Lipid-lowering agents compared
Verified · Oct 2026Most LDL-lowering drugs work by making the liver display more LDL receptors; the triglyceride drugs act on triglyceride-rich particles instead. This page lines up every lipid-lowering drug on the course by where it acts.
Where each drug acts
Hepatic LDL receptors set plasma LDL. When the cell’s cholesterol falls, receptor expression rises and more LDL is cleared; PCSK9, a hepatocyte product secreted into plasma, binds the receptor and sends it for lysosomal degradation, so fewer receptors reach the surface.
Most LDL-lowering drugs lower liver cholesterol. Statins competitively inhibit HMG-CoA reductase; bempedoic acid inhibits ATP-citrate lyase, upstream of it; ezetimibe blocks cholesterol uptake through NPC1L1 at the intestinal brush border; bile-acid sequestrants trap bile acids in the gut, so the liver converts more cholesterol into bile acids. PCSK9 antibodies and inclisiran instead keep more receptors on the cell surface, and lomitapide inhibits MTP so that VLDL is not assembled.
The triglyceride drugs act on triglyceride-rich particles: fibrates activate PPAR-α, raising lipoprotein lipase and lowering apo C-III; icosapent ethyl reduces hepatic VLDL-triglyceride synthesis or secretion and enhances triglyceride clearance; niacin partly inhibits fatty-acid release from adipose tissue and lowers hepatic VLDL synthesis.
Comparison
The drugs compared
| Agent | Target | Main lipid effect | How given | Signature toxicity | Key interaction |
|---|---|---|---|---|---|
| Statins | HMG-CoA reductase (competitive) → more hepatic LDL receptors | LDL ↓ 30–50% (moderate intensity) or more than 50% (high intensity) | Oral tablets | Myopathy, rarely rhabdomyolysis; transaminase rises; higher HbA1c and new-onset diabetes | Strong CYP3A4 inhibitors raise atorvastatin, simvastatin and lovastatin levels; gemfibrozil raises myopathy risk |
| Ezetimibe | NPC1L1 sterol transporter at the intestinal brush border | LDL ↓ about 13–20% alone; used with a statin | Oral tablets | Myopathy and liver-enzyme rises, mainly when combined with a statin | Taken 2 hours before or 4 hours after a bile-acid sequestrant; gemfibrozil raises its exposure |
| Bempedoic acid | ATP-citrate lyase, upstream of HMG-CoA reductase; prodrug activated in the liver (ACSVL1, absent in skeletal muscle) | LDL-C ↓ through less hepatic cholesterol synthesis and more LDL receptors | Oral | Hyperuricemia and gout; tendon rupture | Raises simvastatin and pravastatin levels |
| PCSK9 antibodies | Bind PCSK9 so it cannot bind LDL receptors | LDL-C ↓ 50–60%, alone or with a statin | Subcutaneous injection every 2–4 weeks | Injection-site reactions; hypersensitivity including angioedema | Statins increase PCSK9 activity, which blunts the statins’ own effect |
| Inclisiran | siRNA that directs breakdown of PCSK9 mRNA in hepatocytes | LDL-C ↓ about 50% added to a maximally tolerated statin | Subcutaneous injection by a health professional — initially, at 3 months, then every 6 months | Injection-site reactions; serious hypersensitivity including anaphylaxis and angioedema | Primarily metabolized by nucleases to shorter nucleotides |
| Bile-acid sequestrants | Bind bile acids in the gut → 7-α-hydroxylase converts more cholesterol → more LDL receptors | LDL-C ↓ (about 20% with cholestyramine in LRC-CPPT); triglycerides may rise | Oral; not absorbed | Constipation; fat-soluble vitamin malabsorption; hyperchloremic acidosis (cholestyramine, colestipol) | Bind other oral drugs — doses must be separated |
| Lomitapide | Microsomal triglyceride transfer protein (MTP) → no apo B lipoprotein assembly | LDL-C ↓ in homozygous familial hypercholesterolemia | Oral | Boxed hepatotoxicity (transaminase rises, hepatic steatosis), REMS; GI effects | Moderate or strong CYP3A4 inhibitors are contraindicated |
| Fibrates | PPAR-α agonists → ↑ lipoprotein lipase, ↓ apo C-III | Triglycerides ↓, HDL modestly ↑ | Oral | Gallstones; myopathy; hepatotoxicity and a reversible creatinine rise (fenofibrate) | Gemfibrozil + simvastatin contraindicated (rhabdomyolysis); potentiate warfarin |
| Niacin | Partial inhibition of fatty-acid release from adipose tissue; ↓ hepatic VLDL synthesis | LDL-C, apo B and triglycerides ↓; HDL ↑ | Oral (extended-release; immediate-release Niacor) | Flushing; hepatotoxicity (severe when substituted mg-for-mg); ↑ glucose and uric acid | Rhabdomyolysis risk with statins |
| Icosapent ethyl | EPA ethyl ester → ↓ hepatic VLDL-triglyceride synthesis or secretion, ↑ triglyceride clearance | Triglycerides ↓; labelled to reduce cardiovascular events on a statin | Oral, with food | Atrial fibrillation or flutter; bleeding | More bleeding with aspirin, clopidogrel or warfarin |
High-yield
Practice questions
Q1A 60-year-old man on atorvastatin has triglycerides of 700 mg/dL despite diet, and his physician decides that adding a fibrate is worth the risk.
