Lipids

    Familial Hypercholesterolemia

    • Defective LDL receptor
    • Prevlanece of heterozygote: 1:500 (need homozygote)
    • More common in:
      • French Candian
      • South African
      • Lebanese

    Metabolic Syndrome

    • Central obesity (wast circ >94 in men, >80cm in women) plus 2/4:
      • TG >1.7 mmol/L
      • HDL-C <1.0 mmol/L in men and <1.3 in women
      • Blood pressure >135/85
      • Fasting Blood Glucose >5.6 mmol/L

    Hyperlipidemia

    • Signs:
      • Tendinous Xanthoma
      • Xanthelasma
      • Arcus cornealis
    • Associated with coronary and vascular events (22%)
    • lipidsCAD.jpg

    Lipid Guideline

    Framingham Risk Score

    • Double the risk if family history positive for CVD:
      • Male 1st degree relatives <55 Males, and < 65 Females without Diabetes!.
    • Framingham Risk Score (FRS) --> family hx --> modified FRS.

    LipidGuidelinesTable2013c.png

    • 2012 Lipids Update:
      • Low Risk (FRS 5-9%): 
        • More frequent Yearly assessment.
        • Judicious use of secondary testing.
        • Aggressive non-pharmacologic management (risk modification).
      • Intermediate Risk (FRS ≥ 10% and < 20%)
        • Treat if LDL-C ≥3.5 mmol/L (benefit significant)
        • If LDL-C < 3.5, use Secondary Targets:
          • apo B ≥ 1.2 g/L 
            OR
          • non-HDL-C ≥ 4.3 mmol/L  (Added b/c apoB not always available, calculate TG-HDL= non-HDL.  Especially useful if apoB not available and TG > 1.5 - rendering LDL not accurate)
            Can also consider:
          • hsCRP ≥ 2mg/L (if intermediate risk, use hsCRP in men > 50, women > 60 and LDL < 3.5 to determine need for statin - JUPITER trial)
          • hsCRP may be helpful for re-classifying patients with intermediate CV risk as either high or low risk who don't meet treatment criteria
            • JUPITER trial: Elevated hsCRP in intermediate risk (no indication for statin based on LDL) randomized to statin or no statin, statin therapy = reduces by CV events.  Also lowered hsCRP by 37% (stopped early). Primary end point from 1.36 to 0.77 /100pt years. (Absolute reduction 1.2%)
            • Hence: hsCRP is an independent predictor for adverse CV events, and should be used in patients who are intermediate risk (10-20%) and midly elevated LDL to determine the need for statin therapy.
            • NOTE: CRP is a non-specific indicator… pts with level >1 should have it repeated in 2 weeks b/c high level can reflect underlying infection/inflammatory condition.
        • Notes:
          • LDL is poor indicator, esp if TG > 1.5 since TG start incorporating into LDL. Apo B does not change.  non-HCL-C = TG - HDL-C.
          • non-HDL-C and Apo B do not need fasting.
        • Target:
          • LDL-C ≤ 2.0 mmol/L or ≥ 50% LDL-C reduction.  
            • Most studies used LDL as target.  1 mmol/L decrease in LDL-C = 20-25% CVD mortality and non-fatal MI.
          • Alternate Targets:  (Can be substituted for LDL)
            • apo B ≤ 0.8 g/L
              OR
            • non-HDL-C ≤ 2.6 mmol/L
      • High Risk (FRS ≥ 20 OR High Risk Factors)
        • High Risk:
          • Evidence of atherosclerosis including:
            • CVA/TIA
            • MI
            • Peripheral arterial disease
            • Any Arterial Revasc. Procedures
            • Abdominal Aneurism (not thoracic)
          • Diabetes
            • Type I or Type II and >40yo.
            • Type I or Type II > 15years duration and > 30yo.
            • CVD, microvascular complications.
          • CKD
            • eGFR ≤ 45
              OR
            • ACR ≥ 30 (≥300mg/day)
          • HTN + 3RF's:
            • Male
            • Age > 55yo
            • Smoking
            • TC/HDL-C ratio > 6
            • LVH
            • FHx of premature CVD (<55M and <65F)
            • ECG abnormalities
            • Microalbuminuria
      • Non-Pharmacological Treatment
        • Nutrition Therapy:
          • Step I - <30% total energy as fat, < 10% total energy as saturated fat.
            • Avg LDL-C drop by 12%
          • Step II - < 7% of energy as saturated fat, dietary cholesterol < 200mg/d.
            • Avg LDL-C drop of 16%
