Cpt Hyperlipid

Question 1

• Know that not all statins are equal in their lipid lowering profile

Answer 1

GI disruption, nausea and headache

Competitive inhibition of HMG-CoA reductase
in HMG-CoA to mevalonate pathway
Contributes to upregulation of hepatic LDL receptors
Increased clearance of circulating LDL

Statins have different NNT (number needed to treat to see 1 good outcome) and intensities.
Dose dependant reduction in LDL-C for all.
Cost and side effect severity drives prescribing choices.

Diffuse muscle pain - dose related
Rarely – rhabdomyolysis
Increased liver enzymes

X renal or hepatic impairment
pregnancy! and breastfeeding

Δ CYP 3A4 important – amiodarone, diltiazem, macrolides, amlodipine - increases [plasma] statin.
Grape juice + citrus fruits inhibit CYP3A4

Question 2

• Know which patient groups should be offered a statin including in primary
and secondary prevention of cardiovascular disease

basis
for statin recommendation under UK guidelines

Answer 2

Primary prevention – interventions for individuals at high risk of cardiovascular disease

Secondary prevention - interventions for individuals who already have cardiovascular disease

Primary prevention - 20 mg atorvastatin once daily (10 year CVD risk of >10% using QRISK 3).
Look for:
>40% reduction in non HDL-C at ~ three months

• Secondary prevention - 80 mg atorvastatin once daily.
Look for:
LDL 2.0 mmol per litre or less, or non-HDL cholesterol levels of 2.6 mmol per litre or less.

Question 3

• Know the non-lipid effects of statins that contribute towards a reduction in
cardiovascular disease risk

Answer 3

• Improved vascular endothelial function - ↑NO, VEGF, ↓endothelin

• Stabilisation of atherosclerotic plaque - ↓SMC proliferation ↑collagen

• Improved haemostasis - ↓plasma fibrinogen, platelet aggregation, ↑fibrinolysis

• Anti-inflammatory - ↓proliferation of inflammatory cells into plaque, plasma CRP, adhesion
molecules and cytokines

• Antioxidant - ↓superoxide formation

All contribute to reduction in CVD risk

Question 4

fibrates,

Answer 4

GI upset, myositis, cholelithiasis (gall stones)

Fibric acid derivatives (Fibrates)
• Activation of nuclear transcription factor – P PA R α
(peroxisome proliferation-activated receptor)

PPARα regulate expression of genes that control lipoprotein metabolism – increase production of
lipoprotein lipase

↑triglycerides removal from lipoprotein in plasma ↑fatty acid uptake by the liver
(↑levels of HDL ↑LDL affinity for receptor)

X photosensitivity, gall bladder disease

Δ warfarin – increase anticoagulation

Question 5

Describe the benefits of concomitant drug treatment in patients who do not
tolerate statins in familial disease

Answer 5

Fibrates have Different mechanism to statins – rarely now used alone, co-prescribed in familial
hypercholesterolaemia

Combination of ezetimibe with statin benefit in CKD and in some for secondary CVD prevention
• Those that can only tolerate a low dose statin – addition of ezetimibe maybe additive

AT P -citrate lyase inhibitor • With ezetimibe for primary hypercholesterolaemia or mixed
dyslipidaemia where statin not suitable

Question 6

cholesterol absorption inhibitors,

Answer 6

abdominal pain, GI upset, angioedema

Cholesterol absorption inhibitors

• Inhibit NPC1L1 transporter at brush border in small intestines
• Reduces absorption of cholesterol by the gut ~50%
• Hepatic LDL receptor expression increases
• ↓total cholesterol + LDL

• Pro-drug - hepatic metabolism.
enterohepatic circulation - limits systemic exposure.
secreted by bile.

• Adjunct to statin (where high intensity statin not tolerated) or bempedoic acid

X hepatic failure

Δ ciclosporin, fibrates – gall stones

Question 7

bempedoic acid

•

Answer 7

ATP -citrate lyase inhibitor

A prodrug metabolised to active form almost exclusively in liver –
fewer muscle ADRs reported vs. statin

# hyperuricaemia, anaemia, pain in extremity •

X pregnancy and breastfeeding •

Δ slows excretion of many drugs – inc. statins

Question 8

PCSK9 inhibitors eg alirocumab

Answer 8

When LDL attaches to LDL-R , receptor is internalised,

LDL catabolised and receptor degraded or recycled in cell •

PCSK9 – protein that binds internalised LDL-R – that directs LDL for degradation so LDL is excreted instead.

PCSK9 inhibitors demonstrated highly significant reduction in LDL cholesterol over placebo (statin +/- ezetimibe) in primary hypercholesterolaemia

Inclisiran - siRNA that inhibits hepatic translation of
PCSK9 – less produced

PCSK9 inhibitors:
Long term effects on cholesterol lowering and CVD risk remain to be determined
• Requires lifetime injections
current cost ~50 x statin

Question 9

Know the contributing factors that are used in estimating cardiovascular
disease risk score through QRISK

Question 10

drug classes that are used in the treatment of dyslipidaemias

Answer 10

Statins
ATP citrate lyase inhibitor - bempedoic acid
Fibrates
PCSK9 inhibitors
Cholesterol absorption inhibitors

Question 11

Alternative lipid lowering possibilities – non prescription

Answer 11

Plant sterols provide some LDL cholesterol lowering effects (↓≤0.5 mmol/L)
• Naturally occurring in grains, legumes etc. structurally similar to cholesterol – compete for
absorption

• Ye s t o … .
Fish oils/oily fish
Fibre, whole grains
Vitamin C/E

• Alcohol – increases HDL cholesterol BUT also increases triglycerides

Question 12

evidence that supports use of cholesterol lowering therapy

Answer 12

Cholesterol is modifiable risk factor for CVD

Reduction in total cholesterol of 10% affords ~15% reduction in 10 year CHD mortality and ~11%
in total mortality

Question 13

Understand the role of lipids in the pathophysiology of atherosclerosis

Answer 13

LDL susceptible to oxidation at damaged endothelium

ROS contributes to endothelial
dysfunction increasing adherence of lipid deposits

foam cells formed – precursor to atheromatous plaques