Lipids

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.

• 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]

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.

• 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

Treatment

Fibrate

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