Lipid-lowering drugs
Lipid-Lowering Drugs: Statins, Ezetimibe, PCSK9, Fibrates for FCPS Part 1
Statins, ezetimibe, PCSK9 inhibitors, fibrates, niacin and bile acid resins for FCPS Part 1: mechanisms, which lipid each lowers most, and myopathy. Also explains LDL receptor biology, familial hypercholesterolaemia and why lipoprotein(a) is atherogenic.
LDL receptor biology: the key to every LDL drug
- The liver removes LDL from plasma through LDL receptors, which bind apoB-100, are internalised and then recycle to the cell surface.
- When hepatocyte cholesterol falls, the transcription factor SREBP-2 is activated and the cell makes more LDL receptors (and more HMG-CoA reductase). Almost every LDL-lowering drug works by lowering liver cholesterol or protecting receptors, so that more LDL receptors clear plasma LDL.
- PCSK9 binds the LDL receptor and directs it to lysosomal destruction instead of recycling.
- Familial hypercholesterolaemia (Fredrickson type IIa): autosomal dominant LDL receptor (or apoB, PCSK9) mutation; very high LDL, Achilles tendon xanthomas, corneal arcus, premature MI. Heterozygotes respond to statins; homozygotes with no working receptors respond poorly, because statins act by up-regulating receptors that do not exist.
Statins
- Competitive inhibitors of HMG-CoA reductase, the rate-limiting step of cholesterol synthesis (HMG-CoA to mevalonate).
- The main way they lower plasma LDL is not reduced synthesis itself but the result: hepatocyte cholesterol falls, hepatocytes make more LDL receptors and clear more LDL from the blood (LDL falls 30–60%). Triglycerides fall slightly and HDL rises slightly; plaque-stabilising, anti-inflammatory (pleiotropic) effects add benefit.
- High intensity: atorvastatin 40–80 mg, rosuvastatin 20–40 mg. Short half-life statins (simvastatin, pravastatin) are taken at night, when cholesterol synthesis peaks.
- Before starting: fasting or non-fasting lipid profile, ALT (liver), TSH (hypothyroidism causes both high LDL and myopathy risk), HbA1c and renal function. CK only if muscle symptoms (or a high baseline risk). Recheck lipids and ALT at about 3 months, then at 12 months; stop if ALT exceeds three times the upper limit.
- Myopathy: myalgia, weakness (difficulty rising from a chair), rarely rhabdomyolysis. Risk rises with high dose, age, hypothyroidism, renal impairment, gemfibrozil, macrolides, azoles, ciclosporin, amiodarone and grapefruit juice (CYP3A4 inhibitors raise simvastatin and atorvastatin). Pravastatin and rosuvastatin are not CYP3A4 dependent.
- Contraindicated in pregnancy and breastfeeding, and in active liver disease.
Indications
- Primary prevention: 10-year cardiovascular risk about 10% or more, type 1 diabetes, CKD, familial hypercholesterolaemia; a strong family history of premature CVD with high LDL and low HDL adds to risk.
- Secondary prevention: all with CHD, stroke or TIA, peripheral arterial disease: high-intensity statin (atorvastatin 80 mg), aiming for at least a 40% fall in non-HDL cholesterol; aspirin as well. CKD is not a contraindication to statins or low-dose aspirin.
Other lipid drugs
| Drug | Mechanism | Main effect | Adverse effects |
|---|---|---|---|
| Ezetimibe | Blocks the NPC1L1 cholesterol transporter in the gut | LDL falls about 20% | Headache, GI upset |
| PCSK9 inhibitors (evolocumab, alirocumab; inclisiran siRNA) | Block PCSK9 so more LDL receptors recycle to the surface | LDL falls 50–60% | Injection site reactions |
| Bempedoic acid | ATP citrate lyase inhibitor (liver-activated) | LDL falls | Raises urate; little myopathy |
| Fibrates (fenofibrate, gemfibrozil, bezafibrate) | PPAR-α agonists: more lipoprotein lipase, less VLDL | Triglycerides fall most, HDL rises | Myopathy (gemfibrozil with statin), gallstones, raised creatinine |
| Nicotinic acid (niacin) | Inhibits adipose lipolysis, so less VLDL | HDL rises most, TG and Lp(a) fall | Flushing (prostaglandin D2; aspirin 30 minutes before), hyperglycaemia, hyperuricaemia, hepatotoxicity |
| Bile acid sequestrants (colestyramine, colesevelam) | Bind bile acids in the gut; liver converts more cholesterol to bile acid and up-regulates LDL receptors | LDL falls | Constipation, bloating, rise in triglycerides, malabsorption of vitamins A, D, E, K and of warfarin, digoxin, thyroxine (separate doses) |
| Omega-3 (icosapent ethyl) | Less VLDL synthesis | TG fall | Bleeding, AF |
- Colestyramine also treats pruritus of cholestasis, bile acid diarrhoea, and washes out leflunomide.
