PharmacologyTier 1Medical Sciences concept

Lipid-lowering drug mechanisms (statins, ezetimibe, fibrates, PCSK9i)

Core concept

Almost every LDL-lowering drug works by increasing hepatocyte LDL receptor expression - by different routes to the same endpoint

Class	Mechanism	LDL reduction
Statins	Inhibit HMG-CoA reductase -> dec intracellular cholesterol -> SREBP-2 activation -> inc LDL receptor	30-55%
Ezetimibe	Inhibits NPC1L1 at the jejunal brush border -> dec cholesterol absorption -> inc LDLR	15-20%
PCSK9 mAbs (evolocumab, alirocumab)	Bind circulating PCSK9 -> LDL receptor recycled instead of degraded	50-60%
Inclisiran	siRNA silencing hepatic PCSK9 mRNA; 6-monthly SC	~50%
Bempedoic acid	Inhibits ATP-citrate lyase, upstream of HMG-CoA reductase; prodrug activated only in liver, not muscle	~20%
Bile acid sequestrants (colestyramine)	Bind bile acids -> inc hepatic bile acid synthesis from cholesterol -> inc LDLR	15-25%
Fibrates	PPAR-alpha agonists -> inc lipoprotein lipase, dec apoC-III -> triglyceride clearance	dec TG 30-50%
Icosapent ethyl	High-dose EPA	dec TG, dec CV events (REDUCE-IT)
Obicetrapib (CETP inhibitor)	Blocks cholesteryl ester transfer	LDL and apoB

Key detail

Statin intensity, not dose alone, is what matters
- High intensity (>=50% LDL fall): atorvastatin 40-80 mg, rosuvastatin 20-40 mg
- Doubling a statin dose gives only a further ~6% LDL fall (the "rule of 6") - add a second agent rather than escalate
Statin-relevant metabolism
- CYP3A4: simvastatin, atorvastatin, lovastatin - vulnerable to macrolides, azoles, HIV protease inhibitors, diltiazem, grapefruit
- Not CYP3A4: pravastatin, rosuvastatin, fluvastatin, pitavastatin - the safe substitutions
- Simvastatin and lovastatin are contraindicated with protease inhibitors; use pravastatin, or low-dose atorvastatin/rosuvastatin cautiously
- Gemfibrozil + any statin -> markedly inc myopathy risk (glucuronidation) - use fenofibrate if a fibrate is needed
Class-specific problems
- Fibrates - myopathy (worse with statins), reversible creatinine rise, gallstones, avoid in severe renal impairment
- Bempedoic acid - inc uric acid and gout, tendon rupture; no muscle toxicity - the point of the drug
- PCSK9 inhibitors - injection site reaction only; remarkably well tolerated
- Sequestrants - GI intolerance, inc triglycerides, bind other drugs (levothyroxine, warfarin, digoxin) - separate dosing
Universal Lp(a) measurement once in adult life is now recommended - it refines risk and prompts more aggressive LDL lowering
- Lp(a) falls ~20-30% with PCSK9 inhibitors and inclisiran, not with statins (which may slightly raise it)
- Targeted agents (pelacarsen, olpasiran) are in phase 3

Clinical relevance

Ladder: lifestyle + maximally tolerated statin -> ezetimibe -> PCSK9 inhibitor or inclisiran, with bempedoic acid where statins are truly not tolerated
Secondary prevention and familial hypercholesterolaemia are where PBS-subsidised PCSK9 inhibitors sit in Australia (LDL thresholds on maximal tolerated therapy)
Triglycerides >10 mmol/L -> pancreatitis risk -> fibrate, fish oil, alcohol and carbohydrate restriction, treat secondary causes (diabetes, alcohol, hypothyroidism, oestrogen, thiazide, retinoid, antipsychotic)
Check TSH, LFTs, renal function and glucose before treating a new dyslipidaemia - secondary causes are common
Statins are contraindicated in pregnancy; PCSK9 inhibitor and inclisiran data are limited - plan around conception
Modest inc HbA1c/new diabetes with statins - the cardiovascular benefit substantially outweighs it

Correlations

Statin-associated myopathy - spectrum and risk
PCSK9 function and LDL receptor regulation
CYP450-mediated drug interactions
Familial hypercholesterolaemia; lipoprotein(a)
SGLT2 inhibitor and GLP-1 metabolic effects

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.

Get premium access