Antilipidemic Drugs

Overview of Drug Classes

1. Statins (HMG-CoA Reductase Inhibitors)

1. Inhibit HMG-CoA reductase → ↓ intracellular cholesterol
2. Low intracellular cholesterol → upregulation of LDL receptors on hepatocyte surface
3. More LDL receptors → increased clearance of LDL-C, VLDL, and IDL from blood
4. Also ↓ VLDL secretion from liver

Figure: Inhibition of HMG-CoA reductase by statins leads to decreased intracellular cholesterol, upregulated LDL receptors, and reduced VLDL secretion. — Lippincott Illustrated Reviews: Pharmacology

• Improved endothelial function
• Increased nitric oxide bioavailability
• Anti-inflammatory and antioxidant properties
• Atherosclerotic plaque stabilization and partial resorption

• Short-acting (t½ 1–4 h): Lovastatin, simvastatin, pravastatin, fluvastatin → taken with evening meal (peak HMG-CoA reductase activity at midnight)
• Long-acting (t½ ~14–19 h): Atorvastatin, rosuvastatin → can be taken at any time
• Atorvastatin, simvastatin, and lovastatin are metabolized by CYP3A4 — avoid with macrolides, azole antifungals, cyclosporine, HIV protease inhibitors, and >1 qt/day grapefruit juice

1. Clinical ASCVD
2. LDL-C ≥ 190 mg/dL
3. Diabetes aged 40–75 years
4. Elevated 10-year ASCVD risk (≥7.5%), aged 40–75 years

• Myopathy/Rhabdomyolysis (most serious): Risk <0.1%; creatine kinase >10× ULN = myopathy diagnosis; presents with proximal weakness, myalgia, brown/red urine
• Hepatotoxicity: ALT elevation ≥3× ULN on two occasions; routine LFT monitoring no longer universally recommended by FDA due to low yield
• New-onset diabetes mellitus: ~1/1000 patients per year; higher risk with metabolic syndrome; benefits still outweigh risks

2. Ezetimibe

3. Bile Acid Sequestrants (Resins)

Figure: Bile acid sequestrants interrupt enterohepatic circulation, forcing hepatic cholesterol utilization for bile acid synthesis. — Lippincott Illustrated Reviews: Pharmacology

• GI: Constipation, nausea, flatulence (most common)
• Impair absorption of fat-soluble vitamins (A, D, E, K)
• Interfere with absorption of many drugs (digoxin, warfarin, thyroid hormone) — other drugs should be taken 1–2 h before or 4–6 h after the resin
• Contraindicated in significant hypertriglyceridemia (TG >400 mg/dL) — may raise TG further

4. PCSK9 Inhibitors

• Heterozygous or homozygous familial hypercholesterolemia
• Clinical ASCVD requiring additional LDL-C lowering beyond maximally tolerated statins
• Statin-intolerant patients with high ASCVD risk

5. Bempedoic Acid (ATP-Citrate Lyase Inhibitor)

6. Lomitapide (MTP Inhibitor)

7. Fibrates

• ↑ Lipoprotein lipase (LPL) expression → enhanced VLDL triglyceride hydrolysis
• ↓ Apolipoprotein CIII (an LPL inhibitor)
• ↑ ApoAI and ApoAII expression → ↑ HDL-C by 15–25%
• Net effect: ↓ TG by 40–60%, modest ↓ LDL-C

• Hypertriglyceridemia (especially severe cases to prevent pancreatitis)
• Type III hyperlipidemia (dysbetalipoproteinemia)
• Not indicated primarily for ASCVD event reduction

• Mild GI disturbances (most common)
• Gallstone formation (↑ biliary cholesterol excretion)
• Myositis/rhabdomyolysis — significant risk when gemfibrozil + any statin is combined; gemfibrozil is contraindicated with simvastatin
• Potentiate warfarin anticoagulation — monitor INR
• Contraindicated in severe hepatic or renal dysfunction, preexisting gallbladder disease

8. Niacin (Nicotinic Acid)

• Strongly inhibits lipolysis in adipose tissue (via GPR109A receptor) → ↓ free fatty acid flux to liver → ↓ hepatic VLDL/TG synthesis → ↓ LDL-C
• Blocks HDL catabolism by hepatocytes → ↑ circulating HDL
• Reduces apoB100 catabolism → ↓ LDL

• ↓ TG: 20–50%
• ↓ LDL-C: 10–20%
• ↑ HDL-C: 10–30% (most effective agent for raising HDL)

• Cutaneous flushing (most common, prostaglandin-mediated) — reduced by taking aspirin 30 min prior, slow dose titration, or sustained-release formulation
• Nausea, abdominal pain, pruritus
• Hyperuricemia/gout (inhibits tubular urate secretion)
• Impaired glucose tolerance
• Hepatotoxicity
• Contraindicated in active hepatic disease or active peptic ulcer

9. Omega-3 Fatty Acids

Summary: Drug Selection by Lipid Target

• CYP3A4 inhibitors + atorvastatin/simvastatin/lovastatin → ↑ myopathy risk
• Gemfibrozil + any statin → ↑ rhabdomyolysis (contraindicated with simvastatin)
• Bile acid sequestrants → ↓ absorption of many drugs; give other drugs 1–2 h before or 4–6 h after
• Fibrates + warfarin → ↑ INR; monitor closely

