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Management of dyslipidemia

This document provides an overview of the management of dyslipidemia. It discusses lipoprotein classification and composition. It also outlines the non-pharmacological and pharmacological treatment approaches for different dyslipidemia scenarios, including various drug classes like statins, PCSK9 inhibitors, fibrates and their effects. It discusses treatment approaches for different patient groups such as those with cardiovascular disease, diabetes, chronic kidney disease, inflammatory conditions and others. The guidelines for screening and management of dyslipidemia in various clinical situations are summarized.

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Management of Dyslipidemia
CONTENTS • Introduction to lipoproteins and dyslipidemia • Non pharmacological management • Drugs used • Different Scenarios
Lipoprotiens • Atherogenic • Non atherogenic • Lp(a) ?
Composition
Lipid profiling • Lipoprotein measurement – ApoB • Lipid profile • Fasting or not ? Total Cholesterol 120-200 Triglycerides 10-150 HDL Cholesterol 40-60 LDL Cholesterol <130 VLDL Cholesterol Upto 30
DYSLIPIDEMIA • Dyslipidemias are generally characterized clinically by increased plasma levels of cholesterol, TGs, or both, variably accompanied by reduced levels of HDL cholesterol Dyslipidemia Familial/Genetic Secondary
Familial dyslipidemias
When to suspect? Dutch Lipid Clinic Network diagnostic criteria for FH • Family 👪 history • Physical examination 🔎🩺 • Clinical history 📝🏨 • Lipid profile 🩺 • Genetic testing?🩺
Acquired
Dyslipidemia as a cause of Atherosclerosis
Non Pharmacological Management • Clinical studies – 30% to 40% reduction of serum cholesterol, LDL, and TGs with the combination of diet, lifestyle modifications, and nutritional supplements in most patients.
HYPOLIPIDEMIC DRUGS
STATINS • HMG-CoA reductase* • On LDL: dose dependent reduction till 50% • On TG: 10 to 20% reduction from baseline • ADVERSE EFFECTS 1. Muscle – myopathy> rhabdomyolysis 2. Liver- ALT raise> liver failure 3. New onset Diabetes HMG-CoA reductase inhibition reduction in intracellular cholesterol increased LDL receptor increased uptake of LDL
• Metabolism through the CYP system except pravastatin, rosuvastatin, and pitavastatin • gemfibrozil enhances the risk of myopathy
• Before starting check TSH, HbA1c, SGPT, Urine Proteins, S.Creatinine, total CPK • Titrate dose of statins according to LDL • Avoid Alcohol • Check CpkMB If complains muscle pain • short-acting statins - in the evening – Simva, Lova, Prava • Long-acting statins – at any time of the day – Atorva, Rosuva, Pitava
Intensity of therapy
Cholesterol absorption inhibitors inhibiting cholesterol absorption at intestine upregulating LDLR expression increased clearance of LDL Ezetimibe- monotherapy at 10 mg/day reduces LDL-C by 15 to 22% - with statin additional 21 to 27% Adverse Effects: diarrhea, respiratory infections, fatigue
Bile acid sequestrants Blocks EHC Need to increase more cholesterol synthesis More LDL receptors • Reduction in LDL-C of 18 to 25% • 24 g of cholestyramine OD • 20 g of colestipol OD • 4.5 g of colesevelam OD – best of class • To be taken 4hr before or 1 hr after other drugs • Adverse effects 1. GI -------- low dose, ample fluid 2. Increase TG
PCSK9 inhibitors Mabs against PCSK9 – 1. Alirocumab 75mg s/c once 2 weekly 2. Evolocumab 140 mg s/c once 2 weekly • Reduce LDL by 46 to 73% • Reduce TG by 26% in phase2 trials • Reduce Lp(a) 30 to 40% in phase 2 Adverse Effects 1. Local 2. Flu like symptoms 3. Immunological
Microsomal TG transfer protein inhibitor • Lomitapide – oral daily 5mg to max 60 mg - taken 2hrs before meals • Reduction of LDL by 50% • Used in HoFH studies • Cyp3A4 metabolism so Interactions • Adverse effects- GI side effects 🩺 limiting - Fatty liver, raised enzymes
Mipomersen • Antisense Oligonucleotide to mRNA of ApoB100 • 200 mg weekly s/c injection • Metabolised by tissue endo and exo nucleases • Used mostly in HoFH • Adverse Effects 1. Local 2. Steato-hepatitis – 3 monthly LFT monitoring 3. Flu like symptoms Hybridization in liver Degradation by RNAse H Low ApoB100
Fibrates
• Drugs – 1. Gemfibrozil 600mg tab bid 2. Fenofibrate 40mg, 120mg once daily tab • Effects 1. 50% reduction in TG 2. <20% reduction in LDL 3. <20% increase in HDL • Increased risk of myopathy if prescribed along with statins- less with Fenofibrate • Adverse Effects- GI, skin rash, pancreatitis, Cholelithiasis • Monitor : S.Creatinine, SGPT, CK-MB if prescribed along with statins
