Slide 1 - Lipid-Lowering Agents: Classification, Clinical Use, Adverse-Effect Management and ESC Update

• Classify lipid-lowering drugs
• Explain mechanisms, indications, contraindications and adverse effects
• Manage common drug-related adverse effects
• Apply the current ESC/EAS dyslipidaemia recommendations

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Slide 2 - Why Lower Lipids?

• LDL-cholesterol (LDL-C) is a causal driver of atherosclerotic cardiovascular disease (ASCVD).
• Lowering LDL-C reduces myocardial infarction, stroke, coronary revascularisation and cardiovascular death.
• The greatest benefit occurs with:
  • Earlier initiation
  • Greater absolute LDL-C reduction
  • Long-term adherence
• Triglyceride (TG) lowering has two distinct goals:
  • TG ≥500 mg/dL: prevent acute pancreatitis
  • Moderately raised TG: reduce residual ASCVD risk primarily through lifestyle and statin-based management

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Slide 3 - Lipid-Lowering Drug Classification

Drugs that primarily lower LDL-C

1. Statins
   • Atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, pitavastatin
2. Cholesterol absorption inhibitor
   • Ezetimibe
3. PCSK9-targeted therapy
   • PCSK9 monoclonal antibodies: alirocumab, evolocumab
   • PCSK9 siRNA: inclisiran
4. ATP citrate lyase inhibitor
   • Bempedoic acid
5. Bile-acid sequestrants
   • Cholestyramine, colestipol, colesevelam
6. Specialist therapies for familial hypercholesterolaemia
   • Evinacumab, lomitapide, lipoprotein apheresis

Drugs that primarily lower triglycerides

1. Fibrates: fenofibrate, gemfibrozil
2. Omega-3 fatty acids: icosapent ethyl, EPA/DHA preparations
3. ApoC-III inhibitor: volanesorsen, selected familial chylomicronaemia syndrome
4. Niacin: now rarely used

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Slide 4 - Statins: First-Line LDL-C Therapy

Examples by intensity

Mechanism of action

• Competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis.
• Hepatic intracellular cholesterol falls.
• The liver increases LDL receptor expression.
• Increased LDL receptor activity removes LDL particles from circulation.

Effects

• LDL-C reduction: about 30-60%, depending on agent and dose
• TG reduction: 10-30%
• Mild HDL-C increase

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Slide 5 - Statins: Indications and Contraindications

Major indications

• Secondary prevention in established ASCVD:
  • Coronary artery disease, myocardial infarction, acute coronary syndrome
  • Ischaemic stroke/TIA
  • Peripheral arterial disease
• Primary prevention in high or very-high cardiovascular risk
• Diabetes with elevated cardiovascular risk
• Familial hypercholesterolaemia
• Hypertriglyceridaemia with elevated ASCVD risk

Contraindications

• Pregnancy and breastfeeding
• Active liver disease or unexplained persistent marked transaminase elevation
• Prior serious hypersensitivity reaction

Important interactions

• CYP3A4 inhibitors increase exposure to simvastatin, lovastatin and atorvastatin:
  • Macrolides such as clarithromycin
  • Azole antifungals
  • HIV protease inhibitors/cobicistat
  • Cyclosporine
  • Grapefruit juice, especially in large quantities
• Gemfibrozil markedly increases statin-associated myopathy risk.

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Slide 6 - Statin Adverse Effects and Their Management

A practical approach to suspected statin-associated muscle symptoms

1. Check CK only when symptoms are present or patient is high-risk.
2. Exclude hypothyroidism, strenuous exercise, infection, renal/hepatic dysfunction and interacting drugs.
3. Stop statin temporarily if symptoms are troublesome.
4. After symptoms settle:
   • Rechallenge with same statin at lower dose, or
   • Switch to rosuvastatin/pravastatin, or
   • Use alternate-day rosuvastatin in selected patients.
5. Add ezetimibe, bempedoic acid or PCSK9-targeted therapy if LDL-C target remains unmet.

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Slide 7 - Ezetimibe

Mechanism

• Inhibits intestinal cholesterol absorption by blocking the NPC1L1 transporter at the brush border.
• Reduced cholesterol delivery to liver causes increased hepatic LDL receptor activity.

