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Lipid Therapy

  • 2018 Guideline on the Managment of Blood Cholesterol
  • Hypertriglyceridemia

  • Elevated LDL-C

    • Diet: Trans/Saturated Fats, Weight gain, Anorexia, Alcohol
    • Drug: Diuretics, Cyclosporines, Glucocorticoids, Amiodarone
    • Diseases: Biliary Obstruction, Nephrotic Syndrome
    • Other: Hypothyroidism, Obesity, Pregnancy
  • Elevated Triglycerides
    • Diet: Weight gain, Very low fat diets, High intake of refined carbs, Excessive Alcohol intake
    • Drug: Oral estrogens, Glucocorticoids, Bile Acid Sequestrants, Protease inhibitors, Retinoic acid, Anabolic steroids, Sirolimus, Raloxifene, Tamoxifen, BB (not carvedilol), Thiazides
    • Diseases: Nephrotic Syndrome, Chronic Renal Failure, Lipodystrophies
    • Other: Poorly controlled diabetes, Hypothyroidism, Obesity, Pregnancy
  • Dietary fat has a greater impact on serum LDL-C than does dietary cholesterol intake
    • Fats should be limited to \<30% of total caloric intake
    • Saturated fats should be limited to \<10% of calories (7% if LDL-C above goal)
  • Higher-Risk
    • The following factors that may be considered for the identification of higher-risk patients with clinical CV disease: - Age ≥65 years, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PVD with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with ≥40% stenosis in ≥2 large vessels, HDL \<40 mg/dL for men and \<50 mg/dL for women, hs-CRP ≥2 mg/L, or metabolic syndrome

Liver

  • Statins (HMG-CoA reductase inhibitors, LDL)
    • MOA: RLS in intracellular biosynthesis of cholesterol (competitive inhibition)
      • Increases LDL receptors on liver cell membranes
        • Remove circulating LDL and digest it
        • Reduces serum w/ minimal liver LDL change
      • Decrease CoQ10 synthesis (ubiquinone)
      • Statins metabolized by CYP450 3A4
        • Lovastatin, simvastatin, atorvastatin
    • Benefits
      • Plaque stabilization
      • Inflammation Reduction, decrease CRP
      • Improve endothelial function
      • Decreased Thrombogenicity
    • Potency:
      • High Potency: lower LDL by ≥50%
        • Large LDL Decrease (20-60%, 1st line)
        • Doubling dose adds 6% effect
    • Rosuvastatin (Crestor)
      • High: 20-40mg
      • Moderate: 5-10mg
      • CKD ≥3 or Dialysis: 10mg
      • Can be used in Cirrhosis
    • Atorvastatin (Lipitor)
      • High: 40-80mg
      • Moderate: 10-20mg
      • CKD ≥3 or Dialysis: 20mg
      • Lipophilic, not renally cleared
    • Simvastatin (Zocor)
      • Moderate: 20-40mg
      • Low: 10mg
      • CKD ≥3 or Dialysis: 20mg
      • Lipophilic, not renally cleared
    • Pravastatin (Pravachol)
      • Moderate: 40-80mg
      • Low: 10-20mg
      • CKD ≥3 or Dialysis: 40mg
      • Least muscle SE, preferred in elevated LFTs
      • Not renally cleared, can be used in Cirrhosis
    • Lovastatin (Mevachor)
      • Moderate: 40mg
      • Low: 20mg
      • CKD ≥3 or Dialysis: Not evaluated
      • Lipophilic
    • Fluvastatin
      • Moderate: 80mg
      • Low: 20-40mg
      • CKD ≥3 or Dialysis: 80mg
      • Least muscle SE, not renally cleared
    • Pitavastatin
      • Moderate: 2-4mg
      • Low: 1mg
      • CKD ≥3 or Dialysis: 2mg
    • Most effective, first line to lower cholesterol and LDL
      • Moderate HDL increase
      • Moderate Triglyceride Decrease
    • Trials
      • IMPROVE-IT (2015)
        • Adding ezetimibe to statin further reduces CV events in the population, suggesting the maximal LDL reduction is the key mech
    • SE: Hepatotoxicity
      • If AST/ALT ≥ 3x ULN, reduce or switch
      • Myalgias (symmetrical proximal muscle weakness or tenderness)
        • 1-10%, mc side effect
      • Myositis/Myopathy
        • Elevated CK
      • Rhabdomyolysis
        • 1%, CK ≥ 10x ULN + Renal injury
      • Statin-associated autoimmune myopathy (HMGCR antibodies)
      • High Intensity
        • Renal Dysfunction
          • More common w/Rosuvastatin/Simvastatin
          • Proteinuria, hematuria, AKI
          • Switch to Atorvastatin, Fluvastatin, pravastatin
        • Diabetes Mellitus
          • Increased plasma glucose concentrations
    • CI: Pregnancy, Lactation, Acute liver failure/decompensated cirrhosis
      • VATER association, TE fistulas, anal atresias
    • Interactions
      • Amlodipine, diltiazem, verapamil with simvastatin or lovastatin increases risk of toxicity
      • Gemfibrozil: Increased risk for muscle toc
      • Colestipol and antacids decrease plasma concentration
      • Amiodarone, cranberry, grapefruit
    • Monitoring
      • Lipid profile at baseline, then 2 months after
      • LFTs and TSH at baseline, ± CK level
  • Niacin
    • Drugs: Niacin
    • Lipolysis Decreased in Adipose Tissues
      • Moderate LDL Decrease
      • Large HDL Increase
      • Moderate Triglycerides Decrease
    • Flushing and pruritis is caused by prostaglandin-induced peripheral vasodilation
      • Low dose aspirin may reduce symptoms
  • Lomitapide (Juxtapid)
    • MTTP Inhibitors (VLDL)
  • Mitratapide (Yarvitan)
    • MTTP Inhibitors (VLDL)

