Cholesterol-Lowering Drugs I

Overview of Hyperlipidemia and Lipoprotein Structure

  • Prevalence and Significance: High cholesterol and high triglycerides affect one in five Americans. Guidelines for treating these conditions are becoming more stringent, likely increasing the number of individuals classified as having high lipids.

  • General Lipoprotein Structure: Lipoproteins are large entities designed to transport lipids through the bloodstream.

    • The Core: Consists of triglycerides and cholesterol esters.
    • The Outer Case: Composed of phospholipids, free cholesterol, and specialized proteins called apoproteins.

  • Classification of Lipoproteins: They are categorized based on size, density, and the relative proportion of core lipids and proteins.

    • Chylomicrons: The largest lipoproteins, containing approximately 92%92\% triglycerides. They are very short-lived and primarily measured after consuming a high-fat meal.
    • Very Low Density Lipoprotein (VLDL): The primary carrier of triglycerides in the bloodstream (approximately 64%64\% triglycerides). VLDL and triglycerides are often used interchangeably in clinical discussion.
    • Intermediate Density Lipoprotein (IDL): These possess an intermediate distribution between cholesterol and triglycerides.
    • Low Density Lipoprotein (LDL): Known as "bad cholesterol," it is the main carrier of plasma cholesterol (approximately 50%50\% cholesterol). It delivers cholesterol to atheromas (fatty plaques) on blood vessel surfaces.
    • High Density Lipoprotein (HDL): Known as "good cholesterol," it is very small, rich in apoproteins, and contains relatively little cholesterol.

Lipid Metabolism and Transport

  • Digestion and Absorption: Ingested fats (triglycerides and phospholipids) are broken down by lipases in the saliva, stomach, and small intestine. The products of lipid hydrolysis are emulsified by bile salts into micelles, which travel to intestinal enterocytes.

  • Re-esterification: Within the enterocyte, lipids are hydrolyzed and re-esterified into triglycerides. These travel out of the small intestine into the lymph and then the bloodstream as chylomicrons.

  • Lipoprotein Lipase (LPL): This enzyme is critical for breaking down chylomicrons and VLDL.

    • Action: LPL breaks down chylomicrons into chylomicron remnants and free fatty acids.
    • Fate of Free Fatty Acids: These go to muscle tissue (for energy) or adipose tissue (for storage).
    • VLDL Breakdown: The liver forms VLDL, which is also broken down by LPL into IDLs and free fatty acids.

  • Pathway of IDL and LDL: IDLs either return to the liver or are converted into LDL in the bloodstream. LDL is then taken up by LDL receptors on cell surfaces.

    • Hepatic LDL Receptor Regulation: This is the primary mechanism for controlling plasma cholesterol levels. The quantity of receptors often decreases with age, leading to higher cholesterol levels.

  • Role of HDL and LCAT: HDL removes cholesterol from arterial cells (anti-atherogenic effect).

    • Lecithin Cholesterol Acyl Transferase (LCAT): An enzyme on the surface of HDL that esterifies cholesterol.
    • Excretion: These cholesterol esters are transferred to LDL or VLDL, returned to the liver, converted to bile salts/acids, and excreted from the body.

Clinical Definitions and Diagnostic Guidelines

  • Key Terminology:

    • Hyperlipidemia: A general increase in plasma lipids.
    • Hypercholesterolemia: Specifically an increase in plasma LDL. Causes include genetics (familial mutations in LDL receptors), hypothyroidism, and corticosteroid use.
    • Hypertriglyceridemia: An increase in triglycerides/VLDL. Causes include diabetes, metabolic syndrome (central obesity, HTN), alcohol use, corticosteroids, and oral contraceptives (estrogens).
    • Mixed Hyperlipidemia: A simultaneous increase in both cholesterol and triglycerides.

  • Standard Cholesterol Thresholds:

    • Normal: Total cholesterol < 200 mg/dL200\,mg/dL; LDL < 130 mg/dL130\,mg/dL.
    • Borderline to High: Total cholesterol 200−239 mg/dL200-239\,mg/dL; LDL 130−159 mg/dL130-159\,mg/dL.
    • High: Total cholesterol > 240 mg/dL240\,mg/dL; LDL > 160 mg/dL160\,mg/dL.

  • Target Levels by Risk Category:

    • Moderate Risk (e.g., Diabetes/HTN): Target LDL < 100 mg/dL100\,mg/dL.
    • Very High Risk (e.g., Diabetes + HTN): Target LDL < 70 mg/dL70\,mg/dL.

  • Inflammation and Cardiovascular Risk: Recent discussions suggest measuring markers of inflammation, such as C-reactive protein, as some individuals with "normal" cholesterol still experience heart attacks. However, lowering LDL remains the most proven method for reducing the risk of coronary artery disease.

Pharmacotherapy: Classifications and Statins

  • Lipid-Lowering Drug Classes:

    • HMG-CoA Reductase Inhibitors (Statins).
    • Niacin (Nicotinic Acid / Vitamin B3).
    • Fibric Acid Derivatives.
    • Bile Acid Binding Agents.
    • Inhibitors of Intestinal Sterol Absorption.
    • Newer agents: Lombaza and Alirocumab.

  • Statins (HMG-CoA Reductase Inhibitors):

    • Examples: Lovastatin, Atorvastatin (Lipitor), Rosuvastatin (Crestor).
    • Mechanism of Action: They inhibit the enzyme HMG-CoA reductase, which is the rate-limiting step in hepatic cholesterol synthesis.
    • Synthesis Pathway: Acetyl-CoA $\rightarrow$ HMG-CoA $\xrightarrow{\text{Statin Inhibition}}$ Mevalonic Acid $\rightarrow$ Cholesterol.
    • Indirection Effect: When the liver senses decreased synthesis, it increases the expression of LDL receptors, further pulling LDL from the plasma.
    • Clinical Application: Most effective drugs for reducing LDL; first-line treatment post-Myocardial Infarction.

  • Adverse Effects of Statins:

    • Diabetes: Increased risk; requires blood sugar monitoring.
    • Cognition: Short-lived cognitive impairment, memory loss, or confusion.
    • Hepatitis: Rare; liver enzyme monitoring is no longer routinely recommended by some guidelines due to rarity.
    • Myalgia: Muscle pain is common; can often be managed by changing dose or drug.
    • Severe Myopathy (Rhabdomyolysis): Very rare, but risk increases significantly when combined with fibric acid derivatives (fibrates).

American Heart Association (AHA) Statin Guidelines

Statins are recommended for the following groups:

  1. Individuals aged 40-75 without cardiovascular disease but with a 7.5%7.5\% or higher 10-year risk of heart attack or stroke.
  2. Individuals with a history of cardiovascular events (heart attack, stroke).
  3. Individuals aged 21 or older with LDL $\ge 190\,mg/dL$.
  4. Individuals with Type 1 or Type 2 diabetes aged 40-75 due to high cardiovascular risk.