Effects

• LDL-C reduction: approximately 18-25% as monotherapy
• Additional LDL-C reduction when combined with a statin: approximately 15-25%

Indications

• Add-on to maximally tolerated statin when LDL-C target is not achieved
• Alternative monotherapy in true statin intolerance
• Familial hypercholesterolaemia
• Sitosterolaemia

Adverse effects

• Usually well tolerated
• Diarrhoea, abdominal discomfort, fatigue, headache
• Rare transaminase elevation, especially with a statin
• Rare myalgia

Contraindications/cautions

• Hypersensitivity
• Avoid ezetimibe-statin fixed combinations in pregnancy
• Use caution in active moderate-to-severe hepatic disease

Management

• Mild gastrointestinal effects: reassure and continue if tolerable
• Elevated liver enzymes with statin combination: assess other causes, repeat tests, reduce/withhold therapy if persistent

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Slide 8 - PCSK9 Inhibitors and Inclisiran

PCSK9 monoclonal antibodies

• Alirocumab
• Evolocumab

Mechanism

• PCSK9 normally promotes LDL receptor degradation.
• PCSK9 inhibition preserves hepatic LDL receptors.
• More LDL receptors remove more LDL-C from blood.

Effects

• LDL-C reduction: about 50-60%, in addition to statin therapy
• Demonstrated cardiovascular outcome benefit in high-risk patients

Inclisiran

• Small interfering RNA that reduces hepatic production of PCSK9.
• Dosing is infrequent after initial and 3-month doses, then every 6 months.
• LDL-C lowering is approximately 45-50%.

Indications

• Established ASCVD not at LDL-C goal despite maximally tolerated statin plus ezetimibe
• Familial hypercholesterolaemia
• True statin intolerance when substantial LDL-C reduction is required

Adverse effects and management

• Injection-site reactions: usually mild, use local symptomatic care and rotate site
• Nasopharyngitis or flu-like symptoms: symptomatic care
• Hypersensitivity: stop drug and assess urgently if severe

Contraindications/cautions

• Hypersensitivity
• Avoid in pregnancy and lactation because of insufficient safety data

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Slide 9 - Bempedoic Acid

Mechanism

• Inhibits ATP citrate lyase, an enzyme upstream of HMG-CoA reductase in cholesterol synthesis.
• Activated mainly in the liver, not skeletal muscle.
• Therefore useful in patients with statin-associated muscle symptoms.

Effects

• LDL-C reduction: about 17-23% alone
• Greater reduction with fixed-dose bempedoic acid plus ezetimibe
• Cardiovascular outcome benefit demonstrated in statin-intolerant high-risk patients

Indications

• Patients unable to take statins who require LDL-C lowering
• Add-on to maximally tolerated statin, with or without ezetimibe, when LDL-C goal is not achieved
• Established ASCVD or heterozygous familial hypercholesterolaemia

Adverse effects

• Hyperuricaemia and gout
• Tendon rupture, rare
• Mild increase in liver enzymes
• Increased creatinine
• Cholelithiasis, uncommon

Contraindications/cautions

• Pregnancy and breastfeeding: avoid
• Use caution in gout or marked hyperuricaemia
• Avoid/use caution in patients with previous tendon disorders

Management

• Check uric acid if gout symptoms occur.
• Treat acute gout and consider alternative therapy if recurrent.
• Stop immediately if tendon pain, swelling or rupture is suspected.
• Avoid excess simvastatin or pravastatin doses when co-administered, according to product-specific interaction guidance.

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Slide 10 - Bile-Acid Sequestrants

Drugs

• Cholestyramine
• Colestipol
• Colesevelam

Mechanism

• Bind bile acids in the intestine.
• Prevent enterohepatic bile-acid reabsorption.
• Liver uses cholesterol to synthesise new bile acids.
• Hepatic LDL receptor expression increases.

Effects

• LDL-C reduction: approximately 15-25%
• May raise triglycerides

Indications

• Selected patients with isolated LDL-C elevation
• Useful when systemic drug absorption should be avoided
• Colesevelam may modestly improve glycaemia in type 2 diabetes

Adverse effects

• Constipation, bloating, nausea, flatulence
• Reduced absorption of fat-soluble vitamins A, D, E and K
• Binding and reduced absorption of many oral drugs

Contraindications

• Bowel obstruction
• Severe constipation
• Hypertriglyceridaemia, especially TG >300 mg/dL

Management

• Increase fluids and dietary fibre.
• Consider colesevelam for better gastrointestinal tolerance.
• Give interacting medicines at a separate time, commonly at least 4-6 hours apart.
• Avoid if triglycerides are high because these agents can worsen hypertriglyceridaemia. Lippincott Illustrated Reviews: Pharmacology, p. 268.

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Slide 11 - Fibrates

Drugs

• Fenofibrate
• Gemfibrozil

Mechanism

• Activate PPAR-alpha.
• Increase lipoprotein lipase activity.
• Increase fatty-acid oxidation.
• Reduce apoC-III and improve clearance of triglyceride-rich lipoproteins.

