Lecture 5,6,7 Dyslipidemia Flashcards
Definition of dyslipidemia
Abnormal fats in the blood
Elevation of >1 lipoproteins or reduced HDL-C
Four primary categories proteins
Low-density lipoproteins (LDL-C) = Bad
High density lipoprotein (HDL-C) = Good
Total cholesterol (TC) = all lipoproteins
Triglycerides (TG)
Types of dyslipidemia
Primary = genetic cause
- known as hypercholesterolemia
- most common cause of ASCVD in children
Secondary = Other causes
- most common cause in adults
- sedentary lifestyle
- excessive dietary intake of fat or EtOH
- diseases
- cigarette smoking
- Drugs
Familial hypercholesterolemia (FH)
Autosomal dominant genetic disorder
High LDL-C level
- normal LDL-C = 2-5 mmol/l
-Heterozygous FH (1/5000): LDL-C, 5-13mmol/l
-Homozygous (1/1000000): >13mmol/l
Requires aggressive treatment:
Statins
LDL-C apheresis
Drugs causes of dyslipidemia
Amiodarone
Beta blocker
Carbamazepine
Clozapine
Corticosteroids
Cyclosporine
Loop diuretics
Oral contraceptives
Olanzapine
Phenobarbital
Phenytoin
Protease inhibitors
Retinoids
Thiazide diuretics
T/F there is a positive associated between high TC or LDL-C and CAD
TRUE
Signs and symptoms of dyslipidemia
Most are asymptomatic
Possible signs: xanthoma/xanthelasma, Corneal arch’s, carotid bruits
Who to screen with fasting or non fasting TC, TG, HDL-C, calculated LDL-C and non-HDL-C with ApoB when appropriate.
Men> 40, women > then 40 or postmenopausal at younger age in indigenous and south Asian individuals
What are risk factors of atherosclerotic cardiovascular disease
Hypertension, dyslipidemia, smoking, alcohol, unhealthy diet, physical inactivity, aging, gender, race,genetic predisposition, obesity, diabetes
Framingham risk score risk assessment
Risk prediction tool
Estimated 10 year risk of total CVD=CAD, stroke, PAD, heart failure
Reported as percent
Used in practice to determine risk level, treatment recommendation, therapeutic targer
Framingham risk score component
Age
HDL-C and TC ( not LDL-C)
SBP
DM ( yes or no)
Smokin status (yes or no)
When to consider pharmacotherapy in risk Managment ( low risk, med risk, high risk)
Low risk ( FRS <10%): Therapy not recommended for most low risk indicates, health behaviour modification like smoking cessation, diet, excercise
Med/high risk ( 10-20+ FRS) : discuss healthy modification, initiate statin, discuss add on therapy with patient if levels still high
What are examples of CVD
MI, ACS
Stable angine or documented CAD by coronary angiogram
Previous CABG surgery
ACS
Stroke, transient ischemic attack
PAD
Abdominal aortic aneurysm- an abdominal aorta measuring >3.0cm or previous AAA surgery
Additional high risk patient
Most patients with DM, or microvascular complications
CKD: Age > 50 yrs and >3 months duration with eGFR <60nl/min/1.73m^2 or ACR > 3mg/mmol
Familial hypercholesterolemia: LDL-C > 5.0 mmol/l or documented FH, after excluding all secondary causes
T/F multiple FRS by x3 for any patient with positive family history or premature CVD
False
Multiple by 2
How to screen for dyslipidemia
History and physical examination
Standard lipid profile: Total cholesterol, LDL, HDL, non-HDL, triglycerides
Fasting plasma glucose or A1C
Estimated glomerular filtration
Lipoprotein- once in a person lifetimes with initial screening
What is the Calculation for LDL-C and name of it
Friedwald equations
LDL-C (mmol/l) = TC - HDL - TG/2.2
Apolipoprotein B
Each of the atherogenic lipid particles ( LDL, LP, LDL, VLDL) contains 1 molecule of Apo-B
Serum concentrations of the APO-B reflect total number of these particles
More PARTICICLES = HIGH RISK
Non-HDL-C
Alternate measurement instead of ApoB
Provides an estimated sum of all atherogenic lipoprotein
Calculation: TC- HDL- C
ApoB and non-HDL-C for screening and treatment purposes ?