          • Also: DASH diet recommended (Dietary Approach to Stop Hypertension).
        • Exercise Therapy
          • Recommended: 150min of moderate to vigorous aerobic activity /week in bouts of >10min.
          • Also benefit to add strength training ≥2days/week.
        • Psychological Health
          • Stress is a CVD risk factor (INTERHEART Study)
          • After MI, patient's with depression --> worse prognosis. (unclear if pharmacologic tx reduces risk).
        • Smoking Cessation
          • Single most important health behaviour intervetion for CVD.
    • Other Notes:
      • HDL-based and TG-based targets are unproven.  Also considering niacin and fibrates that act on them do not improve CVD outcomes when added to statin.   Ongoing research as of 2014.
    • Considerations:
      • Relative risk reduction with statins is independent of baseline risk or cholesterol levels, but absolute risk reduction is smaller in low risk individuals.
      • If Low Risk => NNT = ~100
      • Other biomarkers can be used:
        • Lipoprotein A (LpA) - LDL-like particle, proatherogenic.  Plasma conc controlled by LPA gene (90% inheritance) - so helpful if familial CAD/dyslipidemia.
          • Lp(a) 300-760 --> 1.7 fold hazard ratio.
          • Lp(a) > 300 mg/L --> progressive increase in risk.
        • hsCRP
          • Produced in liver in response to inflammatory IL-6 (also produced in adipose, endothelial, and smooth muscle cells). 
          • CRP > 2.0 mg/L --> hazard ratio CVD of 1.5 increase.
          • NOT related to CVD risk, thus not a target of therapy.
          • JUPITER study: men > 50yo and women > 60yo and LDL < 3.5 and hsCRP > 2.0 mg/L --> benefited from rosuvastatin with 50% RRR in major coronary events.
        • Hb A1c
          • EPIC Study: 45-79yo.  <5.0% lowest rate of CVD mortality.  For every 1% increase in RR of death by 1.24.
          • 6.0-6.5% Hazard ratio is 1.78.
        • ACR
          • Associated with HTN and Diabetes.
          • 169,959 pts (meta-analysis): microalbuminuria (30-300 mg/d) ass'd with 2.17-fold increased CAD risk. 
        • Other non-invastive tests:
          • Stress test. (Either positive/negative also high risk if < 6 METs)
          • Carotid ultrasound imaging
          • Ankle Brachial Index (normal 1.0-1.2)  (Useful in smokers for extra risk stratification)
            • > 1.3 - arterial calcification and noncompressible blood vessels --> incr CVD risk.
            • < 0.9 is 2.0 fold incr risk of CVD
            • < 0.60 is 4.3 fold incr risk of CVD.
        • Coronary artery calcium
      • Side Effects of Statins
        • Baseline transaminases (ALT), creatinine, and CK are useful to monitor for potential S/E.  No indication to repeat this.
        • Statins not contraindicated in mild-mod elevations in ALT due to hepatic steatosis, chronic HepC, PBC.
        • Adverse Effects:
    1. Drug Interactions
      • Simvastatin (PRONE TO DRUG-DRUG Interactions), Cyp3A4 metabolized.
        • Amiodarone, Diltiazem, and amlodipine. 
        • Amlodipine - Max simvastatin dose 20mg.
        • Amiodarone, Diltiazem, Verapamil - Max dose 10mg.
        • DO NOT use concurrently with antifungals, gemfibrozil, cyclosporine, macrolide abx.
    2. Neurologic Effects
      • Case reports of memory loss and confusion.  Not emerged in many clinical trials.
        • In fact may reduce risk of Parkinson's.
      • Subarachnoid Hemorrhage?
        • Re-evaluated in 31 RCT's with 180,000 ppl --> no significant risk.  (reduction in all strokes and all-cause mortality observed though).
        • CCT Meta-analysis --> Very small increased risk, but benefits in reducing overall stroke risk supercede it.
    3. Diabetes
      • Increased risk of TIIDM cited with TZD diuretics, B-blockers, glucocorticoids, niacin, protease inhibitors.
        • Mechanism unknown.  Recent suggestion (2014):
          • Statins increase insulin levels, reduce insulin sensitivity, survivor selection bias.
          • Reduction in CVD events outweighs the mintor effect on glucose homeostasis. 
        • Fasting glucose levels influenced by paroxetine + pravastatin (ONLY THIS COMBO - not independently, and not other statins/ssri's). [Tatonetti et al. 2011; 57:1535-45]

