Antihyperlipidaemic Drugs

Lipid-lowering agents reduce atherosclerotic cardiovascular disease (ASCVD) by lowering LDL-cholesterol, triglycerides and remnant lipoproteins. For NEET PG, the highest-yield zones are statin pharmacology and myopathy, the drug of choice for each dyslipidaemia pattern, and the mechanistic classification of fibrates, niacin, sequestrants, ezetimibe and the newer PCSK9/ATP-citrate-lyase agents.

Lipid physiology in one frame

Dietary lipids enter as chylomicrons (apo B-48), are cleared by lipoprotein lipase (LPL). The liver exports VLDL (apo B-100) → IDL → LDL (the main atherogenic, cholesterol-rich particle). HDL (apo A-1) performs reverse cholesterol transport. The hepatic LDL receptor clears circulating LDL; PCSK9 degrades this receptor, so blocking PCSK9 raises receptor numbers and lowers LDL.

High-yield: LDL is cleared by the hepatic LDL receptor. Anything that upregulates the LDL receptor (statins, ezetimibe, sequestrants, PCSK9 inhibitors) lowers LDL-C.

Classification

Class	Prototype drug(s)	Primary mechanism	Main lipid lowered
HMG-CoA reductase inhibitors (statins)	Atorvastatin, rosuvastatin, simvastatin	Inhibit rate-limiting step of cholesterol synthesis → ↑ LDL receptors	LDL ↓↓↓
Cholesterol absorption inhibitor	Ezetimibe	Blocks NPC1L1 transporter in jejunal brush border	LDL ↓
Bile acid sequestrants (resins)	Cholestyramine, colestipol, colesevelam	Bind bile acids in gut → ↑ hepatic LDL receptor	LDL ↓
Fibrates	Fenofibrate, gemfibrozil	PPAR-α agonist → ↑ LPL, ↓ apo C-III	Triglyceride ↓↓↓
Niacin (nicotinic acid)	Niacin	Inhibits hepatic VLDL/TG synthesis; ↓ lipolysis in adipose	Raises HDL most; TG ↓
PCSK9 inhibitors	Alirocumab, evolocumab (mAb); inclisiran (siRNA)	↓ degradation of LDL receptor	LDL ↓↓↓
ATP-citrate lyase inhibitor	Bempedoic acid	Inhibits cholesterol synthesis upstream of HMG-CoA reductase	LDL ↓
Omega-3 fatty acids	Icosapent ethyl (EPA)	↓ hepatic TG production	TG ↓

Statins — HMG-CoA reductase inhibitors

Mechanism

Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme converting HMG-CoA to mevalonate in hepatic cholesterol synthesis. Falling intracellular cholesterol upregulates SREBP-2, which increases LDL receptor expression on hepatocytes, clearing circulating LDL. They also modestly lower triglycerides and raise HDL, and have pleiotropic effects (plaque stabilisation, improved endothelial function, anti-inflammatory — reflected in CRP fall).

High-yield: Statins are most effective when taken at night for short-acting agents (simvastatin, lovastatin, fluvastatin) because cholesterol synthesis peaks at night. Atorvastatin and rosuvastatin have long half-lives and can be given any time of day.

Potency ranking (LDL-lowering)

Rosuvastatin > Atorvastatin > Simvastatin > Lovastatin ≈ Pravastatin ≈ Fluvastatin

Rosuvastatin and atorvastatin are "high-intensity" statins (LDL ↓ ≥50%).

Pharmacokinetics

• Most undergo CYP3A4 metabolism (atorvastatin, simvastatin, lovastatin) → interact with macrolides, azoles, grapefruit juice, protease inhibitors, verapamil/diltiazem.
• Pravastatin, rosuvastatin, pitavastatin are NOT CYP3A4-dependent → safer with CYP3A4 inhibitors.
• All are pregnancy contraindicated (cholesterol needed for fetal steroid/membrane synthesis) — Category X.

Adverse effects

• Myopathy spectrum: myalgia → myositis (↑CK) → rhabdomyolysis (CK >10× ULN, myoglobinuria, acute kidney injury). Risk rises with high dose, advanced age, hypothyroidism, renal impairment, and combination with fibrates (especially gemfibrozil).
• Hepatotoxicity: transaminase rise (usually transient; routine monitoring no longer mandated unless symptomatic).
• New-onset diabetes mellitus (small absolute risk, outweighed by CV benefit).
• Statin-associated autoimmune myopathy with anti-HMGCR antibodies (rare; persists after stopping drug).

High-yield: Gemfibrozil + statin is the classic combination that markedly raises rhabdomyolysis risk because gemfibrozil inhibits statin glucuronidation. If a fibrate must be combined with a statin, choose fenofibrate.

High-yield: Statin myopathy → check creatine kinase (CK). Rhabdomyolysis = CK >10× ULN with myoglobinuria → stop statin, IV fluids, monitor for AKI.

