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Lecture 36 Dyslipidemia Therapeutics Barry
LIPIDS:
PATHOPHYSIOLOGY:
↑ TC or LDL-C = ↑ CVD
↑ HDL-C = ↓ CVD
Association between TG and CVD not established o HyperTG associated with pancreatitis o Reducing TG w/ drug therapy doesn’t ↓ CVD
TYPES OF DYSLIPIDEMIA:
Primary: genetic cause o Familial hypercholesteremia
Autosomal dominant genetic disorder High LDL-C level premature CVD
Normal: 2-5 (mmol/L)
Heterozygous (1/500): 5-13
Homozygous (1/1000000): > 13
Requires aggressive treatment Ex// LDL-C apheresis = “dialysis” of
cholesterol
Secondary: other causes o Sedentary lifestyle o Excessive dietary fat intake o Diseases: hypothyroidism, CKD, obstructive
liver disease o Cigarette smoking o Drugs
Alcohol (excessive)
Amiodarone
Anabolic steroids
Antiepileptics
Antipsychotics
B-blockers (non-ISA)
Corticosteroids
Cyclosporine
Efavirenz
Estrogens
Loop diuretics
Progestins
Protease inhibitors
Retinoids
Tacrolimus
Thiazide diuretics
APPROACH TO TREATMENT: 1. Address all modifiable risk factors 2. Recommend lifestyle modifications 3. Assess need for pharmacotherapy 4. Monitor and follow-up
LIFESTYLE MODIFICATIONS:
Smoking cessation – probably most important health behavior intervention for preventing CVD
Exercise o ≥ 150 min of mod – vigorous aerobic activity per week in bouts of ≥ 10 min o Muscle and bone strengthening activities ≥ 2 days per week
Healthy eating o Moderate caloric intake to maintain healthy weight o Veggies, fruits, whole grain cereals, polyunsaturated & monosaturated oils (ex// omega-3 FAs from fish)
Do not recommend omega-3 FAs supplements to reduce risk of CVD o Avoid trans fats and limit saturated and total fat to < 7% & < 30% of daily and total caloric intake, respectively o Increase daily fibre intake to > 30 g o Limit cholesterol intake to 200 mg daily o Mediterranean dietary pattern
Moderate alcohol consumption o 1 drink/day for women o 1-2 drinks/day for men
Moderate sleep duration (6-8 hours)
Stress management 0 – 5 – 30 rule 0 cigarettes 5 servings of fruits/veggies 30 mins of exercise
Lecture 36 Dyslipidemia Therapeutics Barry
PRIMARY PREVENTION FRS CONSIDER STATIN THERAPY SIMPLIFIED (
≥ 20% All patients Strongly encourage discussing initiation of statin therapy (preferably high-intensity)
10 – 19%
LDL-C ≥ 3.5 mmol/L
apoB ≥ 1.2 g/L
non-HDL-C ≥ 4.3 mmol/L
Men ≥ 50 or women ≥ 60 with ≥ 1 CV risk factor
Suggest discussing initiation of statin therapy (preferably moderate-intensity)
< 10% Not recommended Suggest repeat CV risk assessment in 5 years
* CV risk factors: elevated waist-to-hip ratio (abdominal obesity), low HDL-C (< 1.0 mmol/L in men, <1.3 in women), current or recent (≤ 5 yr) tobacco use, impaired fasting glucose, impaired glucose tolerance, uncomplicated diet-controlled DM, FamHx of premature CAD, mild renal dysfunction
PHARMACOLOGIC TREATMENT: Drug Class LDL-C HDL-C TG
Statins ↓ 20-65% ↑ 5-15% ↓ 7-30%
Ezetimibe ↓ 18% ↑ 1% ↓ 6%
Fibrates ↓ 5-20% ↑ 10-20% ↓20-50%
Niacin ↓ 5-25% ↑ 15-35% ↓ 20-35%
BAS ↓ 15-30% ↑ 3-5% -
STATINS: DOSING:
Simvastatin 80 mg PO daily no longer recommended (increased risk of myopathy)
Atorvastatin and rosuvastatin can be taken at anytime o Take other statins with evening
meal or at HS (Cpeak matches liver producing more cholesterol at night)
Potency: RASLPF o In general, doubling statin dose
↓LDL-C by a further 6%
TARGET LIPID LEVELS: RISK CATEGORY PRIMARY TARGET ALTERNATE TARGET
Statin indicated condition
LDL-C < mmol/L
> 50% reduction in LDL-C
ApoB < 0.8 g/L
Non-HDL-C < 2.6 mmol/L Primary
prevention
