Dyslipidemia Tx Options - Statins Flashcards
Health Behaviour Modifications
• Recommend for all patients at risk of CVD
- Smoking cessation
- Single most important health behaviour intervention for CVD prevention
- Dietary – it is recommended that all individuals adopt a health dietary pattern
- dietary modifications: calorie restriction, dietary fibre intake of >30 g daily, substitute unsaturated fats for saturated/trans fats, fruits and vegetables, limit cholesterol intake
- referral to dietician/nutritionist, where appropriate
- Exercise – it is recommended adults accumulate 150 mins/week of moderate to vigorous intensity aerobic physical activity
- Limit EtOH intake ‐‐ limit to 1‐2 drinks per day
- Psychological stress management
Pharmacologic Treatment
- HMG-CoA reductase inhibitors (statins)
- Cholesterol absorption inhibitor (ezetimibe)
- Niacin
- Fibrates
- Bile acid sequestrants (BAS)
- PCSK9(Proprotein Convertase Subtilisin/Kexin type 9) inhibitors
- Icosapent ethyl (IPE)
Relative Effects of Different Agents
see slide 45 for more
Statins LDL-D decrease 30‐50% (agent and dose dependent) HDL-C dec 4‐10% TG dec 20‐30% (>effect with higher TG)
Ezetimibe LDL-C dec 15‐20%
PCSK9‐i LDL-C dec 50‐60%
Statins – Mechanism of Action (MOA)
• Statins are the cornerstone of dyslipidemia management ‐‐ recommended as the initial lipid‐lowering agent of choice for treatment.
• Maximum dose or maximally tolerated statin should be used for all patients in whom treatment is indicated.
- upregulation of LDL‐receptors
- causes increased removal and catabolism of LDL‐C
- decreased VLDL production (VLDL carries serum TG’s)
- Promotes conversion of VLDL to LDL‐C
- these mechanisms lead to reduction in TC, LDL‐C and TG’s
Comparison of Statin LDL Lowering Rosuvastatin \_\_\_\_\_\_\_\_\_ Atorvastatin\_\_\_\_\_\_ Simvastatin 35 – 50 Lovastatin 25 – 40 Pravastatin 20 – 35 Fluvastatin \_\_\_\_\_\_
what are the doses for high intensity doses?
40 – 65
35 – 60
20-35
Everything except for rosu and ator is limited to moderate intensity reduction
ator: 40‐80 mg
rosu: 20‐40 mg
Statins LDL Lowering Effects
The law of diminishing returns
♥ “Rule of Sixes”: double dose = 6% LDL‐C lowering
Contraindications for statins
- Active liver disease
- Includes unexplained persistent elevations in ALT or AST and non‐alcoholic steatohepatitis (NASH)
- Use low dose in chronic stable liver disease
- No guidelines for dose reduction
- Monitor more frequently for adverse effects
- Pregnancy and lactation
- Hypersensitivity
Statin Clinical Pearls
timing of dosing
why we Do not recommend simvastatin 80 mg daily – previously marketed dose?
• Pravastatin only statin not metabolized by ________
- Less potent: take with evening meal or at hs
- Atorvastatin and rosuvastatin: take any time
- Atorvastatin and Rosuvastatin are the most potent statin, only ones that are truly high‐intensity
simvastatin
• No benefit over 40 mg daily
• Increased risk of myopathy
• Pravastatin only statin not metabolized by Cytochrome P450 enzymes
– useful when concerned about serious/significant drug interactions
statin metabolism
Atorvastatin CYP3A4 Fluvastatin CYP2C9 Lovastatin CYP3A4 Pravastatin Not well understood (not CYP) Rosuvastatin CYP2C9 Simvastatin CYP3A4
• Mnemonic for CYP3A4 statins: A.L.S.
what increases statin levels by interacting with CYP34A inhibitors
- Macrolide antibiotics (e.g., clarithromycin)
- Grapefruit juice
- Azole antifungals
- Protease inhibitors
- Other drugs that may decrease statin metabolism: amiodarone, diltiazem, verapamil, cyclosporine/tacrolimus, ± amlodipine
Decrease Statin Levels
- Rifampin
- Carbamazepine
- Phenytoin
- Bosentan
- Efavirenz
- Antacids
- Rosuvastatin + magnesium/aluminum antacids
- Dose antacid 2 hr after rosuvastatin
Approach to Drug Interactions
- Assess level of risk based on interaction, patient, situation
- If low risk, no additional monitoring required
- If high risk, consider alternative
- If no alternative exists, consider duration of therapy
- If duration ≥10 days, consider reducing dose/monitoring
- Caution in specialty populations
- Solid organ transplant (SOT) recipients and patients with HIV
Adverse Effects
- “Generally well tolerated” by the great majority of patients
- GI: nausea/vomiting/diarrhea
- MSK: myopathy
- HEPATIC: elevated liver enzymes
- ENDO: diabetes –in those predisposed (IFG, IGT, or prediabetes)
- Multiple rare adverse effects (<1%)
- “Nocebo effect”: people who have negative expectations about medicine or a treatment experience harmful symptoms they otherwise wouldn’t have.
describe the Statin Nocebo Effect
“Nocebo effect”: A situation in which a patient develops side effects or symptoms that can occur with a drug or other therapy just because the patient believes they may occur.