Ezetimibe

Inhibits NPC1L1 (Niemann-Pick C1-Like 1) at the intestinal brush border, blocking cholesterol absorption. Lowers LDL ~18–20% alone; synergistic with statins (dual blockade of synthesis + absorption). Glucuronidated and undergoes enterohepatic recycling. IMPROVE-IT trial showed added CV benefit of ezetimibe on top of simvastatin — frequently tested.

High-yield: Ezetimibe target = NPC1L1 transporter. First add-on when a maximally tolerated statin fails to reach LDL goal.

Bile acid sequestrants (resins)

Cholestyramine, colestipol, colesevelam are large anion-exchange resins that bind bile acids in the gut lumen, preventing reabsorption. The liver diverts cholesterol to replace lost bile acids and upregulates LDL receptors.

• Not absorbed → safe in pregnancy and children; colesevelam also lowers glucose (used in T2DM).
• Adverse effects: constipation, bloating, GI discomfort; can raise triglycerides (avoid if TG high); malabsorption of fat-soluble vitamins (A, D, E, K).
• Drug interactions: bind many co-administered drugs (digoxin, warfarin, thyroxine, thiazides) → give other drugs 1 h before or 4 h after the resin.

High-yield: Sequestrants can worsen hypertriglyceridaemia → contraindicated when TG markedly elevated. Cholestyramine is also used for bile-acid diarrhoea and pruritus of cholestasis.

Fibrates

Fenofibrate and gemfibrozil are PPAR-α (peroxisome proliferator-activated receptor alpha) agonists. Activation:

1. ↑ Lipoprotein lipase activity → faster TG clearance
2. ↓ apo C-III (an LPL inhibitor)
3. ↑ apo A-1/A-2 → modestly raise HDL
4. ↑ fatty-acid β-oxidation

Drug of choice for severe hypertriglyceridaemia (to prevent pancreatitis).

Adverse effects: myopathy (worse with statins), cholelithiasis (↑ biliary cholesterol — classic with gemfibrozil), dyspepsia, raised transaminases, reversible rise in creatinine (fenofibrate).

High-yield: Fibrate → think PPAR-α, triglyceride lowering, gallstones, and myopathy risk with statins. Fenofibrate is preferred over gemfibrozil for statin combinations.

Niacin (nicotinic acid)

Inhibits hepatic VLDL/TG synthesis and adipocyte lipolysis (via GPR109A). Has the greatest HDL-raising effect of any agent and can lower lipoprotein(a).

Adverse effects:

• Cutaneous flushing and pruritus — prostaglandin-mediated; pre-treat with aspirin to blunt it.
• Hyperglycaemia (caution in diabetes), hyperuricaemia/gout, hepatotoxicity (especially sustained-release). Largely fallen out of favour because outcome trials (AIM-HIGH, HPS2-THRIVE) showed no added CV benefit on statins, plus harm.

High-yield: Niacin = best HDL raiser + lowers Lp(a); flushing is prostaglandin-mediated and reduced by aspirin pre-dosing.

Newer agents

• PCSK9 inhibitors (alirocumab, evolocumab): monoclonal antibodies, subcutaneous; LDL ↓ up to 60% on top of statin. Used in familial hypercholesterolaemia and high-risk ASCVD not at goal (FOURIER, ODYSSEY trials). Inclisiran is a small interfering RNA against PCSK9 mRNA — twice-yearly dosing.
• Bempedoic acid: ATP-citrate lyase inhibitor acting upstream of HMG-CoA reductase; a prodrug activated in liver but not in muscle, so causes less myopathy — useful in statin-intolerant patients. Can raise uric acid.
• Lomitapide (MTP inhibitor) and mipomersen (apo B antisense) — reserved for homozygous familial hypercholesterolaemia.
• Icosapent ethyl (EPA): REDUCE-IT trial showed CV benefit in high-TG patients on statins.

Drug of choice by lipid pattern

Lipid abnormality	First-line / DOC	Notes
↑ LDL (isolated hypercholesterolaemia)	Statin	High-intensity for ASCVD; add ezetimibe ± PCSK9i if not at goal
Isolated hypertriglyceridaemia (severe, risk of pancreatitis)	Fibrate (fenofibrate)	Omega-3 EPA alternative; treat if TG > 500 mg/dL urgently
Mixed dyslipidaemia (↑LDL + ↑TG)	Statin (treat LDL first); add fibrate/EPA if TG persists	Use fenofibrate, not gemfibrozil, with statin
Low HDL	Niacin (most effective) but poor outcome data; lifestyle	—
Familial hypercholesterolaemia	High-intensity statin + ezetimibe + PCSK9 inhibitor	Homozygous: lomitapide, LDL apheresis
Statin intolerance / myopathy	Ezetimibe, bempedoic acid, PCSK9i	Bempedoic acid spares muscle
Elevated Lp(a)	Niacin (modest); PCSK9i	Novel antisense agents in trials

High-yield: Isolated hypertriglyceridaemia → fibrate. Mixed dyslipidaemia → statin first (because LDL drives ASCVD risk most). This statin-vs-fibrate decision is a recurring NEET PG one-liner.