Recommend that for any patient with triglycerides >1.5mmol/l, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening
TG
Causes of hyperrtriglycermia…
High dietary fat intake
Excessive EtOH
Poor DM control
Very high TG associated with pancreatitis
Reducing TG with pharmacologic therapy does not reduce CV events
Healthy behaviour modifications
Smoking cessation
Diet: caloric restriction, fibre intake > 30g daily, substitute unsaturated fats or saturated/trans fats,fruit and vegetables
Excercise
Limit EtOH intake
Stress Managment
Pharmacological treatment for dyslipidemia
Statins
Cholesterol absorption inhibitor ( Ezetimibe)
niacin
Vibrates
Bile acid suquestrants
PCSK9
Icosapent Ethyl (IPE)
Relative effects of different agents
Statins :
LDL-C : lowers 30-50%
HDL-L : increases 4-10%
TG: Lowers 20-30% (> effect with higher TG)
PCSK9-i:
LDL-C: lowers 50-60%
HDL-C: increases 10-15%
TG: lowers 20-50%
Ezetimibe:
LDL-C : lowers 15-20%
Niacin:
LDL-C: lowers 15-20%
HDL-C: increase >30%
TG: Lowers 20-50%
Fibrates:
HDL-C: increase 5-20%
TG: Decrease 25-50%
IPE:
TG: lowers 30%
When do consider pharmacotherapy in risk Managment in dyslipidemia
Low risk: FRS < 10%, statin therapy not recommend, health behaviour modifications
Intermediate risk: FRS 10-19.9%, discuss health behaviour -> initiate statin treatment
High risk : FRS >20%, health behaviour modifications, initiate statin treatment.
What conditions are statins indicated in
LDL > 5.0 mmol/L
Most patients with diabetes:
- age >40
- age >30 yrs and DM x > 15 hr duration
- microvasculate disease
CKD:
- Age >50yrs and eGFR <660 ml/min or ACR >3mg.mmol
ASCVD (Athersclerotic cardiovasculate disease)
Statins Mechanism of action
leads to reduced cholesterol synthesis via???
-Upregulation of LDL receptors
- decreased VLDL production
- these mechanism lead to reduction in TC, LDL-C and TGs
MOA:
Blocks HMG-Coa reducatse, blocks synthesis of cholesterol in liver
Statin LDL lowering comparison
Rosuvastatin : lowers by 40-65%
Atrovastatin : Lowers by 35-60%
All others are less
Statins, recommended dose range
Atrovastatin: 10-80mg
Fluvastatin: 20-80mg
Lovastatin: 20-80mg
Pravastatin: 10-40mg
Rosuvstatin: 5-40mg
Simvastatin: 10-40mg
What is the law of diminishing returns
“Rule of sixes”: double statin dose= 6% additional LDL-C lowering
Contraindications of Statins
Active liver disease
Pregnancy and lactation
Hypersensitivity
_____ are the cornerstone of dyslipidemia Managment- recommended as the initial lipid lowering agent of choice for treatment
Statins***
______ dose or ________ tolerated statin should be used for all patients in whom treatment is indicated
Maximum, maximally
____ % reduction in MVE per 1 mmol/l reduction in ldl-c achieved with statin therapy
20-40
Statin metabolism :
Atrovastatin, lovastatin, simvastatin : CYP3A4
Fluvastatin, rosuvastatin: CYP2C9
Pravastatin : not understood
What can increase and decrease statin levels
Increase (with CYP3A4 Inhibitors)
- macrolide antibiotics
- grapefruit juice
- azole antifungals
- protease inhibitors
Decrease:
Rifampin
Carbamazepine
Bosentant
Efavirenz
Antacids
Adverse effects of statins
GI
MSK
Hepatic
Endo
GI: nausea/vomiting/diarrhea
MSK: Myopathy
Hepatic: elevated liver enzymes
Endo: diabetes- in those predisposed
Nocebo effects: people who have negative expectation about medicine or treatment experience harmful symptoms they otherwise wouldn’t have
Terminology
CK
Myopathy
Myalgia
Myosin is
Rhabdomyolysis
CK: creatinine kinase, tissue enzyme that is released during muscle breakdown
Myopathy: muscle related pathology
Myalgia: Muscle pain with CK<ULN
Myositis is: Myalgia with CK> ULN
Rhabdomyolysis: Muscle breakdown with CK> 10x ULN +/- serum myoglobin and renal failure
Myopathy, incidence rate and risk factors
Incidence 1.5-5%
Dose related
Occurs usually in first 6 months
Risk factors:
Hx of myalgias with statins
Hypothyroidism
Renal or hepatic impairment
Female
Small body frame
Advanced age
Drug interactions
Rhabdomyolysis
Very rare
Diagnosed by : Myoglobinemia -> myoglobinuria ( darkens urine) , can lead to acute renal failure
Not well predicted by myalgias
Likely dose repeated
Increased risk with vibrate combination
Discontinue statin and do not rechallenge
Approach to monitoring statin use
Baseline CK and TSH in all patients
CK-> ULN —-> reasses symtpoms and CK in 6-12 weeks
Monitoring
CK < 10x ULN
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
What step do statins inhibit
HMG-CoA -> Mevalonate
Coenzyme Q10 effect?