     

    US Lipid Guideline

    • Identified four "Statin Benefit" risk groups in whom CV risk reduction outweighs adverse effects risk.
    • Secondary Prevention: "High-Intensity Statin" (example: Rosuvastatin 20-40mg or atorvastatin 80mg)
    • Primary Prevention: "Moderate or High-Intensity Statin"  (example simvastatin 20-40mg)
    • LDL or non-HDL treatment targets were REMOVED!
    • 4 Groups that benefit from statin therapy:
      • 1. Atherosclerotic CVD (ASCVD)
      • 2. Primary elevations of LDL ≥190 mg/dL (4.9 mmol/L)
      • 3. Diabetes patients 40-75yo with LDL of 70-189 (1.8-4.9)
      • 4. Estimated 10-year CV risk ≥7.5%

    Treatment

     

    Metabolic Effects of Lipid Altering Medication
    Medication Effect
    Crestor (Rosuvastatin) ↓LDL ↑HDL (more potent drug) 
    Atorvastatin ↓ LDL, ↓ TG
    Fibrate

    ↑ HDL, ↓ TG (Poor LDL effect,

                          cannot combine with statin)

    Ezetimibe

    Same effect as statin

    Can increase S/E if combined w statin)

    Niacin ↑ HDL, ↓ LDL
    Cholesterimine ?

     

    Statins

    • Mechanism: Block HMG-CoA reductase in Liver to limit endogenous biosynthesis of cholesterol (~80% of it is endogenous)
    • Reduce cardiovascular disease risk by 25-35%
    • Rule of 6's:
      • (i.e. atorvastatin)
      • 1st Dose 10mg: 38% lowering
      • 2nd Dose - double: 20mg: 6% more lowering
      • 3rd Dose - double: 40mg:  6% more lowering
      • 4rth Dose -double: 80mg: 6% more lowering 
      • Note: Always double, no point prescribing in between.

    StatinEffects.jpg

     

    • If cannot tolerate statin, decrease dose, space out intervals.
    • One study: Weekly 5-10mg of rosuvastatin (randomized, double-blind, but small study) -> 10% lipid lowering in pts with hx of statin-associated myalgia.
    • PREGNANCY CLASS X (do not use)
      • If pregnant, use colesevelam.
    • Liver enzyme elevation with statins:
      • FDA guidelines indicated measuring baseline liver enzymes, and repeat not needed unless signs of liver disease.
      • Elevation up to 3 times ULN is allowed, represents a transient leak of liver enzymes due to increase in hepatocyte permeability (not hepatocellular damage). 
      • If liver enzymes elevate too much, then d/c statin, and repeat enzymes, and likely workup other causes of liver disease (Hepatitis screening, alcohol, etc..)
    • CK Elevation and Myopathy
      • If patient has mild symptoms and/or has mild elevation of CK, either decrease dose or switch statin to a more hydrophilic one (i.e. pravastatin, rosuvastatin). 
      • HOLD statin if CK is >5x ULN or patient has SEVERE symptoms

    Statin Types

    • Statin (inr potency)  Lipophilic** Doses Notes
      Pravastatin - - -

      Mod Intensity: 40mg

      High Intensity: 80mg (myopathy risk)

      NOTE: 80mg pravastatin has high risk of myopathy

      If High intensity statin is needed, upgrade to more

      potent one (atorva or rosuva) 

      Simvastatin

      +++

      Mod Intensity: 20-40mg

      - HIGH Risk of drug interactions

      Contraindicated combos: ketoconazole,
         erythromycin, protease inhibitors, gemfibrozil,
        cyclosporine, danazol

      CAUTION:
      - Diltiazem, verapamil, amiodarone, dronaderone can

        be used but the dose of simvastatin must be ≤ 10mg

      - Amlodipine can be combined, but simva dose

         must be ≤ 20mg

      Lovastatin ++    
      Fluvastatin +    
      Atorvastatin +

      Starting dose: 10-40mg

      Mod Intensity: 10-20mg

      High Intensity: 40-80mg

       
      Rosuvastatin -

      Starting dose: 20mg

      Mod Intensity: 5-10mg

      High Intensity: 20-40mg

       
    • **Lipophilic  - can cross blood brain barrier, and some believe it can cause more CNS s/e such as insomnia and concentrate in muscle to cause myopathy.