- Niacin as a vitamin (B3): deficiency causes pellagra: dermatitis, diarrhoea, dementia.
| Goal | Most effective drug class |
|---|---|
| Lower LDL | Statins, then ezetimibe, bile acid resins |
| Lower triglycerides | Fibrates, then niacin, then statins |
| Raise HDL | Niacin, then fibrates |
| Lower Lp(a) | Niacin, PCSK9 inhibitors (modest) |
Exam trap Bile acid sequestrants lower LDL but can raise triglycerides; avoid them in hypertriglyceridaemia.
Lipoprotein(a)
- Lp(a) is an LDL particle with apolipoprotein(a) attached to apoB-100 by a disulfide bond. Its level is mostly genetic.
- It is atherogenic (LDL-like, enters the arterial wall, carries oxidised phospholipids) and prothrombotic because apo(a) is structurally similar to plasminogen: it competes with plasminogen for binding to fibrin and impairs fibrinolysis.
- A man with premature MI and normal LDL should have Lp(a) measured.
Remember Statins and PCSK9 inhibitors both end up doing the same thing: more LDL receptors on the liver.
Matching drug to problem
- High LDL: statin, then add ezetimibe, then PCSK9 inhibitor.
- Very high triglycerides (above 10 mmol/L, about 885 mg/dL): fibrate and omega-3 with lifestyle change, to prevent pancreatitis.
- Statin intolerance: low-dose or alternate-day rosuvastatin, ezetimibe, bempedoic acid, PCSK9 inhibitors.
- Exclude secondary causes first: hypothyroidism, diabetes, nephrotic syndrome, cholestasis, alcohol, thiazides, steroids, retinoids, antipsychotics.
Somatostatin analogues (tested with this chapter)
- Octreotide mimics somatostatin: it reduces splanchnic blood flow and portal pressure and inhibits GI and pancreatic secretion. Uses: bleeding oesophageal varices, high-output pancreatic or enterocutaneous fistula, acromegaly, carcinoid and VIPoma symptoms. Gallstones with long-term use.
Exam trap Gemfibrozil with a statin is the classic myopathy combination; fenofibrate is preferred when a fibrate must be added.
How FCPS asks about this
- Main way statins lower LDL: hepatocytes make more LDL receptors and clear LDL.
- PCSK9 inhibitor mechanism: more LDL receptors recycle instead of being degraded.
- Why Lp(a) is prothrombotic: apo(a) mimics plasminogen.
- Tests before a statin: lipids, ALT, TSH; CK only if muscle symptoms.
- Colestyramine side effects: constipation, raised triglycerides, fat-soluble vitamin loss.
- Best drug for triglycerides and for HDL: fibrates; niacin (flushing prevented by aspirin).
- Muscle weakness on lipid therapy: statin myopathy, worse with gemfibrozil.
Test yourself on this topic
5 of the 18 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 56-year-old has just had an MI. His LDL cholesterol is 2.8 mmol/L (108 mg/dL). Which statin approach is recommended?
Answer: High-intensity statin
After an acute coronary syndrome, a high-intensity statin is started regardless of baseline cholesterol, because lowering LDL further reduces recurrent events. Atorvastatin 80 mg is typical (lower if interactions or kidney disease). The aim is a large LDL reduction (often over 40–50%, or a target such as below 1.8 mmol/L, depending on guideline). Ezetimibe or PCSK9 inhibitors are added if targets are not met.
Statins after MI
- Start high-intensity statin
- Regardless of baseline LDL
- Atorvastatin 80 mg
- Add ezetimibe if needed
Remember After MI: high-dose statin for everyone.
Exam trap Check liver tests and ask about muscle pain at follow-up.
Why the other options are wrong
- No statin; LDL is near normal Secondary prevention benefits at any LDL.
- Simvastatin 10 mg Low intensity.
- Statin only if LDL exceeds 5 mmol/L Not the threshold.
- Fibrate instead of statin Fibrates do not replace statins.
Which lipid-lowering drug reduces LDL by inhibiting the rate-limiting enzyme of cholesterol synthesis, and what is its important muscle adverse effect?
Answer: Atorvastatin; myopathy
Statins competitively inhibit HMG-CoA reductase, lowering hepatocyte cholesterol; hepatocytes then upregulate LDL receptors and clear more LDL from blood (the main effect). They also reduce cardiovascular events independent of baseline cholesterol. Adverse effects: myalgia and myopathy (risk raised by fibrates, especially gemfibrozil, macrolides, azoles, ciclosporin and grapefruit via CYP3A4), rare rhabdomyolysis, and raised transaminases. Being given at night matters for short-acting statins as synthesis peaks overnight. Ezetimibe blocks intestinal cholesterol absorption (NPC1L1); bile acid sequestrants bind bile acids; PCSK9 inhibitors increase LDL receptor recycling; fibrates activate PPAR-alpha mainly to lower triglycerides.