• people who have negative expectations about statins may experience symptoms of side effects that they otherwise wouldn’t have.
• opposite of a placebo effect
muscle‐related pathology
muscle pain with CK ≤ ULN
myalgia with CK > ULN
muscle breakdown with CK >10x ULN ± serum myoglobin and renal failure
• Creatine kinase (CK): tissue enzyme (particularly in
skeletal muscle) that is released during muscle
breakdown
mypoathy
myalgia
myositis
Rhabdomyolysis
Myopathy from statin
- Incidence: 1.5 – 5%
- Class effect
- Possibly dose‐related
- Usually occurs in first 6 months of therapy
- Does not require CK elevation (myalgia)
- Pain usually presents in large muscle groups
- ≥40% of patients will tolerate another statin
Risk Factors for Myopathy
- Hx of myalgias with statins
- Hx of unexplained muscle aches or positive FamHx
- Hypothyroidism
- Renal or hepatic impairment
- Female
- Small body frame
- Advanced age
- Drug interactions
Rhabdomyolysis
Incidence 0.04% (1 in 2,500 patients)
• Myoglobinemia myoglobinuria
• Can lead to acute renal failure (darkens urine)
• Not well predicted by myalgias
• Likely dose‐related
• Increased risk with fibrate combination
• Discontinue statin and do not rechallenge
Approach to Monitoring for myopathy
- Baseline CK and TSH in all patients
- Asymptomatic no routine CK monitoring
- CK elevated by exercise, trauma, infection
- Symptomatic d/c statin and measure CK
- CK ≤ ULN reassess symptoms and CK in 6‐12 weeks
- Resume statin once patient asymptomati
- CK <10x ULN consider other causes, follow until CK ≤ ULN and patient asymptomatic, then restart different statin or lower dose
- CK >10x ULN hydrate PRN, follow until CK ≤ ULN and patient asymptomatic, then restart different statin or lower dose (if moderate to severe, consider alternate therapy)
- Muscle biopsies have no role – low diagnostic yieldc
Coenzyme Q10
• Meta‐analysis of 6 RCTs (N = 302) showed no effect on muscle pain or
CK in patients on statin therapy
• Not recommended as per CCS guidelines
• No known risks of coenzyme Q10
• Patients that have a perceived effect (placebo) should not be dissuaded
Statin‐Induced Liver Enzyme Elevation
- Incidence: 0.1 – 3%
- Most often will present with ALT elevation
- More specific to liver vs AST
- Generally asymptomatic
- Usually occurs in first 6 months of therapy
- May be dose‐related
- Does not predict liver damage or failure
- 1 in 1.14 million
Approach to Monitoring Liver Enzyme Elevation
what are some signs and symptoms?
- Baseline ALT
- Check ALT at 6‐12 wk post‐statin initiation
- If ≤3x ULN, no routine ALT monitoring required
- If >3x ULN, d/c statin and reassess in 6‐12 wk
- If persistently >3x ULN investigate etiology
- If ≤3x ULN, restart at lower dose or switch statin and reassess in 3‐6 wk
- Asymptomatic elevation in ALT may return to normal with continuation of statin, dose reduction or discontinue
- Monitor for signs and symptoms of liver failure
- Jaundice, fever, malaise, lethargy, dark‐coloured urine, or abdominal pain
- If occur, d/c statin and seek medical attention
New Statin Safety Concerns
- Diabetes: associated with small increased risk but benefits outweigh risk. Statins only unmask diabetes in patients at risk (IFG, IGT, or prediabetes)
- Cancer: no association and may actually improve survival in some populations
- Cognition: no association with cognitive decline; rare adverse effect
- Fatigue: poor quality evidence
- Cataracts: small association in retrospective cohort data
Statin Adherence
what did the Ontario Cohort Study show?
Tips to Improve Adherence
Adherence rate to statins over 2 yr: • Recent ACS: 40.1% • Chronic CAD: 36.1% • Primary prevention: 25.4%
- Educate patient emphasizing benefits
- Challenge in preventative therapy
- Demystify concerns over harm
- Address patient‐specific concerns
- Simplify regimen
- Adherence aids
- Contact and follow‐up
