Primary and Secondary Dyslipidaemias – diagnoses and pharmacotherapies

Question 1

what does atherosclerosis cause

Answer 1

infarct, stroke, gangrene and aneurysm
CVD risk associated with smoking, hypertension and hypercholesterolaemia
When co-exist the effect is often exponential

Question 2

what did the framingham heart study look at

Answer 2

major CVD risk factors - high BP, cholesterol, smoking, obesity, diabetes, physical activity
also related factors TG, HDLC, age, gender, psychosocial issues

Question 3

what did the cholesterol treatment Trialists collaboration (CTT`) look at

Answer 3

statin therapy and their efficacy and safety

Question 4

what did the CTT find out

Answer 4

reduction oh LDLC using state therapy reduces risk of major vascular events
more intensive treatment leads to further reductions
effective in M, F, diabetic

Question 5

what did the Copenhagen city heart study look into

Answer 5

ongoing prospective cardiovascular pop study - prevention of CHD and stroke

Question 6

what did the CCHS find out

Answer 6

relating mortality and morbidity to CHD (genetic, psychical factors, epilepsy, dementia, alcohol intake etc) and lung diseases

Question 7

what are modifiable risk factors for CHD

Answer 7

Smoking or env exposure
obesity
sedentary lifestyle 
diabetes
high cholesterol or abnormal blood lipids 
hypertension 
excess alcohol intake

Question 8

what are unmodifiable risk factors for CHD

Answer 8

Age >50 years
gender <64y, men
genetic factors/family history (CVD, ethnicity)
pre-existing CHD

Question 9

What are risk calculator tools

Answer 9

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

Question 10

what is QRISK3

Answer 10

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

Question 11

What does a QRISK3 over 10 mean

Answer 11

(10% risk of CVD event over next 10 years) indicates that primary prevention with lipid lowering therapy (eg statins) should be used

Question 12

what is the lipid modification guideline

Answer 12

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

Question 13

how can dyslipidaemia be determined

Answer 13

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

Question 14

what is primary and secondary prevention

Answer 14

no prev history of CVD - statin 20mg

prev history of CVD statin 80mg

Question 15

Why treat asymptomatic lipid disorders

Answer 15

Reduce atherosclerotic process and incidence of clinical vascular disease
Prevent pancreatitis, associated with grossly increased serum TG (>10mmol/l, usually >20mmol/L)

Question 16

what is LDLRs

Answer 16

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

Question 17

what do statins do

Answer 17

HMGCoA reductase

stops HMG-CoA - cholesterol

Question 18

what is ezetimibe

Answer 18

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

Question 19

what are PCSK9 inhibitors

Answer 19

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

Question 20

what causes hypercholesterolaemia

Answer 20

(high TC and LDLC) – familial (TC 7-20 mmol/L, avg 9) in heterozygotes, higher (but rare) in homozygotes (15-30)

Question 21

what causes mixed hyperlipidaemia

Answer 21

(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

Question 22

what causes hypertriglyceridaemia

Answer 22

pure less common, familial and unlike others can cause harm by acute pancreatitis

Question 23

what is lipoprotein(a)

Answer 23

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

Question 24

what is Apo(a)

Answer 24

glycoprotein, similar to plasminogen
Physiological function unclear
Pathological function – atherosclerosis and thrombosis formation

Question 25

how is Lp(a) measurement

Answer 25

Intermediate or high risk of CVD
Premature CVD
FH
Fhx of premature CVD or raised Lp(a)
Recurrent CVD despite statins

Question 26

how is raised Lp(a) treated

Answer 26

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)

Question 27

what is FH

Answer 27

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)

Question 28

how does clinical presentation FH

Answer 28

tendon xanthoma
corneal arcus
LDLC cholesterol

Question 29

how is FH treated

Answer 29

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