease cholesterol synthesis in the liver and upregulate LDL-receptors Efficacy ↓ LDL by 15-20%;  ↓HDL by 6% and small ↑ TGs 3% ADRs​ Hyperuricemia, cholelithiasis Precautions tendon rupture, benign prostate hyperplasia (BPH) Drug interactions Avoid concomitant use with doses of simvastatin > 20 mg or pravastatin > 40 mg Monitoring​ FLP at baseline and 4-12 weeks; 3 to 12 months thereafter Bile Acid Sequestrants No known effect on CV morbidity and mortality Colestipol (Colestid), Cholestyramine (Questran), Colesevalam (Welchol) MOA​ Binds with bile acids in the intestine to form an insoluble complex that is eliminated in feces. ↑ excretion of bile acids leads to ↑ oxidation of cholesterol to bile acid and a ↓ serum cholesterol. Efficacy ↓ LDL by 15-30%;  ↑ HDL by 6% and no effects on TG ADRs​ GI upset, constipation, impaired fat-soluble vitamin absorption Precautions Hyperchloremic acidosis, bleeding, constipation, hypothyroidism, hyperTG (200-299 mg/dL) CI Elevated TG > 300 mg/dL, chronic constipation, pre-existing biliary obstruction, history of bowel obstruction Monitoring​ FLP at baseline and after 4-12 weeks at target dose Bile Acid Sequestrants: Patient Counseling Administration Administer other drugs at least 1 hour before or 4 hours after BAS Numerous drug interactions due to decreased absorption Granules: mix with ≥ 90 mL liquid Tablets: take one at a time with plenty of fluid May suggest stool softener Treatment Guidelines on the Management of Blood Cholesterol: Hypertriglyceridemia Adults with ASCVD and Persistent Hypertriglyceridemia (TG 150-499 mg/dL) Adults with Diabetes Mellitus and Persistent Hypertriglyceridemia (TG 150-499 mg/dL) Adults ≥ 20 years of age (without ASCVD or Diabetes Mellitus) & Persistent Hypertriglyceridemia (TG 150-499 mg/dL) Adults ≥ 20 years of age with Severe Hypertriglyceridemia (TG ≥ 500 mg/dL) Agents that Primarily Lower Triglycerides Fibric Acid Derivatives No known effect on CV morbidity and mortality Fenofibrate (numerous brands), Gemfibrozil (Lopid) MOA​ Activates lipoprotein lipase that leads to a decrease in TG and may induce synthesis of HDL Efficacy ↓ LDL by 5-20%;  ↑HDL by 10-20% and ↓ TGs 20-50% ADRs​ LFT elevation, abdominal pain, gallstones, dyspepsia (gemfibrozil) Precautions Caution use in combination with other drugs that elevate LFTs or cause myopathy CI Severe hepatic impairment, pre-existing gallbladder disease; CrCl < 30 mL/min Monitoring​ See slide 57 for more information Fibric Acid Derivatives: Patient Counseling and Interactions Administration Fenofibrate is dosed one tablet daily with or without food Renally dose adjusted Gemfibrozil is dosed one tablet twice daily with breakfast and dinner Drug interactions Statins - Fibrates have an independent risk of myopathy, which is worse with gemfibrozil Warfarin Niacin Bile acid sequestrants Fibric Acid Derivatives: Monitoring Parameters Lipid panel Baseline 4-12 weeks after start or therapy change LFTs Baseline 4-12 weeks after start or therapy change CPK Baseline if history of myopathy When symptomatic of muscle aches/weakness Renal Status Baseline Within 3 months of initiation Every 6 months Omega-3 Fatty Acid Omega-3 acid ethyl esters (DHA and EPA) and Icosapent Ethyl (EPA-Only) MOA​ ↑ hepatic oxidation of free fatty acids, ↑ LDL hydrolysis by activating PPARgamma and inhibiting apoprotein C-III Efficacy ↑ LDL by 30%;  ↑HDL by 11-13% and ↓ TGs 40-45% ADRs​ Dyspepsia, fishy burps, diarrhea, prolonged bleeding time; atrial fibrillation/flutter Precautions Caution in patents with allergy or sensitivity to fish and/or shellfish Monitoring​ FLP at baseline and 4-12 weeks after start or change in therapy; LFTs at baseline EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid Omega-3 Fatty Acids: Icosapent Ethyl (Vascepa) Pleiotropic Effects Decrease inflammation Decrease oxidative stress Increase plaque stabilization Increase membrane stabilization Reduces risk of CV events and CV death Place in Therapy Add-on to maximally tolerated statin if: History of ASCVD or T2DM w/ additional CV risk factors AND Baseline TG levels ≥150 mg/dL Dose: 2 grams by mouth twice daily with meals Omega-3 Fatty Acids: Patient Education and Interactions Administration Ways to decrease fishy burps: Store capsules in the refrigerator Avoid hot liquids Take with meals Use enteric coated products OTC products are generally taken TID → high capsule burden Drug Interactions Medications that increase bleeding risk: Anticoagulants P2Y12 inhibitors SNRIs or SSRIs NSAIDs Niacin No known effect on CV morbidity and mortality Niacin (several OTC and RX products) MOA​ Reduces hepatic VLDL production -->  ↓ production of TG and LDL. It also inhibits the breakdown of HDL Efficacy ↓ LDL by 5-25%;  ↑HDL by 13-35% and ↓ TGs 20-50% ADRs​ flushing, pruritis, hyperuricemia, hyperglycemia, LFT elevations Precautions Caution use in combination with other drugs that elevate LFTs or cause myopathy CI Hypersensitivity, severe hypotension, active chronic liver disease, unexplained LFT elevations, active peptic ulcer Monitoring​ See slide 63 for more information Niacin: Patient Counseling and Interactions Administration Ways to decrease flushing: Take with food Pre-medicate with ASA Avoid hot liquids, spicy foods or alcohol Absorption of ER formulation increases with food Drug Interactions Alcohol – may worsen flushing Anticoagulants Statins Bile acid sequestrants Niacin: Monitoring Parameters Lipid panel Baseline After 6 weeks at target dose LFTs Baseline 2-3 months after initiation Every 6 months thereafter CPK Baseline if history of myopathy When symptomatic for muscle aches/weakness Blood glucose and A1c if history of DM Baseline Routine monitoring as needed for DM management Uric acid if history of gout Baseline 2-3 months after initiation Every 6 moths thereafter Summary of Treatment Guidelines ASCVD risk reduction focuses on lowering LDL-C Statins are the most cost-effective agents for lowering LDL-C Ezetimibe, PCSK9 mAbs, ACL, inclisiran, and BAS may be added after max tolerated statin therapy Recognize the patient management groups → patients who need secondary or primary prevention Recommend healthy lifestyle for patients who do not need lipid-lowering therapy Monitoring parameters include lipid panel, LFTs, and CPK (if clinically indicated)