Which choice and reason are correct?
- A.Gemfibrozil — it lowers statin levels by inhibiting OATP1B1
- B.Fenofibrate — fibrates are mainly glucuronidated, and fenofibrate changes statin exposure only modestly
- C.Icosapent ethyl — it is a fibrate with no statin interactions
- D.Fenofibrate — it strongly inhibits CYP3A4, so less statin is needed
- E.Either — fibrates never alter statin exposure
Show answer
B. Fenofibrate — fibrates are mainly glucuronidated, and fenofibrate changes statin exposure only modestly — Gemfibrozil inhibits OATP1B1, a hepatic transporter, raising exposure of substrates such as atorvastatin and simvastatin; simvastatin with gemfibrozil is contraindicated, and the combination has caused rhabdomyolysis. Fibric acids are metabolized mainly by glucuronidation with minimal effect on cytochrome P450, and fenofibrate changed atorvastatin and pravastatin exposure only modestly — yet its label still advises against combining it with a statin unless the benefit outweighs the risk. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid, not a fibrate.
Q2A 58-year-old woman with coronary disease still has a high LDL cholesterol on a statin. Her physician adds an oral drug that lowers LDL by reducing cholesterol absorption from the intestine.
What is that drug’s molecular target?
- A.HMG-CoA reductase
- B.PPAR-α
- C.The NPC1L1 sterol transporter at the intestinal brush border
- D.PCSK9
- E.The LDL receptor
Show answer
C. The NPC1L1 sterol transporter at the intestinal brush border — Ezetimibe blocks the sterol transporter NPC1L1 at the brush border of the small intestine; it neither increases bile-acid excretion nor inhibits hepatic cholesterol synthesis. Less cholesterol reaches the liver, hepatic stores fall and LDL receptors increase, so it adds to a statin. PPAR-α is the fibrates’ target, and its activation mainly lowers triglycerides by increasing fatty-acid oxidation and VLDL catabolism.
Q3A 52-year-old man with type 2 diabetes and high LDL cholesterol was started on a new lipid-lowering drug that also improved his glycemic control. His fasting triglycerides are now 620 mg/dL.
Which drug should be stopped?
- A.Colesevelam
- B.Ezetimibe
- C.Evolocumab
- D.Fenofibrate
- E.Icosapent ethyl
Show answer
A. Colesevelam — Colesevelam, like other bile-acid sequestrants, can increase serum triglycerides, and hypertriglyceridemia can cause acute pancreatitis. Triglycerides above 500 mg/dL are a contraindication, and colesevelam is discontinued if triglycerides exceed 500 mg/dL. Colesevelam is also indicated for glycemic control in type 2 diabetes; the others act differently: fenofibrate and icosapent ethyl lower triglycerides, ezetimibe blocks intestinal cholesterol absorption, and evolocumab blocks PCSK9 binding to the LDL receptor.
