7.6 Lipid-Lowering Agents
Lipid-lowering drugs reduce cardiovascular risk by decreasing LDL cholesterol and other atherogenic lipoproteins. Statins are first-line therapy with extensive evidence for reducing MI, stroke, and cardiovascular mortality.
Lipoproteins Overview
Atherogenic Lipoproteins
LDL-C: Primary target—direct correlation with CV risk
VLDL: Triglyceride-rich, precursor to LDL
Lp(a): LDL-like + apo(a), independent risk factor
Protective Lipoproteins
HDL-C: Reverse cholesterol transport, anti-inflammatory
Higher HDL → lower CV risk (but raising HDL hasn't shown benefit)
Statins (HMG-CoA Reductase Inhibitors)
Mechanism
Inhibit HMG-CoA reductase—rate-limiting enzyme in cholesterol synthesis
↓ Hepatic cholesterol → ↑ LDL receptor expression → ↑ LDL uptake from blood
Result: ↓ LDL-C (20-60%), modest ↓ TG (10-30%), modest ↑ HDL (5-15%)
Pleiotropic Effects
Plaque stabilization, ↓ inflammation (↓ CRP), improved endothelial function
↓ Thrombogenicity, antioxidant effects
Benefits beyond LDL lowering—contribute to CV risk reduction
Common Statins
High-intensity: Atorvastatin 40-80mg, rosuvastatin 20-40mg (↓ LDL ≥50%)
Moderate-intensity: Atorvastatin 10-20mg, rosuvastatin 5-10mg, simvastatin 20-40mg, pravastatin 40-80mg (↓ LDL 30-50%)
Low-intensity: Simvastatin 10mg, pravastatin 10-20mg, lovastatin 20mg (↓ LDL <30%)
Naming: "-statin" suffix
Clinical Evidence & Indications
↓ CV events, MI, stroke, all-cause mortality (~25-40% relative risk reduction)
Primary prevention: High CV risk (diabetes, LDL >190, 10-yr ASCVD risk >7.5%)
Secondary prevention: Established ASCVD (CAD, prior MI, stroke, PAD)—high-intensity statin
Consider moderate-intensity if age >75 or not tolerating high-intensity
Adverse Effects
Myopathy: Muscle pain, weakness (5-10%), ↑ CK
Rhabdomyolysis (rare but serious): Severe myopathy, myoglobinuria, acute renal failure
Risk factors: High dose, drug interactions (CYP3A4 inhibitors—esp. with simvastatin), renal/hepatic impairment
Hepatotoxicity: ↑ transaminases (~1%), usually mild—monitor LFTs at baseline
New-onset diabetes: Modest ↑ risk (9% over 4 years)—benefits outweigh risks
Cognitive effects controversial—large trials show no clear harm
Drug Interactions
Most statins metabolized by CYP3A4 (atorvastatin, simvastatin, lovastatin)
Avoid with simvastatin: Gemfibrozil, azole antifungals, macrolides, CCBs (diltiazem, verapamil), grapefruit juice
Safer options: Pravastatin, rosuvastatin (not CYP3A4), pitavastatin
Ezetimibe
Mechanism
Inhibits NPC1L1 transporter in small intestine brush border
Blocks cholesterol absorption (dietary + biliary cholesterol)
↓ LDL-C ~15-20% as monotherapy
Clinical Use
Add-on to statin when LDL goal not achieved (synergistic effect)
Alternative for statin-intolerant patients (less effective alone)
IMPROVE-IT trial: ezetimibe + statin ↓ CV events vs. statin alone
Safety
Well-tolerated, few side effects (GI upset, fatigue)
No significant drug interactions
Safe to combine with statins—no ↑ myopathy risk
PCSK9 Inhibitors
Mechanism
Monoclonal antibodies against PCSK9 (proprotein convertase subtilisin/kexin type 9)
PCSK9 normally binds LDL receptors → lysosomal degradation
Inhibition → ↑ LDL receptor recycling → ↑ LDL clearance
↓ LDL-C 50-60% (most potent LDL-lowering agents)
Available Agents
Evolocumab (Repatha), Alirocumab (Praluent)
SC injection every 2 weeks or monthly