No effect on muscle pain or CK in patients on statin therapy
Not recommended as per CCS guidelines
Statin induced liver enzyme elevation
Incidence
Most often will present with ___elevation
0.1-3%
ALT
Asymptomatic
May be dose related
Approach to monitoring statin induced liver enzyme elevation
Baseline ALT
Check alt ever 6-12 weeks post statin initiation
If <3x ULN, no routine ALT monitoring required
If >3x ULN, d/c statin and reassess in 6-12 weeks
Monitor for signs and symptoms of liver failure, jaundice, fever, malaise, lethargy, abdominal pain
New statin safety concerns
Diabetes
Cancer
Cognition
Fatigue
Cataracts
Diabetes: associated small increased risk, but benefits outweigh risks
Cancer: no assocition and may actually improve survival in some population
Cognition: no associated
Fatigue : poor quality evidence
Cataracts: Small association in retrospective cohort data
Ezetimibe, dose range, indicated to lower LDL by how much
Ezetimibe - 10mg, lower by 15-20%
Ezetimibe contraindications, and drug interaction
Contraindications:
- combination with statin in patients with active liver disease or unexplained liver enzyme elevation
- hypersensitivity
- pregnancy and lactation
Drug interaction:
- cyclosporine
- fibrates
- BAS ( Decrease Ezetimibe levels)
Fibrates recommended dose range,
Bezafibrate, 400mg
Fenofibrate 48-200mg
Gemfibrozil 600-1200mg
First line therapy to reduce TG ( 20-50%)
Fibrates (AE, Indication, contraindication, drug interaction)
AE: GIT, Myositis, galllstones
Indication: 1st line for mixed dyslipidemia
Drug interaction: increase risk of myopathy when combined with statins
Contraindication: patient with impaired renal fx, pregnant, preexisting gall bladder disease
Niacin, dose range, LDL lowering %, AE,Indication,contraindication,MOA
Crystalline Niacin 1-3G
ER niacin - 500-2000mg hs
Lowers lDL by 20% in combo with statin
Increases HDL by 20%
MOA: Lowers TG, and thus VLDL Synthesis, inhibits diacylglycerol acyltransferase-2 a key enzyme for TG synthesis
AE: impaired of glucose tolerance, increase uric acid, reversible increase in liver enzymes -> hepatotoxicity
Indication: monotherapy or in combo with Fibrate, resin or statin, patient with High TG and low HDL
Contraindication: Gout, peptic uncle, hepatotoxicity, DM
What are the 3 types of NIACIN
Crystalline niacin ( OTC)
- requires titration to develop tolerance to flushing
Extended release niacin (RX only)
- reduced incidence of flushing
- associated with hepatotoxicity
Flush - free niacin (OTC)
- studied in rabbits
- contains inositol
Do not recommend as alternative to niacin
Bile acid sequestrants - MOA, 3 drugs, usual dose, lowering of LDL
MOA - make cholesterol absorption easier form the intestine - both endogenous cholesterol (synthesized in the liver and enterhepatically recirculated) and exogenous cholesterol
Cholestyramine - 2-24g
Colestipol- 5-30g
Colesvelam - 1.25-3.75g
Lowers LDL by additional 10-15%
Multiple GI adverse effects
PCSK9 inhibitors
= proprotein convertase subtilisin/ kexin
Serum PCSK9 is inversely related to density of LDL-C receptors on hepatocytes
PCSK9 modulates formation of atherosclerosis
PCSK9 Inhibitors
Evolocumab (Repatha - Sanofi
- SQ injection a 2-4 weeks ( 140mg q2 weeks or 420 mg a month)
Alirocumab (praluent) - sanofi/regeneron
- SQ injection ever 2 weeks : 75 or 150mg q2 weeks
PCSK9 inhibitors indications
Lower LDL-C in patients HeFH without clinical ASCVD whose LDL-C remains above target despite maximally tolerated statin therapy with or without Ezetimibe
For patients with HeFH and ASCVD whose LDL-C remain above threshold >1.8mmol/l despite maximally tolerated statin with or without Ezetimibe
For all secondary prevention CVD patients in whom LDL-C remains above>1.8mmol/l on maximally tolerated statin dose
Icosapent Ethyl (IPE)
MOA
Indication
MOA: reduces hepatic very low density lipoprotein triglycerides synthesis, and/or secretion, and enhances TG clearance from circulating VLDL particles
Indication: recommend used of IPE to lower risk of CV events in patients with ASCVD, or with diabetes 1 or more CVD risk factors, who have elevated fasting TG levels of 1.5-5.6mmol/l despite treatment with maximally tolerated statin therapy.
What are the potential mechanism of cardio protection for omega-3 fatty acids
Lower TG rich lipoproteins
Anti thrombotic effects
Antiarrhythmic actions
Altered prostaglandin synthesis
Anti inflammatory actions
Augmented specialized pro-resolving mediators
T/F low dose omega 3 mixtures show no significant cardiovascular benefit
True
Beyond statins, when to add on intensity therapy
Ensure statin dose optimized
Lipid threshold is the current focus of the 2021 guidelines
- threshold = the quantitive point at which an action is triggered
Prior to initiating lipid lowering therapy, what tests to do
Lipid profile
TSH
ALT
CK
Scr
FBG
Follow up
In 6-8 wk or as planned
- LIPID profile
- ALT
Annual
- Lipid profile
Suspected myopathy
- CK
- +/- TSH
On going
- Signs and symptoms of CV events
- signs and symptoms of adverse effects