LDL-C > 5.0 mmol/L
> 50% reduction in LDL-C N/A
No RCT has targeted a specific LDL-C
Higher intensity statin therapy superior to lower intensity
↓ LDL-C associated with ↓risk of CV events
May aid clinicians in optimizing statin therapy
Absence of evidence to contradict previous guidelines
STATIN METABOLISM:
Atorvastatin CYP3A4
Lovastatin
Simvastatin
Fluvastatin CYP2C9
Rosuvastatin
Pravastatin Not CYP
INCREASE STATIN LEVELS:
CYP3A4 inhibitors: o Macrolide antibiotics o Grapefruit juice o Azole antifungals o Protease inhibitors * can’t separate times because inhibition persists for the day
Other drugs that inhibit statin metabolism: o Amiodarone o Colchicine o Cyclosporine o Diltiazem o Verapamil o Amlodipine
DECREASE STATIN LEVELS
Rifampin
Carbamazepine
Phenytoin
Phenobarbital
St. John’s wort
Rosuvastatin + magnesium/ aluminum antacids o Separate dose by 2 hrs
APPROACH TO STATIN DRUG INTERACTIONS:
Assess level of risk (interaction, pt, situation)
If low risk monitor
If mod/high risk consider alternative o If no alternative exists, is patient able to monitor?
Consider dose reduction/holding statin
STATINS: ↓ LDL-C Rosuvastatin ↓ 40-65%
Atorvastatin ↓ 35-60%
Simvastatin ↓35-50$
Lovastatin ↓25-40%
Pravastatin ↓ 20-35%
Fluvastatin
Doubling statin dose ↓LDL-C by a further 6%
Lecture 36 Dyslipidemia Therapeutics Barry
STATINS CONTINUED….
ADVERSE EFFECTS:
ENT: cataracts
GI: NVD
MSK: myopathy
HEPATIC: elevated liver enzymes
ENDO: diabetes
Multiple rare adverse effects (<1%) my
MYOPATHY: Coenzyme Q10 supplement not recommended for myopathy f
DEFINITIONS:
Creatine kinase (CK): tissue enzyme that is released during muscle breakdown (particularly skeletal muscle)
Myopathy: muscle related pathology
Myalgia: muscle pain with CK ≤ ULN
Myositis: myalgia with CK > ULN
Rhabdomyolysis: muscle breakdown with CK > 10 x ULN ± serum myoglobin and renal failure
INCIDENCE: up to 5%
Class effect
Possibly dose-related
Usually occurs in first 6 months of therapy
Doesn’t require CK elevation (myalgia)
Pain usually presents in large muscle groups
≥ 40% of patients will tolerate another statin
RISK FACTORS FOR MYALGIAS:
Hx of myalgias with statins or unexplained muscle aches
FamHx of muscle disorders
Female
Small body frame
Advanced age
Hypothyroidism
Renal or hepatic impairment
Drug interactions
RHABDOMYOLYSIS:
Incidence: 1-2 per 10,000 person-year
Myoglobinemia myoglobinuria
Can lead to acute renal failure (darkens urine)
Not well predicted by myalgias
Likely dose-related
Increased risk with COCOMITANT FIBRATE
DISCONTINUE STATIN and do not rechallange
MONITORING:
Baseline CK and TSH
If asymptomatic do not measure CK
If symptomatic hold/stop statin and measure CK o If CK not elevated, restart statin o If CK elevated, follow algorithm
Restart, switch or lower dose once CK ≤ ULN
NOTE: CK elevated by exercise, trauma, infection
LIVER ENZYME ELEVATION:
Also known as transaminitis
Incidence up to 3%
Alanine aminotransferase (ALT) > 3x ULN
Generally asymptomatic and reversible
Usually occurs in first 3-4 months of therapy
May be dose-related MONITORING:
Baseline ALT
Serial ALT monitoring no longer recommended
Does not predict liver damage of failure o Liver failure 1 in 2
million
CONTRAINDICATIONS:
Active liver disease
Unexplained persistent elevations in serum liver transaminases
Pregnancy or lactation
Hypersensitivity
Rosuvastatin 40mg PO daily contraindicated in Asian patients or patients with pre-disposing factors for myopathy/rhabdomyolysis
Lecture 36 Dyslipidemia Therapeutics Barry
STATIN MYTH-BUSTING:
Should statins be used in elderly patients?