Lipid drugs
- Statins: HMG-CoA reductase → LDL receptors↑
- Risk: myopathy (with gemfibrozil, macrolides, azoles)
- Ezetimibe: NPC1L1, gut absorption
- Fibrates: PPAR-α, triglycerides↓
- PCSK9 inhibitors: more LDL receptors
Remember Statin starves the liver of cholesterol, so it grabs LDL from blood.
Why the other options are wrong
- Ezetimibe; hepatotoxicity Ezetimibe acts on gut absorption.
- Cholestyramine; myopathy Bile acid binder; GI upset.
- Niacin; peptic ulcer only Flushing, hyperglycaemia, gout.
- Fenofibrate; hypoglycaemia Fibrate, mainly triglycerides.
A 55-year-old man on simvastatin for hypercholesterolaemia has persistently high triglycerides, and another lipid-lowering drug is added. Three weeks later he has aching thighs, dark urine and a creatine kinase of 15,000 U/L. Which of the following drugs was most likely added?
Answer: Gemfibrozil
Statins and fibrates can both cause myopathy, and gemfibrozil also blocks the glucuronidation and hepatic uptake (OATP1B1) of statins, so statin levels rise sharply. This makes rhabdomyolysis much more likely, so gemfibrozil should not be combined with a statin. If a fibrate is needed, fenofibrate has a much smaller interaction. Ezetimibe, omega-3, bile acid binders and PCSK9 inhibitors do not raise statin levels.
Statin plus fibrate
- Both cause myopathy
- Gemfibrozil blocks statin glucuronidation
- Statin levels rise: rhabdomyolysis
- Use fenofibrate if a fibrate is needed
Remember Never pair gemfibrozil with a statin.
Exam trap Dark urine with high CK is myoglobinuria; the dipstick shows blood but no red cells are seen.
Why the other options are wrong
- Ezetimibe Little interaction; often combined with statins.
- Omega-3 fatty acids Do not raise statin levels.
- Colesevelam A bile acid binder; does not cause myopathy.
- Evolocumab A PCSK9 antibody; no statin interaction.
A 52-year-old man without cardiovascular disease has a 10-year cardiovascular risk of 14%. Lifestyle advice is given. What drug is recommended for primary prevention?
Answer: Atorvastatin 20 mg
For primary prevention, UK guidance offers atorvastatin 20 mg when 10-year cardiovascular risk is 10% or more (for example by QRISK), after addressing lifestyle. Secondary prevention after a cardiovascular event uses high-intensity atorvastatin 80 mg. Lipids are rechecked at 3 months aiming for a large non-HDL cholesterol reduction.
Primary prevention statins
- 10-year risk ≥ 10%
- Atorvastatin 20 mg
- Secondary prevention: 80 mg
- Recheck at 3 months
Remember Primary prevention: atorvastatin 20.
Exam trap Risk tools may underestimate risk in South Asians; consider ethnicity.
Why the other options are wrong
- Atorvastatin 80 mg Secondary prevention dose.
- Fibrate Not first-line.
- Niacin No outcome benefit.
- No drug at this risk Risk is above the treatment threshold.
A man with premature MI has normal LDL but very high lipoprotein(a). Why is Lp(a) atherogenic and prothrombotic?
Answer: Apo(a) mimics plasminogen
Lipoprotein(a) is an LDL-like particle with apoB-100 covalently linked to apolipoprotein(a), which has kringle domains homologous to plasminogen; it competes with plasminogen, impairing fibrinolysis, and deposits cholesterol and oxidised phospholipids in arterial walls. Levels are largely genetically determined (LPA gene), little affected by diet or exercise, and are an independent risk factor for coronary disease, stroke and calcific aortic stenosis. Statins do not lower it (may raise it slightly); PCSK9 inhibitors lower it modestly, and specific RNA therapies are in development. Measuring it once helps assess risk in premature disease or strong family history.
Lipoprotein(a)
- LDL particle + apo(a) (plasminogen-like)
- Atherogenic + inhibits fibrinolysis
- Mostly genetic; diet has little effect
- Risk: premature CHD, stroke, aortic stenosis
- Statins don't lower it; PCSK9 inhibitors modestly
Remember Lp(a) looks like plasminogen and blocks clot breakdown.
Why the other options are wrong
- It is a form of HDL It is LDL-like, not HDL.
- It is a chylomicron Not correct.
- It lowers blood pressure Not correct.
- It comes only from diet Mostly genetic.
Where this sits in the CPSP syllabus
- Paper 1: Cardiovascular and blood drugs, Lipid-lowering drugs
- Medicine & Allied, Paper 2: Systemic drugs, Lipid-lowering drugs
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