Newer Drugs • CETP Inhibitors - Anacetrapib – 1. raises HDL-C and ApoA-I levels (by 104 and 36%, respectively) 2. lowers LDL-C and ApoB (by 17 and 18%, respectively) • Only Anacetrapib has shown reduced coronary events by 9% • Apolipoprotein A1 mimetic – D-4Fpeptide - reverse cholesterol uptake • Thromimetic – Sobetirome, Eprotirome
Bempedoic acid inhibits cholesterol synthesis by inhibiting the action of ATP citrate lyase Small interfering RNA (siRNA) molecule Inclisiran— inhibits the synthesis of PCSK9—reduced LDL-C by up to 50% Evinacumab is monoclonal antibody that is an inhibitor of angiopoietin-like 3 which regulates lipid metabolism by increasing triglycerides Volanesorsen is an antisense oligonucleotide - binds to apoC-III mRNA - leading to its degradation and preventing translation of apoC-III protein, which inhibits triglyceride metabolism and hepatic clearance of chylomicrons
Miscellaneous Phytosterols 1.6 to 3.0 g/d in divided doses with food Red yeast rice 2400 mg per night Pantethine: 300 mg 3 times per day Niacin various forms at 500 to 3000 mg/d Soy γ-/δ-Tocotrienols: 200 mg per night with food ω-3 Fatty Acids: at 3 to 5 g/d at a ratio of 3 parts EPA, 2 parts DHA, and GLA
Different scenarios
What are we trying to do with these drugs? ASCVD Major ASCVD events includes 1. Recent ACS (within the past 12 mo) 2. History of MI (other than recent ACS event listed above) 3. History of ischemic stroke 4. Symptomatic peripheral arterial disease
High-Risk Conditions include 1. Age ≥65 y 2. Heterozygous familial hypercholesterolemia 3. History of prior CABG or PCI outside of the major ASCVD event(s) 4. Diabetes mellitus 5. Hypertension 6. CKD (eGFR 15-59 mL/min/1.73 m2) 7. Current smoking 8. Persistently elevated LDL-C (LDL-C ≥100 mg/dL 9. History of congestive HF Very High-Risk Conditions include 1. Multiple major events 2. 1 Major plus multiple high risk conditions
SECONDARY PREVENTION
• High dose statin therapy is initiated or continued as early as possible • Goal 50% reduction of LDL-C, to <55 mg/dL • Initial Ezetimibe then PCSK9 inhibitors • Loading with high dose statins before PCI. • Intensive statin therapy after TIA & Stroke
PRIMARY PREVENTION
Risk calculators
Raised LDL
DIABETES • IA--- > 40 to 75 years age with diabetes– moderate intensity Statins • II A---- assess ascvd risk and If multiple RFs – higher intensity Statins to reduce ldl by 50 % • II A ---- > 75 years-old, if on statins- continue • II B --- Adults with diabetes with ascvd risk >20% -add ezetimibe. • II B----- >75 years old with DM, not on statins – start based on risk- benefit ratio
Old age • For given TC higher risk in elderly. • Multiple co-morbities, Medications • Different pharmacokinetics and dynamics • Statins to be started at low doses and titrate.
Children • Family history of early CVD & hypercholesterolemia – screening from 2years • With obesity and Metabolic syndrome- testing • Lifestyle changes and caloric restrictions. • >190 or >160 mg/dL with FH after failure of above • Reverse cascade of screening.
WOMEN • Statins are preferred. • OCPs ? >160mg/dL • Oestrogen Replacing therapy ? • Pregnancy and lactation BAS and lipid apheresis
CKD • Increased risk of both atherosclerotic vascular disease and structural heart disease • Specifically rise of TG, Lp(a)
CKD contd
Inflammatory conditions • Rheumatoid arthritis (RA), glomerulosclerosis, or pulmonary fibrosis • CVD has been cited as the top cause of death in people with RA • HIV - Immune dysregulation, Systemic inflammation, Antiretroviral therapy & Dyslipidemia • Role of hs-CRP, CAC, intimal thickness. • Assess Risk score and start based on score • Start on low doses and check for drug interactions.
Raised TG • TGs are associated but not causal for ascvd • Drugs used are statins, fibrates, niacin, ω-3 Fatty Acids • Treatment to be started If > 200 mg/dL • Lifestyle and dietary modifications • 885 and 1000 • Lipid apheresis, And insulin infusion till 500
Dyslipidemia as a cause of Pancreatitis
Lipoprotein (a) • Screen if Premature ASCVD, Familial • Limited evidence in reducing ascvd on lowering levels • Drugs – PCSK9 inhibitors, Niacin • Statins increase
References • 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk • 2018AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA /PCNA Guideline on the Management of Blood Cholesterol • Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Eleventh Edition • KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease • Upt0date
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