GI Tract

  • Ezetimibe (Zetia)
    • Cholesterol Absorption Inhibitor at Intestinal Border, NPC1L1
    • Moderate LDL Decrease (15-20%, 2nd line)
    • May be used in ASCVD w/very high risk on max statin with LDL ≥70 or non-HDL ≥100
    • HDL Unchanged
    • Triglycerides Unchanged
  • Bile Acid Sequestrants/Resins (LDL)
    • Drugs: Cholestyramine, Colesevelam (Welchol), Colestipol
    • Inhibits reabsorption of bile acids, decreasing lipoprotein levels
    • Alone or in combo with Stains
    • Moderate LDL Decrease
    • Mild HDL Increase
    • Triglycerides Unchanged-Increased

Blood Vessels

  • Fibrates (Lipoprotein lipolysis Induction, PPAR)
    • Drugs: Fenofibrate (Tricor), Gemfibrozil (Lopid)
      • Not as favorable CV effects as statins or niacin
    • Moderate LDL Decrease
    • Moderate HDL Increase
    • Large Triglycerides Decrease (35-50%)
  • PCSK9 Inhibitors (LDL)
    • MOA: Proprotein convertase subtilisin/kexin type 9 (PCSK9), produced by liver that leads to degradation of hepatocyte LDL receptors via internalization and destruction
    • Evolocamab
    • Alirocumab (Praluent)
    • Trials
      • FOURIER (2017)
        • Among patients with clinical atherosclerotic disease and LDL ≥ 70 despite high or moderate intensity statin therapy (70% high intensity), Evolocumab resulted in an absolute 1.5% reduction in MACE at 26m. Mainly from reduction in nonfatal MI, stroke, and revascularization.
          • No mortality benefits
          • Absolute reduction in CVE was greater with more advanced CKD
      • ODESSEY OUTCOMES (2021)
        • In recent ACS and LDL ~70 on optimized statin therapy, PCSK9 inhibitors provide clinical benefit only when lp(a) is at least mildly elevated.
        • Mortality benefit in the long term
    • SE: Injection site reaction