Effects

• TG reduction: approximately 30-50%
• HDL-C increase: 5-15%
• LDL-C effect is variable

Indications

• Severe hypertriglyceridaemia, particularly TG ≥500 mg/dL, to reduce pancreatitis risk
• Selected mixed dyslipidaemia

Adverse effects

• Dyspepsia
• Elevated transaminases
• Gallstones
• Creatinine increase
• Myopathy/rhabdomyolysis, especially with statin combination
• Potentiation of warfarin effect

Contraindications/cautions

• Severe renal impairment
• Active liver disease
• Gallbladder disease
• Avoid gemfibrozil with statins whenever possible

Management

• Prefer fenofibrate, not gemfibrozil, if a fibrate is necessary with a statin.
• Monitor renal function and liver enzymes.
• Stop and check CK if muscle symptoms occur.
• Monitor INR closely in patients receiving warfarin.

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Slide 12 - Omega-3 Fatty Acids and Icosapent Ethyl

Mechanism

• Reduce hepatic VLDL-triglyceride synthesis and secretion.
• Increase triglyceride clearance.

Drugs

• Icosapent ethyl: purified EPA
• Mixed EPA/DHA formulations

Effects

• TG reduction: approximately 20-30% or more at prescription doses

Indications

• Severe hypertriglyceridaemia
• Icosapent ethyl as adjunct to statin therapy in selected high-risk patients with persistent TG elevation

Adverse effects

• Dyspepsia, fishy taste, diarrhoea
• Atrial fibrillation/flutter risk, especially in predisposed individuals
• Bleeding tendency, particularly with antiplatelets or anticoagulants

Management

• Ask about palpitations and assess for atrial fibrillation.
• Monitor clinically for bleeding in patients receiving anticoagulants.
• Reinforce that over-the-counter fish oil is not interchangeable with prescription icosapent ethyl.

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Slide 13 - Niacin and Specialist Therapies

Niacin

• Reduces hepatic VLDL production and lowers LDL-C/TG; raises HDL-C.

• No clear additional ASCVD outcome benefit when added to statins.
• Poor tolerability.

• Flushing, pruritus
• Hyperglycaemia
• Hyperuricaemia/gout
• Hepatotoxicity
• Gastrointestinal upset

• Aspirin 30 minutes before immediate-release niacin can reduce prostaglandin-mediated flushing.
• Titrate slowly.
• Stop if significant hepatotoxicity, uncontrolled hyperglycaemia or gout.

Specialist therapies

• Evinacumab: ANGPTL3 monoclonal antibody, for homozygous familial hypercholesterolaemia.
• Lomitapide: microsomal triglyceride-transfer protein inhibitor, for homozygous familial hypercholesterolaemia; hepatotoxicity and hepatic steatosis are important concerns.
• Lipoprotein apheresis: selected severe familial hypercholesterolaemia or refractory cases.

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Slide 14 - Lipid Targets: ESC/EAS Risk-Based Approach

LDL-C goals retained from the 2019 ESC/EAS guideline

Very-high-risk examples

• Established ASCVD
• Diabetes with target-organ damage or multiple major risk factors
• Severe CKD: eGFR <30 mL/min/1.73 m²
• Familial hypercholesterolaemia plus ASCVD or another major risk factor
• SCORE2/SCORE2-OP ≥20%

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Slide 15 - Important Correction: “2026 ESC Guidelines”

• There is no separate 2026 ESC/EAS dyslipidaemia guideline at present.
• The current ESC document is the 2025 Focused Update of the 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias.
• It updates evidence published up to 31 March 2025.
• It supplements rather than replaces the 2019 full guideline.
• The LDL-C targets above remain unchanged.

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Slide 16 - 2025 ESC/EAS Update: LDL-C Lowering Strategy

Core management pathway

1. Assess cardiovascular risk.
2. Optimise lifestyle measures.
3. Start a statin at the maximally tolerated intensity.
4. Check adherence, tolerance and lipid response.
5. If LDL-C target is not met:
   • Add ezetimibe, and/or
   • Add a PCSK9 monoclonal antibody, and/or
   • Add bempedoic acid.
6. Choose therapy according to:
   • Baseline LDL-C and required LDL-C reduction
   • ASCVD risk
   • Statin tolerance
   • Drug interactions
   • Cost/access and patient preference

New or emphasised recommendations

• Bempedoic acid is recommended for patients unable to take statins to achieve LDL-C goal: Class I, Level A.
• Adding bempedoic acid to maximally tolerated statin therapy, with or without ezetimibe, should be considered in high- or very-high-risk patients not at LDL-C goal: Class IIa, Level B.
• Evinacumab should be considered for homozygous familial hypercholesterolaemia in patients aged ≥5 years not at goal despite maximal therapy: Class IIa, Level C.

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Slide 17 - 2025 ESC/EAS Update: Acute Coronary Syndrome

Major change: treat early during the index admission

• Intensify treatment during the index ACS hospitalisation to further lower LDL-C.
• Recommendation: Class I, Level C

• Consider starting high-intensity statin plus ezetimibe during the index hospitalisation if statin alone is unlikely to achieve LDL-C goal.
• Recommendation: Class IIa, Level B

Clinical message

• Do not delay intensification until a later outpatient visit.
• Early intensive reduction is appropriate because recurrent risk is highest in the first weeks to months after ACS.
• Select drugs based on the amount of additional LDL-C reduction needed.