New Dyslipidemia Guidelines (2025–2026)

1. 2026 ACC/AHA Multisociety Dyslipidemia Guideline

🔵 New Risk Assessment Tool: PREVENT™

• Estimates 10-year and 30-year risk of fatal and non-fatal ASCVD events
• Incorporates kidney function (eGFR) and metabolic factors
• Better calibrated across sex, race, and age groups
• Aligns with the concept of cardiovascular-kidney-metabolic (CKM) syndrome

🔵 Restored LDL-C Treatment Goals

• Non-HDL-C = LDL-C target + 30 mg/dL
• ApoB target for very high risk: < 65 mg/dL

🔵 Updated Primary Prevention Strategy

• LDL-lowering therapy may be considered for primary prevention in adults with 10-year PREVENT-ASCVD risk of 3–<5% (borderline risk), with shared decision-making
• Statin therapy recommended at ≥5–<7.5% risk with risk-enhancing factors
• Statin therapy recommended at ≥7.5% 10-year ASCVD risk

🔵 Expanded Risk-Enhancing Factors

• Lipoprotein(a) [Lp(a)] — should be measured at least once in all adults; elevated Lp(a) is a risk-enhancing factor and an indicator for more aggressive LDL-C lowering
• Coronary artery calcium (CAC) scoring — recommended for men ≥40 years and women ≥45 years to refine risk assessment; absolute CAC value and sex/age/race-standardized percentile are both used
• Remnant particles and TG-rich lipoproteins — elevated TG and remnant cholesterol now recognized as independent ASCVD risk factors
• CKM syndrome — kidney disease and metabolic factors formally integrated into risk

🔵 New and Expanded Drug Recommendations

🔵 Hypertriglyceridemia

• TG ≥ 150 mg/dL: lifestyle modification first
• TG ≥ 500 mg/dL: fibrate or omega-3 to prevent pancreatitis
• Icosapent ethyl preferred over mixed omega-3 for ASCVD risk reduction

🔵 Children and Adolescents

• Lipid screening recommended starting at age 9–11 (and again 17–21)
• Earlier statin initiation considered for familial hypercholesterolemia in children ≥8–10 years
• Expanded guidance for pediatric dyslipidemia management

🔵 Referral to Lipid Specialist

• HoFH or suspected FH with inadequate response
• Very high Lp(a) (≥ 100 mg/dL or ≥250 nmol/L)
• Statin intolerance with persistent LDL-C above goal
• Complex mixed dyslipidemias

2. 2025 ESC/EAS Focused Update on Dyslipidaemias

🔴 Risk Assessment: SCORE → SCORE2 / SCORE2-OP

• SCORE2 — estimates both fatal and non-fatal CVD events in adults 40–89 years without known CVD or diabetes
• SCORE2-OP (Older Persons) — better calibrated for elderly patients
• Additional risk modifiers: family history, ethnicity, hs-CRP, Lp(a), subclinical atherosclerosis (imaging or CAC score by CT)

🔴 New Drug Recommendations

• Class IB — recommended for patients unable to take statins (statin intolerance)
• Class IIaC — may be used as add-on to maximally tolerated statin ± ezetimibe in high-risk patients not at LDL-C target

• Recommended specifically for homozygous familial hypercholesterolemia (HoFH) as adjunct to other LDL-lowering therapy (based on Phase 3 ELIPSE HoFH trial)
• Can reduce LDL-C by ~47% in HoFH where LDL receptors are non-functional

• Formally endorsed; given twice yearly subcutaneously; reduces LDL-C by ~50%

🔴 ACS: Start Lipid Lowering at Index Hospitalization

• High-intensity statin + ezetimibe should be started during the index ACS hospitalization
• LDL-C should be rechecked at 4–6 weeks; if target not met, add PCSK9 inhibitor or inclisiran
• Goal: LDL-C < 1.4 mmol/L (55 mg/dL) and ≥50% reduction within 4–6 weeks of ACS

🔴 Lipoprotein(a) [Lp(a)]

• Lp(a) is formally recognized as an independent cardiovascular risk factor
• Measurement recommended at least once in all adults; elevated Lp(a) (≥50 mg/dL or ≥125 nmol/L) should trigger more intensive LDL-C lowering
• No specific Lp(a)-lowering drug is yet approved (pelacarsen, olpasiran in trials); current management is to treat overall ASCVD risk more aggressively

🔴 Special Populations

Key Comparisons: 2026 ACC/AHA vs. 2025 ESC/EAS

Bottom Line

1. Lower is better — LDL-C targets are now more aggressive, especially for very high-risk patients (< 55 mg/dL / 1.4 mmol/L)
2. Lp(a) matters — universal screening is now recommended; it refines risk stratification
3. New drugs have a formal role — bempedoic acid, evinacumab, and inclisiran are now guideline-endorsed
4. Treat earlier and more intensively — especially in ACS, start combination therapy at hospitalization
5. Personalized risk assessment — PREVENT™ and SCORE2 replace older tools; CAC and Lp(a) refine the picture
6. Supplements do not work — dietary supplements and vitamins are not recommended for CVD prevention