FOURIER & ODYSSEY trials: ↓ CV events (15-20% relative risk reduction)
Indications
High CV risk with LDL >70 despite maximally tolerated statin + ezetimibe
Familial hypercholesterolemia (FH)
Statin intolerance with high CV risk
Expensive—cost-effectiveness considerations
Side Effects
Generally well-tolerated
Injection site reactions, flu-like symptoms (uncommon)
No safety concerns with very low LDL levels (<25 mg/dL)
Fibrates
Mechanism
PPAR-α (peroxisome proliferator-activated receptor alpha) agonists
↑ Lipoprotein lipase (LPL) → ↑ TG clearance, ↓ VLDL production
↓ TG (30-50%), ↑ HDL (10-20%), variable LDL effect
Common Fibrates
Fenofibrate, gemfibrozil
Naming: "-fibrate" or "-fibrozil" suffix
Clinical Use
Primary indication: Severe hypertriglyceridemia (>500 mg/dL) to prevent pancreatitis
Mixed dyslipidemia (low HDL + high TG) in metabolic syndrome
CV benefit unclear—trials show modest/no benefit over statins
NOT first-line for ASCVD prevention (statins superior)
Adverse Effects & Interactions
Myopathy (especially with statins—avoid gemfibrozil + statin)
Fenofibrate safer than gemfibrozil for combination (if needed)
Cholelithiasis (gallstones)—↑ cholesterol in bile
GI upset, ↑ LFTs, potentiates warfarin
Omega-3 Fatty Acids
Mechanism & Effects
EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid)
↓ VLDL synthesis, ↑ TG clearance → ↓ TG (20-50% at high doses)
Anti-inflammatory, antiplatelet, membrane stabilizing effects
Clinical Use
Severe hypertriglyceridemia (>500 mg/dL)—adjunct to fibrates/lifestyle
Prescription formulations (4g EPA): icosapent ethyl (Vascepa), omega-3-acid ethyl esters
REDUCE-IT trial (icosapent ethyl): ↓ CV events in high TG patients on statins
Side Effects
Fishy aftertaste, GI upset, ↑ bleeding (high dose)
May ↑ LDL in some patients
Bile Acid Sequestrants (Resins)
Mechanism
Bind bile acids in intestine → ↓ reabsorption (interrupt enterohepatic circulation)
Liver converts cholesterol to bile acids → ↑ LDL receptor expression
↓ LDL-C 15-30%, may ↑ TG
Agents & Use
Cholestyramine, colestipol, colesevelam
Add-on to statin (rarely used—poor tolerability)
Safe in pregnancy (not absorbed systemically)
Side Effects
GI: constipation, bloating, nausea (major limitation—poor adherence)
Interfere with absorption of fat-soluble vitamins (A, D, E, K) and many drugs
Give other meds 1h before or 4h after resin
Contraindicated if high TG (>300 mg/dL)
Bempedoic Acid
Newer Oral Agent
Inhibits ATP citrate lyase—enzyme upstream of HMG-CoA reductase
Prodrug activated only in liver (not muscle)—↓ myopathy risk
↓ LDL-C ~15-25%
Clinical Use
Add-on to statins or for statin-intolerant patients
CLEAR Outcomes trial: ↓ CV events
Combination product with ezetimibe available
Treatment Approach Summary
ASCVD Risk Reduction (High LDL)
1. Statin (first-line)—intensity based on risk/indication
2. Add ezetimibe if LDL goal not met (typically LDL <70 for secondary prevention)
3. Add PCSK9 inhibitor if still above goal with high/very high risk
Alternative: Bempedoic acid if statin-intolerant or additional LDL lowering needed
Hypertriglyceridemia
Moderate (150-499 mg/dL): Lifestyle, statin (if CV risk), consider fibrate if severe
Severe (≥500 mg/dL): Fibrate + omega-3 fatty acids (prevent pancreatitis)
Address secondary causes: diabetes control, alcohol, medications (thiazides, beta-blockers, estrogen)