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