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Slide 18 - 2025 ESC/EAS Update: Hypertriglyceridaemia

First priorities

• Exclude and treat secondary causes:
  • Poorly controlled diabetes
  • Alcohol excess
  • Obesity
  • Hypothyroidism
  • Chronic kidney disease
  • Drugs that raise TG
• Lifestyle:
  • Weight loss
  • Eliminate alcohol in severe hypertriglyceridaemia
  • Restrict simple carbohydrates
  • Very-low-fat diet in severe hypertriglyceridaemia
  • Improve glycaemic control

Drug treatment

• Statins remain first choice in high-risk patients because LDL-C reduction remains the main ASCVD prevention goal.
• Icosapent ethyl 2 g twice daily should be considered with a statin in high- or very-high-risk patients with fasting TG 135-499 mg/dL:
  • Class IIa, Level B
• Volanesorsen 300 mg weekly should be considered in familial chylomicronaemia syndrome with TG >750 mg/dL to reduce TG and pancreatitis risk:
  • Class IIa, Level C
• For persistent TG ≥500 mg/dL, consider fibrate and/or prescription omega-3 fatty acid to reduce pancreatitis risk.

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Slide 19 - 2025 ESC/EAS Update: Risk Modifiers and Special Populations

Risk assessment

• Use SCORE2 in apparently healthy people <70 years.
• Use SCORE2-OP in older people.
• Do not use SCORE2/SCORE2-OP to “reassess” patients with established ASCVD or those already on lipid-lowering therapy.

Risk modifiers

• Lipoprotein(a) >50 mg/dL or >105 nmol/L
• Family history of premature cardiovascular disease
• Coronary artery calcium or subclinical coronary atherosclerosis on imaging
• Chronic inflammatory disease
• HIV infection
• Premature menopause or hypertensive pregnancy disorders
• Obstructive sleep apnoea, obesity, physical inactivity and psychosocial factors

Special populations

• HIV: statin treatment is recommended for primary prevention in people aged ≥40 years, regardless of calculated risk or LDL-C, while carefully checking antiretroviral drug interactions.
• Cardiotoxic cancer treatment: statins should be considered in adults at high/very-high risk of chemotherapy-related cardiovascular toxicity to reduce anthracycline-related cardiac dysfunction.

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Slide 20 - Practical Treatment Algorithm

Patient with raised LDL-C

• Full lipid profile
• Secondary causes: diabetes, hypothyroidism, nephrotic syndrome, cholestasis, alcohol, medications
• Cardiovascular risk category
• Family history and possible familial hypercholesterolaemia
• Baseline ALT; CK only if muscle symptoms/high-risk features

• Mediterranean-style diet
• Reduce saturated and trans fats
• Increase fibre
• Weight reduction when indicated
• Exercise
• Smoking cessation
• Control diabetes, blood pressure and alcohol intake

• Start maximally tolerated statin.
• Add ezetimibe if target unmet.
• Add PCSK9-targeted treatment and/or bempedoic acid for persistent elevation, particularly in high/very-high risk.
• Refer severe/familial cases to a lipid specialist.

• Reassess lipid profile about 4-12 weeks after initiation or dose change.
• Review adherence, tolerance, interactions and achievement of LDL-C goal.
• Continue long-term monitoring.

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Slide 21 - Take-Home Messages

• Statins are the foundation of LDL-C lowering and ASCVD prevention.
• Ezetimibe is usually the first add-on drug.
• PCSK9 inhibitors provide large additional LDL-C reductions for very-high-risk and familial hypercholesterolaemia patients.
• Bempedoic acid is an important oral option, especially in statin intolerance.
• Treat adverse effects systematically rather than stopping lipid therapy permanently.
• Avoid gemfibrozil with statins where possible.
• Severe hypertriglyceridaemia requires urgent lifestyle correction and TG-lowering therapy to reduce pancreatitis risk.
• The current ESC update is the 2025 Focused Update, not a 2026 guideline.
• In ACS, start or intensify lipid-lowering therapy during the index hospitalisation.

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Slide 22 - References

1. Mach F, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias. Atherosclerosis. 2025;409:120479. PMID 40885687.
2. The official ESC 2025 slide set.
3. Harrison’s Principles of Internal Medicine, 22e, p. 3293.
4. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, p. 755-760.
5. Lippincott Illustrated Reviews: Pharmacology, p. 268.
6. Zhang S, et al. Statins, ezetimibe and fibrates in hyperlipidaemia: systematic review and network meta-analysis. Eur J Med Res. 2025. PMID 40551216.