Lecture 36 Dyslipidemia Therapeutics Barry LIPIDS:

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1 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/ ): > 13 Requires aggressive treatment Ex// LDL-C apheresis = dialysis of cholesterol APPROACH TO TREATMENT: 1. Address all modifiable risk factors 2. Recommend lifestyle modifications 3. Assess need for pharmacotherapy 4. Monitor and follow-up 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) Efavirenz Amiodarone Estrogens Anabolic steroids Loop diuretics Antiepileptics Progestins Antipsychotics Protease inhibitors B-blockers (non-isa) Retinoids Corticosteroids Tacrolimus Cyclosporine Thiazide diuretics 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 rule 0 cigarettes 5 servings of fruits/veggies 30 mins of exercise

2 PRIMARY PREVENTION FRS CONSIDER STATIN THERAPY SIMPLIFIED ( 20% All patients Strongly encourage discussing initiation of statin therapy (preferably high-intensity) Suggest discussing initiation of statin therapy (preferably moderate-intensity) 10 LDL-C 3.5 mmol/l 19% apob 1.2 g/l non-hdl-c 4.3 mmol/l Men 50 or women 60 with 1 CV risk factor < 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: 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% 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 LDL-C < mmol/l ApoB < 0.8 g/l condition Primary prevention > 50% reduction in LDL-C Non-HDL-C < 2.6 mmol/l 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 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 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

3 STATINS CONTINUED. ADVERSE EFFECTS: MYOPATHY: ENT: cataracts DEFINITIONS: GI: NVD Creatine kinase (CK): tissue enzyme that is released during MSK: myopathy muscle breakdown (particularly skeletal muscle) HEPATIC: elevated liver enzymes Myopathy: muscle related pathology ENDO: diabetes Myalgia: muscle pain with CK ULN Multiple rare adverse effects (<1%) my Myositis: myalgia with CK > ULN LIVER ENZYME ELEVATION: Rhabdomyolysis: muscle breakdown with CK > 10 x ULN ± Also known as transaminitis serum myoglobin and renal failure Incidence up to 3% INCIDENCE: up to 5% RISK FACTORS FOR MYALGIAS: Alanine aminotransferase Class effect Hx of myalgias with statins (ALT) > 3x ULN Possibly dose-related or unexplained muscle aches Generally asymptomatic and Usually occurs in first 6 reversible FamHx of muscle disorders months of therapy Usually occurs in first 3-4 Female Doesn t require CK months of therapy Small body frame elevation (myalgia) May be dose-related Advanced age Pain usually presents in Hypothyroidism large muscle groups Renal or hepatic impairment 40% of patients will Baseline ALT Drug interactions tolerate another statin Serial ALT monitoring no longer recommended RHABDOMYOLYSIS: Does not predict liver Incidence: 1-2 per 10,000 person-year damage of failure Myoglobinemia myoglobinuria o Liver failure 1 in 2 Can lead to acute renal failure (darkens urine) million Not well predicted by myalgias Likely dose-related CONTRAINDICATIONS: Increased risk with COCOMITANT FIBRATE Active liver disease DISCONTINUE STATIN and do not rechallange Unexplained persistent elevations in serum liver transaminases Baseline CK and TSH Pregnancy or lactation If asymptomatic do not measure CK Hypersensitivity If symptomatic hold/stop statin and measure CK Rosuvastatin 40mg PO daily o If CK not elevated, restart statin contraindicated in Asian o If CK elevated, follow algorithm patients or patients with predisposing factors for Restart, switch or lower dose once CK ULN NOTE: CK elevated by exercise, trauma, infection myopathy/rhabdomyolysis Coenzyme Q10 supplement not recommended for myopathy

4 STATIN MYTH-BUSTING: Should statins be used in YES consider if life expectancy > 3-5 year elderly patients? If a patient s CK is elevated, Not always should the statin be stopped? 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 Debatable without CK elevation, should Tolerable watch and wait the statin be stopped? Intolerable hold and restart, switch, or lower dose once asymptomatic If a patient has a documented Some patients will tolerate another statin statin-related myopathy, can Start low, go slow they be changed to another o Dose every other day or once-weekly statin? o Try several statins Rhabdomyolysis do not rechallenge If a patient is not at their LDL- No C target with a statin, is Statin + gemfibrozil CONTRAINDICATED adding a fibrate a good o Increased risk of myopathy adjunct therapy? No benefit observed with statin + fenofibrate Dose high-dose statin Possibly therapy, as compared to low Limited evidence to support statement dose, increase the risk of No increased risk of myopathy in clinical trials myopathy? 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 No association impairment? Rare idiosyncratic adverse effect Do statins cause cancer? No association Does the dose of statin It depends matter in primary Use dose from RCTs whenever possible prevention? 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 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

5 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