Lipid Lowering Agents


LDL LOWERING DRUGS

1. STATINS (HMG-CoA REDUCTASE INHIBITORS)

Statins are first-line therapy because they:

  • Reduce LDL substantially
  • Stabilize plaques
  • Reduce inflammation
  • Reduce MI, stroke, mortality

MECHANISM

Statins inhibit:HMG-CoA→Mevalonate→Cholesterol

This causes:

  • ↓ hepatic cholesterol synthesis
  • ↑ LDL receptor expression
  • ↑ LDL clearance

LDL REDUCTION POTENCY

Intensity

LDL Reduction

High intensity

≥50%

Moderate intensity

30–49%

Low intensity

<30%

HIGH-INTENSITY STATINS

Drug

Dose

Atorvastatin

40–80 mg

Rosuvastatin

20–40 mg

MODERATE-INTENSITY STATINS

Drug

Dose

Atorvastatin

10–20 mg

Rosuvastatin

5–10 mg

Simvastatin

20–40 mg

Pravastatin

40–80 mg

Pitavastatin

2–4 mg

PLEIOTROPIC EFFECTS

  • Plaque stabilization
  • Improved endothelial function
  • Anti-inflammatory action
  • Reduced oxidative stress
  • Antithrombotic effects

ADVERSE EFFECTS

Muscle Toxicity

  • Myalgia——Myositis—-Myopathy—-Rhabdomyolysis

Hepatic Effects

  • Mild AST/ALT elevation common
  • Severe hepatotoxicity rare

Avoid in:

  • Active liver disease
  • Acute hepatitis

IMPORTANT DRUG INTERACTIONS

CYP3A4 Interactions

Especially with:

  • Simvastatin
  • Lovastatin
  • Atorvastatin

Interacting drugs:

  • Macrolides
  • Azoles
  • Verapamil
  • Diltiazem
  • Protease inhibitors

WHEN TO USE HIGH-INTENSITY STATIN ACC/AHA Indications

1.Clinical ASCVD Examples:

  • MI
  • Stroke
  • PAD

2.LDL ≥190 mg/dL

3.Diabetes with high ASCVD risk

4.10-year ASCVD risk ≥20%

MONITORING

Test

Timing

Lipid profile

Baseline + 4–12 weeks

LFT

Baseline

CK

Only if symptomatic

STATIN INTOLERANCE

Approach

  1. Confirm true intolerance
  2. Rule out hypothyroidism/Vit D deficiency
  3. Retry different statin
  4. Use lower dose
  5. Alternate-day rosuvastatin
  6. Add ezetimibe
  7. Consider bempedoic acid or PCSK9 inhibitor

2. EZETIMIBE

Blocks intestinal cholesterol absorption via:NPC1L1 transporter inhibition

INDICATIONS

  • Add-on to statin
  • Statin intolerance
  • Familial hypercholesterolemia

Drug

Dose

Ezetimibe

10 mg daily

ADVANTAGES

  • Very safe
  • Minimal systemic absorption
  • Few side effects

3. PCSK9 INHIBITORS

Drug

Alirocumab

Evolocumab

MECHANISM

PCSK9 normally destroys LDL receptors.

Inhibition causes:

  • ↑ LDL receptors
  • Massive LDL clearance

INDICATIONS

  • Very high-risk ASCVD
  • Familial hypercholesterolemia
  • Statin intolerance
  • LDL uncontrolled despite maximal statin + ezetimibe

ADMINISTRATION

Subcutaneous injection:

  • Every 2 weeks or monthly

ADVERSE EFFECTS

  • Injection site reaction
  • Flu-like symptoms
  • Nasopharyngitis

4. BEMPEDOIC ACID

Inhibits ATP citrate lyase:Upstream of statins


ADVANTAGE

Activated only in liver:Less muscle toxicity


INDICATIONS

  • Statin intolerance
  • Add-on therapy

SIDE EFFECTS

  • Hyperuricemia
  • Tendon rupture
  • Gout

5. BILE ACID SEQUESTRANTS

Drug

Cholestyramine

Colesevelam

Bind bile acids in intestine:

  • Prevent reabsorption
  • Liver uses cholesterol to synthesize more bile acids

Lipid

Change

LDL

↓ 15–25%

TG

May increase

SIDE EFFECTS

  • Constipation
  • Bloating
  • Drug interactions
  • Poor palatability

Avoid if:TG >300 mg/dL


TRIGLYCERIDE LOWERING DRUGS

6. FIBRATES

Drug

Fenofibrate

Gemfibrozil

Activate:PPAR-α

Effects:

  • ↑ Lipoprotein lipase
  • ↑ TG clearance
  • ↓ VLDL

INDICATIONS

Severe Hypertriglyceridemia

Especially:

  • TG >500 mg/dL
  • Pancreatitis prevention

IMPORTANT POINT

Fenofibrate preferred with statins because:

  • Lower myopathy risk

Gemfibrozil + statin:

  • Higher rhabdomyolysis risk

SIDE EFFECTS

  • Gallstones
  • Myopathy
  • Elevated creatinine
  • Hepatotoxicity

7. OMEGA-3 FATTY ACIDS

Drug

Icosapent ethyl

EPA/DHA formulations

REDUCE-IT Trial

Icosapent ethyl:Reduced cardiovascular events


INDICATIONS

  • Persistent hypertriglyceridemia
  • Residual ASCVD risk

SIDE EFFECTS

  • Fishy taste
  • GI upset
  • Atrial fibrillation risk
  • Bleeding tendency

8. NIACIN (NICOTINIC ACID)

Modern guidelines rarely use niacin because:

  • No clear ASCVD benefit
  • Significant side effects

SIDE EFFECTS

  • Flushing
  • Hyperglycemia
  • Hyperuricemia
  • Hepatotoxicity

NEWER AGENTS

9. INCLISIRAN

siRNA against PCSK9 production.

Very infrequent dosing:Every 6 months


10. LOMITAPIDE

  • Used in:Homozygous familial hypercholesterolemia
  • Mechanism:Microsomal TG transfer protein inhibition
  • Major issue:Severe fatty liver

11. EVINACUMAB

Monoclonal antibody against:ANGPTL3

Used in:Homozygous familial hypercholesterolemia