Primary and Secondary Dyslipidaemias – diagnoses and pharmacotherapies Flashcards
what does atherosclerosis cause
infarct, stroke, gangrene and aneurysm
CVD risk associated with smoking, hypertension and hypercholesterolaemia
When co-exist the effect is often exponential
what did the framingham heart study look at
major CVD risk factors - high BP, cholesterol, smoking, obesity, diabetes, physical activity
also related factors TG, HDLC, age, gender, psychosocial issues
what did the cholesterol treatment Trialists collaboration (CTT`) look at
statin therapy and their efficacy and safety
what did the CTT find out
reduction oh LDLC using state therapy reduces risk of major vascular events
more intensive treatment leads to further reductions
effective in M, F, diabetic
what did the Copenhagen city heart study look into
ongoing prospective cardiovascular pop study - prevention of CHD and stroke
what did the CCHS find out
relating mortality and morbidity to CHD (genetic, psychical factors, epilepsy, dementia, alcohol intake etc) and lung diseases
what are modifiable risk factors for CHD
Smoking or env exposure obesity sedentary lifestyle diabetes high cholesterol or abnormal blood lipids hypertension excess alcohol intake
what are unmodifiable risk factors for CHD
Age >50 years
gender <64y, men
genetic factors/family history (CVD, ethnicity)
pre-existing CHD
What are risk calculator tools
A large consolidated database derived from the health records
Aim to develop and maintain a high quality database of general practice data linked to secondary care data to use in ethical medical research
Generating QRISK risk calculator tool – updated regularly most recent being QRISK3 2018
what is QRISK3
Accounts for many of the traditional RFs (eg age, sex, cholesterol, BP, diabetes and smoking)
Plus additional RFs such as ethnicity, deprivation score, blood pressure treatment, family history, renal failure, BMI, migraine, RA, atypical antipsychotics, severe mental illness, SLE, steroids
What does a QRISK3 over 10 mean
(10% risk of CVD event over next 10 years) indicates that primary prevention with lipid lowering therapy (eg statins) should be used
what is the lipid modification guideline
Full formal risk assessment (QRISK, familial hypercholesterolaemia etc)
use clinical judgement
Do not use lipid cut off values alone to judge familial lipid disorder (use findings and family history)
CVD risk may be underestimated in people with underlying conditions and treatments
how can dyslipidaemia be determined
Measure full lipid profile (TC, HDL, non-HDL, TG)
Exclude possible common secondary causes of dyslipidaemia (excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease, nephrotic syndrome) before referring to specialist
Fasting sample not needed
what is primary and secondary prevention
no prev history of CVD - statin 20mg
prev history of CVD statin 80mg
Why treat asymptomatic lipid disorders
Reduce atherosclerotic process and incidence of clinical vascular disease
Prevent pancreatitis, associated with grossly increased serum TG (>10mmol/l, usually >20mmol/L)
what is LDLRs
Cell surface receptor recognises ApoB-100 which is embedded in phospholipid outer layer of LDL particles
Present on most cells, majority liver
LDLR on hepatocytes binds to LDL particles and removes them from circulation, returns to surface to repeat
what do statins do
HMGCoA reductase
stops HMG-CoA - cholesterol
what is ezetimibe
A potent and selective inhibitor of absorption in the small bowel
The drug and its active glucuronide metabolite impair the Intestinal reabsorption of dietary and hepatically excreted biliary cholesterol by inhibiting membrane transporter NPC1L1
what are PCSK9 inhibitors
Binding protein – promotes LDLR degradation - Prevented if blocked
Expressed primarily in hepatocytes
Bi-monthly subcutaneous injections
Monoclonal antibodies to PCSK9
Loss of function polymorphisms in PCSK9 – lower LDLC levels
what causes hypercholesterolaemia
(high TC and LDLC) – familial (TC 7-20 mmol/L, avg 9) in heterozygotes, higher (but rare) in homozygotes (15-30)
what causes mixed hyperlipidaemia
(high TC and LDLC with raised TG, often low HDLC), glucose intolerance and diabetes, arises from increased production and reduced breakdown of TG rich lipoproteins
what causes hypertriglyceridaemia
pure less common, familial and unlike others can cause harm by acute pancreatitis
what is lipoprotein(a)
Macromolecular complex in plasma
LDL like + AopB + Apo(a)
Lipoprotein made by liver
Elevated Lp(a) concentrations associated with MI, stroke and aortic valve stenosis
what is Apo(a)
glycoprotein, similar to plasminogen
Physiological function unclear
Pathological function – atherosclerosis and thrombosis formation
how is Lp(a) measurement
Intermediate or high risk of CVD Premature CVD FH Fhx of premature CVD or raised Lp(a) Recurrent CVD despite statins
how is raised Lp(a) treated
Lifestyle change – trials with marginal effects
Approved and investigational drugs
3 effective therapies on continued trial
Lipid apheresis
PCSK9i
Antisense therapy (small molecules that bind to apo(a) mRNA in hepatocyte nucleus)
what is FH
Common genetic disorder with increased serum LDLC and early CVD, autosomal dominant
Mutations in LDLR gene that encodes LDLR protein which reduces function
Can also be ApoB mutation (part of LDL binding to receptor or gain of function of mutation in LDL receptor degradation PCSK9)
Wide age range at first CVD event in heterozygous (50y M and 60y F)
how does clinical presentation FH
tendon xanthoma
corneal arcus
LDLC cholesterol
how is FH treated
low sat fat diet and exercise
possible addition of cholesterol absorption inhibitor
anti-pcsk9
involve patient self help group, offer DNA testing and get family tested
