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Lipid Lowering Agents

Metabolism of Fats in the Body

  • Overview of Fat Metabolism:
    • Fats enter the circulation and can be:
    • Stored as fat
    • Used as energy
    • Absorbed into circulation
    • Can lead to the development of atheroma in injured or inflamed vessels, forming remnants
  • Liver Processing of Fats:
    • The liver processes fats into:
    • Low-Density Lipoproteins (LDLs)
    • High-Density Lipoproteins (HDLs)
    • These lipoproteins then enter circulation to reach the periphery.
  • Bile Functionality:
    • Bile is recycled back to the liver and plays a crucial role by breaking fat into micelles:
    • Micelles Absorption:
      • Micelles are absorbed into the wall of the small intestine.
      • They are then packaged as chylomicrons and absorbed into the lymphatic system.
  • Dietary Fats Pathway:
    • Dietary fats undergo the following pathway:
    1. Stomach: Initial digestion begins.
    2. Small Intestine: Further processes occur, where biliary actions facilitate fat digestion.
    3. Gallbladder: Contracts to release bile into the small intestine for fat emulsification.

Lipoproteins

  • Types of Lipoproteins:
    • Chylomicrons: Made in the small intestine wall.
    • Very-Low-Density Lipoproteins (VLDLs): Produced in the liver.
    • Intermediate-Density Lipoproteins (IDLs)
    • Low-Density Lipoproteins (LDLs)
    • High-Density Lipoproteins (HDLs)

Cholesterol

  • Functions of Cholesterol:
    • Serves as a base unit for steroid hormone formation.
    • Is a crucial element in the formation and maintenance of cell membranes.
  • Diet Significance:
    • A diet high in saturated fat increases cholesterol production in the liver.

Hyperlipidemia

  • Definition:
    • Hyperlipidemia is characterized by high levels of lipids in the blood.
  • Causes of Hyperlipidemia:
    • Excessive dietary intake of fats.
    • Genetic alterations in fat metabolism.
  • Treatment Strategies:
    • Dietary modifications are often successful in managing hyperlipidemia.
    • Drug therapy may be required if genetic alterations are the cause or dietary measures fail to sufficiently lower serum lipid levels.

Lipid Lowering Agents

  • Function: These agents lower serum levels of cholesterol and various lipids.
  • Classes of Lipid-Lowering Agents:
    • Bile Acid Sequestrants.
    • HMG-CoA Reductase Inhibitors (Statins).
    • Cholesterol Absorption Inhibitors.
    • PCSK9 Inhibitors.
    • Others approved for use in combination with dietary and exercise adjustments.

Focus on Drug Therapy Across the Lifespan

  • Children:

    • Familial hypercholesterolemia may occur.
    • Due to the necessity of lipids in nervous system development, treatments generally focus on strict dietary restrictions.
    • Fibrates may be used in resistant genetic hypercholesterolemia.
    • HMG-CoA inhibitors (e.g., Lovastatin, Pravastatin) have appropriate dosing for pediatric patients.
    • Evolocumab (Repatha) studied for adolescents aged 13 to 17 with familial hypercholesterolemia; not indicated for those younger than 13.

  • Adults:

    • Lifestyle changes (dietary restrictions, exercise, cessation of smoking, stress reduction) are recommended before or alongside drug therapy.
    • HMG-CoA reductase inhibitors are typically the first medication choice for hypercholesterolemia in those at risk for or with ASCVD.
    • Due to cost-effectiveness and better tolerance, combination therapy with Ezetimibe is first suggested if radical lipid diets are unsatisfactory.
    • Pregnant individuals should avoid HMG-CoA reductase inhibitors, while bile acid sequestrants are preferred if needed.

  • Older Adults:

    • Similar lifestyle changes apply, with particular caution regarding renal function.
    • In light of the higher incidence of renal impairment in older adults, lower dosages of HMG-CoA reductase inhibitors may be warranted.
    • Regular assessment of liver enzymes, cholesterol levels, and monitoring for muscle pain is crucial due to heightened risk of myalgia and rhabdomyolysis.

Bile Acid Sequestrants

  • Purpose:
    • Used to reduce plasma cholesterol levels.
  • Available Medications:
    • Cholestyramine (Prevalite)
    • Colestipol (Colestid)
    • Colesevelam (Welchol)

Prototype Summary: Cholestyramine

  • Indications:
    • Reduction of elevated serum cholesterol in primary hypercholesterolemia.
    • Treatment for pruritus associated with partial biliary obstruction.
  • Mechanism of Action:
    • Binds bile acids in the intestine, promoting fecal excretion to reduce serum cholesterol by encouraging oxidation in the liver.
  • Pharmacokinetics:
    • Not absorbed systemically and is excreted in feces.
  • Adverse Effects:
    • Includes rash, headache, anxiety, vertigo, dizziness, constipation (can lead to fecal impaction), exacerbation of hemorrhoids, cramps, flatulence, nausea, increased bleeding tendencies, vitamin A and D deficiencies, and muscle/joint pain.