YES consider if life expectancy > 3-5 year
If a patient’s CK is elevated, should the statin be stopped?
Not always
Rule out other causes
If CK ≤ 5x ULN continue o Repeat in 6-12 weeks
If patient symptomatic hold o Restart, switch, or lower dose once CK ≤ ULN
If a patient has myalgias without CK elevation, should the statin be stopped?
Debatable
Tolerable watch and wait
Intolerable hold and restart, switch, or lower dose once asymptomatic
If a patient has a documented statin-related myopathy, can they be changed to another statin?
Some patients will tolerate another statin
Start low, go slow o Dose every other day or once-weekly o Try several statins
Rhabdomyolysis do not rechallenge
If a patient is not at their LDL-C target with a statin, is adding a fibrate a good adjunct therapy?
No
Statin + gemfibrozil CONTRAINDICATED o Increased risk of myopathy
No benefit observed with statin + fenofibrate
Dose high-dose statin therapy, as compared to low dose, increase the risk of myopathy?
Possibly
Limited evidence to support statement
No increased risk of myopathy in clinical trials o EXCEPTION: simvastatin 80 mg po daily
Do statins cause diabetes? Positive association
NNT for reducing CB events < NNH
Higher risk for patients with pre-existing risk factors for DM
Do statins cause cognitive impairment?
No association
Rare idiosyncratic adverse effect
Do statins cause cancer? No association
Does the dose of statin matter in primary prevention?
It depends
Use dose from RCTs whenever possible
Good approach is to start low and go slow
Starting dose: 20-40% reduction in LDL-C o Doubling dose: additional 6% reduction
STATIN ADHERENCE:
Educational interventions: o Provide written and/or verbal information o Remind pt/family of indication/benefit o Demystify pt-specific concerns over harm
Behavioral interventions: o Motivational interviewing o Simplify regimen o Recommend adherence aid or reminder system o Follow-up
MONITORING:
Baseline: o Lipid profile, ALT, CK o A1c, TSH, SCr if clinically indicated
Efficacy: o CV events o Lipid profile (if utilizing targets)
Safety: o Adverse effects
Lecture 36 Dyslipidemia Therapeutics Barry
EZETIMIBE:
Indicated to lower LDL-C as adjunct to statin o ↓ LDL-C by 18%
Synergistic with statin o Increased liver enzymes when in
combination with statins
Monotherapy if patient statin intolerant
Limited CV outcome data
FIBRATES: Bezafibrate, fenofibrate, gemfibrozil
First line therapy to ↓ TG (20-25%) to reduce risk of pancreatitis
↓ LDL-C by 5-20%
Limited CV outcome data
BILE ACID SEQUESTRANTS: Cholestyramine, colesevelam, colestipol Indicated to lower LDL-C
(15-30%) as adjunct to statin
Multiple GI adverse effects
Multiple drug interactions
NIACIN: crystalline niacin, ER niacin
Indicated for combined dyslipidemia o ↓LDL-C by 5-25% o ↑ HDL-C by 20-35%
Limited CV outcome data
ADVERSE EFFECT: CUTANEOUS FLUSHING
Prostaglandin-mediated o NOT histamine
Lessens with tolerance
Dose after meals or at HS
FORMULATIONS:
ER niacin decreases flushing but increases risk of hepatotoxicity
Flush-free niacin contains inositol NOT ABSORBED = ineffective
PCSK9 INHIBITORS: Alirocumab, Evolocumab
PCSK = proprotein convertase subtilisin-kexin
PCSK9 inhibitors are fully human or humanized mAb
Phase 2 data: dose-dependent LDL-C lowering of 40-70% in combination with statin
Limited phase 3 data