Table of contents
- 1. Familial Hypercholesterolemia
- 2. Metabolic Syndrome
- 3. Hyperlipidemia
- 4. Lipid Guideline
- 5. US Lipid Guideline
- 6. Treatment
- 6.1.1. Statins
- 6.2. Statin Types
- 6.2.1. Ezetimibe (Esotrol)
- 6.2.2. Niacin
- 6.2.3. Bile Acid Sequestrants
- 6.2.4. Fibrates
- 7. Hypertrigliceridemia
- 7.1. Treatment
- 8. PCSK9 Inhibitors
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
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.
- 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.
- apo B ≥ 1.2 g/L
- 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
- apo B ≤ 0.8 g/L
- LDL-C ≤ 2.0 mmol/L or ≥ 50% LDL-C reduction.
- 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)
- eGFR ≤ 45
- HTN + 3RF's:
- Male
- Age > 55yo
- Smoking
- TC/HDL-C ratio > 6
- LVH
- FHx of premature CVD (<55M and <65F)
- ECG abnormalities
- Microalbuminuria
- Evidence of atherosclerosis including:
- High Risk:
- Low Risk (FRS 5-9%):
-
- 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).
- Step I - <30% total energy as fat, < 10% total energy as saturated fat.
- 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.
- Nutrition Therapy:
- Non-Pharmacological Treatment
- 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
- Lipoprotein A (LpA) - LDL-like particle, proatherogenic. Plasma conc controlled by LPA gene (90% inheritance) - so helpful if familial CAD/dyslipidemia.
- 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:
- 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.
- Simvastatin (PRONE TO DRUG-DRUG Interactions), Cyp3A4 metabolized.
- 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.
- Case reports of memory loss and confusion. Not emerged in many clinical trials.
- 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]
- Mechanism unknown. Recent suggestion (2014):
- Increased risk of TIIDM cited with TZD diuretics, B-blockers, glucocorticoids, niacin, protease inhibitors.
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
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.
- 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, danazolCAUTION:
- Diltiazem, verapamil, amiodarone, dronaderone canbe 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)
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
- Primary Hyperlipidemia: adjunct to diet and maximally tolerated statin therapy for treatment of heterozygous familial hypercholesterolemia (HeFH)
- 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
- adjunct to diet and maximally tolerated statin therapy in adults with HeFH
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