HMG-CoA Reductase Inhibitors

  • Medications Listed:
    • Atorvastatin (Lipitor)
    • Fluvastatin (Lescol XL)
    • Lovastatin (Altoprev)
    • Pitavastatin (Livalo, Zypitamag)
    • Pravastatin (Pravachol)
    • Rosuvastatin (Ezallor Sprinkle, Crestor)
    • Simvastatin (Flolipid, Zocor)

Prototype Summary: Atorvastatin

  • Indications:
    • Used as adjunct therapy for increased cholesterol, triglyceride, and LDL levels, and for the prevention of myocardial infarction (MI), stroke, and angina.
    • Approved for children (10-17 years) with familial hypercholesterolemia after diet failure.
  • Mechanism of Action:
    • Inhibits HMG-CoA, lowering serum cholesterol, triglyceride, and LDL levels while increasing HDL levels.
  • Pharmacokinetics:
    • Route: Oral
    • Onset: Slow
    • Peak: 1-2 hours
    • Duration: 20-30 hours
    • T₁/₂: 14 hours; metabolized in the liver and excreted in bile.
  • Adverse Effects:
    • Headache, flatulence, abdominal pain, cramps, constipation, risk of rhabdomyolysis with acute renal failure, liver impairment, myalgias.

Cholesterol Absorption Inhibitor

  • Ezetimibe (Zetia):
    • Usage as an adjunct with statins to help lower total and LDL cholesterol, also applicable in treatment of homozygous familial hyperlipidemia, and can be used alone when statins cannot be tolerated.

PCSK9 Inhibitors

  • Available Medications:
    • Alirocumab (Praluent)
    • Evolocumab (Repatha)
  • Prototype Summary: Evolocumab (Repatha):
    • Indications:
    • Prevents risk of MI, stroke, and coronary revascularization in adults
    • Adjunct therapy for LDL lowering in patients with primary hyperlipidemia.
    • Mechanism of Action:
    • Binds to free PCSK9, enabling the liver to reduce blood LDL levels.
    • Pharmacokinetics:
    • Route: Subcutaneous
    • Onset: Fast
    • Peak: Maximum enzyme suppression in approximately 4 hours
    • T₁/₂: 11 to 17 days; dependent on binding to PCSK9.
    • Adverse Effects:
    • Hypersensitivity reactions, upper respiratory tract infections, nasopharyngitis, influenza, injection site reactions.

Other Lipid-Lowering Agents

  • Fibrates:
    • Fenofibrate (Tricor, others) - Increases lipolysis and decreases triglycerides.
    • Gemfibrozil (Lopid) - Inhibits breakdown of lipids, reduces triglycerides and LDLs while increasing HDL.
    • Fenofibric acid (Trilipix) - Activates hepatic receptor for enhanced lipid breakdown.
  • Vitamin B3 (Niacin):
    • Inhibits the release of free fatty acids; affects triglyceride removal from plasma and reduces LDL while increasing HDL.
  • Omega-3 Fatty Acids:
    • Omega-3-acid ethyl esters (Lovaza) and Icosapent ethyl (Vascepa); they inhibit enzymes to reduce triglyceride synthesis in the liver.
  • Other Therapies:
    • Bempedoic acid (Nexletol)
    • Lomitapide (Juxtapid) - Black box warning for hepatotoxicity.

Combination Therapy

  • Initiated when a patient does not respond to strict diet, exercise, and lifestyle changes using one agent.
  • Example: Bile acid sequestrant combined with niacin.
  • The aim is to decrease LDL synthesis and serum levels; careful to avoid combinations that increase risk of rhabdomyolysis.

Prototype Summary: Ezetimibe

  • Indications:
    • As an adjunct to lower serum cholesterol levels along with diet and exercise; in combination with atorvastatin for treating homozygous familial hypercholesterolemia.
  • Mechanism of Action:
    • Acts in small intestine to inhibit cholesterol absorption.
  • Pharmacokinetics:
    • Route: Oral
    • Onset: Moderate
    • Peak: 4-12 hours
    • T₁/₂: 22 hours; metabolized in liver and small intestine.
  • Adverse Effects:
    • Headache, dizziness, abdominal pain, diarrhea, upper respiratory infections, back pain, myalgia, arthralgia, potential liver dysfunction or hepatitis.