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Lipid Therapy

  • 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