Q4A 14-year-old with homozygous familial hypercholesterolemia has two LDL-receptor–negative alleles. His LDL cholesterol remains very high despite treatment.
Which drug lowers LDL-C through a mechanism that does not depend on LDL receptors?
- A.Evolocumab
- B.Atorvastatin
- C.Ezetimibe
- D.Cholestyramine
- E.Lomitapide
Show answer
E. Lomitapide — Lomitapide inhibits microsomal triglyceride transfer protein, preventing assembly of apo B-containing lipoproteins; less VLDL synthesis lowers plasma LDL-C, and it is labelled for homozygous familial hypercholesterolemia. PCSK9 antibodies work by preserving LDL receptors, and patients with two receptor-negative alleles did not respond to evolocumab; statins lower LDL by upregulating LDL receptors, and lovastatin was less effective in homozygous familial hypercholesterolemia without functional receptors. Ezetimibe and bile-acid sequestrants such as cholestyramine also lower LDL-C by increasing hepatic LDL receptors.
Sources
- Statin Medications — StatPearls (NCBI)
- LOPID (gemfibrozil) — FDA label — FDA / DailyMed
- PREVALITE (cholestyramine for oral suspension) — FDA label — FDA / DailyMed
- PRALUENT (alirocumab) — FDA label — FDA / DailyMed
- ZETIA (ezetimibe) — FDA label — FDA / DailyMed
- PCSK9 Inhibitors — StatPearls (NCBI)
- NEXLETOL (bempedoic acid) — FDA label — FDA / DailyMed
- Niacin extended-release tablets — FDA label — FDA / DailyMed
- JUXTAPID (lomitapide) — FDA label — FDA / DailyMed
- LIPITOR (atorvastatin) — FDA label — FDA / DailyMed
- Biochemistry, LDL Cholesterol — StatPearls (NCBI)
- Colesevelam hydrochloride tablets — FDA label — FDA / DailyMed
- Biochemistry, Cholesterol — StatPearls (NCBI)
- CRESTOR (rosuvastatin) — FDA label — FDA / DailyMed
- Fibric Acid Antilipemic Agents — StatPearls (NCBI)
- ANTARA (fenofibrate) capsules — FDA label — FDA / DailyMed
- LIPOFEN (fenofibrate) capsules — FDA label — FDA / DailyMed
- Antilipemic Agent Bile Acid Sequestrants — StatPearls (NCBI)
- VASCEPA (icosapent ethyl) — FDA label — FDA / DailyMed
- Pravastatin — mechanism and pharmacokinetics — StatPearls (NCBI)
- Ezetimibe — NPC1L1, glucuronide, enterohepatic recycling — StatPearls (NCBI)
- REPATHA (evolocumab) — mechanism, pharmacodynamics, pharmacokinetics, HoFH receptor-negative response (FDA label) — FDA / DailyMed
- Leqvio (inclisiran) — FDA label: siRNA mechanism, pharmacodynamics, half-life — FDA / DailyMed
- COLESTID (colestipol) tablets — enterohepatic cycle, LDL receptors, absorption, drug binding (FDA label) — FDA / DailyMed
- The use of stems in the selection of INN (stems -entan, -afil, -ciguat, prost) — World Health Organization
- Niacin Toxicity — GPR109A flushing, hepatic pathways — StatPearls (NCBI)
- Atorvastatin — OATP1B1 (SLCO1B1) hepatic uptake — StatPearls (NCBI)
- Rhabdomyolysis — mechanisms and complications — StatPearls (NCBI)
- Zocor (simvastatin) — FDA label: OATP1B1 inhibitors raise simvastatin acid — FDA / DailyMed
- Bempedoic Acid — ATP-citrate lyase, ACSVL1 absent from muscle — StatPearls (NCBI)
- Niacor (niacin) — FDA label — FDA / DailyMed
- Fenofibrate — lipoprotein lipase, apo C, fatty-acid oxidation — StatPearls (NCBI)
- Lovastatin tablets — lactone, CYP3A4, homozygous FH (FDA label) — FDA / DailyMed
- Gemfibrozil — PPAR-α and lipoprotein lipase, OATP1B1 — StatPearls (NCBI)
Each class page compared lists its full sources; this page reuses facts verified there.
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.