Stepwise approach to LDL management

Step 1: Estimate ASCVD risk and set LDL goal → Step 2: Start maximally tolerated statin (high-intensity if high risk) → Step 3: Recheck lipids in 4–12 weeks; if LDL above goal add ezetimibe → Step 4: Still above goal → add PCSK9 inhibitor (or bempedoic acid if statin-intolerant) → Step 5: Address residual TG with fenofibrate or icosapent ethyl.

Management of suspected statin myopathy

1. Patient on statin reports muscle pain/weakness → measure CK.
2. CK normal/mildly raised + tolerable symptoms → reassure, continue or switch statin.
3. CK 4–10× ULN → hold and reassess; rule out hypothyroidism, drug interaction.
4. CK >10× ULN ± dark urine → rhabdomyolysis: stop statin, give IV fluids, treat AKI/hyperkalaemia, avoid future high-dose statin.
5. Persistent weakness after stopping → consider anti-HMGCR autoimmune myopathy (needs immunosuppression).

Complications & contraindications

• Pregnancy: statins contraindicated; bile acid sequestrants are the safest lipid-lowering agents in pregnancy (not absorbed).
• Active liver disease: caution with statins, fibrates, niacin.
• Severe renal impairment: rosuvastatin dose-adjust; gemfibrozil safer than fenofibrate renally but worse for myopathy.
• Gallstones: fibrates (esp. gemfibrozil).
• Gout/diabetes worsening: niacin.

Key differentials / "which drug" pearls

Clue in question	Answer
Targets NPC1L1	Ezetimibe
PPAR-α agonist	Fibrate
Inhibits HMG-CoA reductase	Statin
Monoclonal antibody lowering LDL	PCSK9 inhibitor (evolocumab/alirocumab)
siRNA against PCSK9	Inclisiran
Flushing relieved by aspirin	Niacin
Best HDL raiser, lowers Lp(a)	Niacin
Spares muscle, raises uric acid, prodrug	Bempedoic acid
Safe in pregnancy, causes constipation	Bile acid sequestrant
Rhabdomyolysis when combined with statin	Gemfibrozil

Recently asked / exam angle

• Mechanism-matching: ezetimibe → NPC1L1; fibrate → PPAR-α; statin → HMG-CoA reductase; niacin → ↓VLDL synthesis. Single most repeated theme.
• Drug of choice questions: isolated high TG → fibrate; mixed → statin; statin intolerance → ezetimibe/PCSK9i/bempedoic acid.
• Adverse-effect vignettes: elderly patient on simvastatin + a macrolide/azole or gemfibrozil presents with muscle pain and dark urine → rhabdomyolysis (CYP3A4 interaction or glucuronidation inhibition).
• Time of administration: simvastatin/lovastatin at night; atorvastatin/rosuvastatin any time.
• Pregnancy-safe lipid drug → bile acid sequestrant.
• Novel agents: inclisiran (siRNA), bempedoic acid (ATP-citrate lyase), icosapent ethyl (REDUCE-IT) — increasingly tested.
• Trial associations: IMPROVE-IT (ezetimibe), FOURIER/ODYSSEY (PCSK9i), REDUCE-IT (EPA), HPS2-THRIVE/AIM-HIGH (niagra negative).

Mnemonic — statins lower LDL by upregulating receptors: "Statins Make Livers Recruit" (Statin → ↓Mevalonate → ↓cholesterol → ↑LDL Receptor).

Mnemonic — fibrate effects (PPAR-α): "Fibrates Lower Lipids, Form Gallstones, Fight Muscles" — ↑LPL, ↓TG, cholelithiasis, myopathy with statins.

Rapid revision

1. Statin = HMG-CoA reductase inhibitor; upregulates hepatic LDL receptors; most potent class for LDL.
2. Rosuvastatin is the most potent statin; rosuvastatin/atorvastatin are high-intensity and can be dosed any time.
3. Simvastatin/lovastatin taken at night; metabolised by CYP3A4 (interact with macrolides, azoles, grapefruit).
4. Statin + gemfibrozil = highest rhabdomyolysis risk; prefer fenofibrate for combination.
5. Rhabdomyolysis → CK >10× ULN, myoglobinuria, AKI → stop statin + IV fluids.
6. Ezetimibe blocks NPC1L1 intestinal cholesterol transporter (IMPROVE-IT trial).
7. Bile acid sequestrants are pregnancy-safe, cause constipation, raise TG, bind co-drugs — separate dosing.
8. Fibrates are PPAR-α agonists; DOC for isolated severe hypertriglyceridaemia; cause gallstones.
9. Niacin = best HDL raiser, lowers Lp(a); flushing blocked by aspirin; worsens gout & glucose.
10. PCSK9 inhibitors (evolocumab/alirocumab) and inclisiran (siRNA) give large LDL falls in familial hypercholesterolaemia.
11. Bempedoic acid (ATP-citrate lyase) spares muscle → useful in statin intolerance; raises uric acid.
12. Isolated high TG → fibrate; mixed dyslipidaemia → statin first. Statins are pregnancy Category X.