     

     

     

    Non-Statins

    • No studies demonstrated decrease in CVD event rate with statins + non-statin lipid lowering drugs.
    • Only exception is SHARP trial of simvastatin + ezetimibe --> decreased CVD rates, but no statin-only arm.
    • If cannot tolerate statin (or only low doses) reduction LDL can be achieved by adding bile acid resins, ezetimibe, or niacin.

    Ezetimibe (Esotrol)

    • Blocks intestinal absorption of cholesterol - liver decreases LDL production and turns on LDL receptor
    • 18% decrease in lipids (equivalent to 3x doubling of the statin - 6%x3 = 18%),
      • Instead of doubling the statin dose 3 times, can add ezetimibe on the statin.  Both options maximize LDL lowering.
    • IMPROVE-IT trial
      • Added ezetimibe to simvastatin in pts with ACS = 2% ARR in composite end point
      • No improvement in mortality (unlike statins that have robust mortality data)
    • Pregnancy class X (AVOID in pregnancy)

    Niacin

    • Lowers LDL-C, TG and one of the most effective agents in raising HDL (up to 40%)
    • Daily dose >2g/d for significant lipid effect
    • Main side effect: flushing (2/3 of patients based on trial)
      • The "flush blocker" development underway.
    • Two meta-analysis in 2014 and 2010 demonstrated no benefit of niacin in patients already taking a statin, but may be helpful as a monotherapy. (Keene 2014, BMJ)
    • Niacin monotherapy shown decrease CVD rates.  (1986 Trial Canner et al J. Am. Coll. Cardiol.;27:1683-90)

    Bile Acid Sequestrants

    • Examples: Colesevelam, Cholestyrimine
    • Shown to lower LDL by upt o 18%.
    • Shown to reduce risk of CAD in primary prevention trials.
    • S/E:
      • GI: Constipation, Abdominal Pain, Bloating, Flatulence
      • Reduce absorption of some drugs, do not take other drugs 1h before and 4h after.
    • Colesevelam: pregnancy class B (SAFE)

    Fibrates

    • I.e. Gemfibrozil
    • Increase HDL, and VERY effective in lowering TG levels.
    • As of Jan 2017 - Not consistently shown to improve CV risk (reserved fo pts with severely elevated TG or ver low HDL-C)
    • ACCORD Lipid Trial
      • Simvastatin + Fenofibrate --> No benefit in CVD mortality        
      • Subgroup analysis Possible benefit fibrates in group with high TG (>2.3) and low HDL-C (<0.88) [converted US units]
      • Not as conclusive, weak evidence, only one trial.  (2014)

     

    Eicosapentaenoic Acid Fish Oil

    • Reduces TG concentration (if very severely high TG > 500mg/dL)
    • No Evidence of CV protection (Jan2017)

    Hypertrigliceridemia

    TG <1.7 mmol/L Ideal
    TG 3-10 mmol/L

    Modest elevation - risk of CHD

    TG >10 mmol/L Risk of acute pancreatitis
    • Signs of Severe Hypertrigliceridemia (>10mmol/L)
      • Lipemia retinalis - pale retinal artery (person giving this talk said he has seen one in his career)
      • Eruptive Xanthoma (papules on skin)

    Treatment

    Fibrate

    • LPL not working, hence VLDL and CM accumulate, LDL is low.  Fibrate activates LPL.
    • LipidMetabolism.jpg

     

    PCSK9 Inhibitors

    Available in CANADA:

    • Alirocumab (Praluent)
      • SC injection (Pre-filled syringe)
      • Indication:
        • Primary Hyperlipidemia: adjunct to diet and maximally tolerated statin therapy for treatment of heterozygous familial hypercholesterolemia (HeFH)
          OR
        • Clinical CVD who require additional lowering of LDL-C
    • Evolucumab (Repatha)
      • SC injection (authoinjector 140mg/mL)
      • Indications
        • adjunct to diet and maximally tolerated statin therapy in adults with HeFH
          OR
        • Clinical CVD who require additional lowering of LDL-C
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