Pharmacology of major drug classes used - lipid-modifying agents

Classes

Class	Agents	LDL effect
Statin	Atorvastatin, rosuvastatin, simvastatin, pravastatin	dec 30-55%
Absorption inhibitor	Ezetimibe	dec ~15-20% (additive)
PCSK9 inhibitor	Evolocumab, alirocumab	dec ~60%
siRNA	Inclisiran	dec ~50%, 6-monthly
Fibrate	Fenofibrate, gemfibrozil	Variable - acts on triglycerides
Bile acid sequestrant	Colestyramine	dec ~15-20%

Every effective LDL-lowering drug works by increasing hepatic LDL receptor availability

Statins are among the most prescribed drugs in Australia
PCSK9 inhibitors are PBS-restricted - familial hypercholesterolaemia, or established CVD with LDL-C above threshold on maximally tolerated oral therapy
Non-adherence, not drug failure, is the commonest reason a lipid target is not met

Inhibits HMG-CoA reductase
- -> dec intracellular hepatic cholesterol
- -> inc LDL receptor expression
- -> inc LDL clearance from plasma

Blocks NPC1L1 at the enterocyte brush border
- -> dec intestinal cholesterol absorption
- -> same final pathway (inc LDL receptors)
- Additive to statin - IMPROVE-IT

PCSK9 binds the LDL receptor and chaperones it to lysosomal degradation
- Blocking PCSK9 -> inc LDL receptor recycling -> dec LDL-C

PPAR-alpha agonist -> inc lipoprotein lipase, dec apoC-III -> dec triglycerides

Lipids at baseline, 6-12 weeks after any change, then annually
LFTs at baseline
Routine CK monitoring is not required - measure only if symptomatic
Do not stop a statin for a mildly raised ALT
HbA1c - statins slightly increase new-onset diabetes (absolute benefit far outweighs it)

High-intensity statin first line - atorvastatin 40-80 mg or rosuvastatin 20-40 mg
Not at target -> add ezetimibe
Still not at target and high risk -> PCSK9 inhibitor

Rechallenge - most reported intolerance is not reproducible on blinded rechallenge
Lower dose, alternate-day rosuvastatin, or switch agent
Ezetimibe +/- PCSK9 inhibitor if genuinely intolerant

TG >10 mmol/L -> pancreatitis risk
Fenofibrate, alcohol abstinence, glycaemic control, low-fat diet
Gemfibrozil + statin markedly increases myopathy risk - use fenofibrate if combining

High-intensity statin from diagnosis, then ezetimibe; PCSK9 inhibitor commonly needed
Cascade screening of first-degree relatives

CYP3A4 inhibitors raise statin levels -> myopathy
- Azole antifungals, clarithromycin and erythromycin, HIV protease inhibitors
- Verapamil, diltiazem, amlodipine
- Ciclosporin, amiodarone, danazol
- Pravastatin and rosuvastatin are least CYP3A4-dependent - the useful substitutes
Gemfibrozil + statin - avoid
Grapefruit juice - simvastatin, atorvastatin
Cholestatic liver disease raises lipoprotein-X - abnormal profile without increased CV risk

Symmetric proximal weakness
CK >10x ULN that persists after stopping the statin - the discriminator from simple myalgia
Myopathic EMG, muscle oedema on MRI, anti-HMG-CoA reductase antibodies
Can occur in patients who have never taken a statin
Treat: stop statin; prednisolone ~1 mg/kg; add methotrexate, azathioprine or MMF; IVIg if refractory

Other

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