Pocket Guide to Hypolipidemic Drugs

Pocket Guide to Hypolipidemic Drugs

1. Core Principle

Atherosclerotic cardiovascular disease is driven by elevated atherogenic lipoproteins, especially LDL. Most lipid-lowering drugs reduce hepatic cholesterol synthesis or availability, leading to upregulation of LDL receptors and increased LDL clearance. Some agents reduce triglycerides by decreasing hepatic VLDL production and/or increasing lipoprotein lipase–mediated clearance. Certain drugs raise HDL, but this effect has limited direct impact on outcomes. The overall goal is to reduce atherogenic lipoproteins, stabilize plaques, and decrease cardiovascular morbidity and mortality.

2. STATINS (First-line)

Examples: Atorvastatin, Rosuvastatin, Simvastatin

Mechanism

1. ↓ hepatic cholesterol synthesis (HMG-CoA reductase)
2. ↑ LDL receptor expression → ↑ LDL clearance

Effects

1. LDL ↓↓↓ (20 to 60%)
2. HDL ↑
3. TG ↓

Uses

1. First-line for ASCVD prevention

Adverse

1. Myopathy, ↑ LFTs
2. Risk ↑ with CYP3A4 inhibitors
3. Slight ↑ diabetes risk

3. EZETIMIBE

Mechanism

1. Inhibits NPC1L1 → ↓ cholesterol absorption
2. ↓ hepatic cholesterol → ↑ LDL receptors

Effects

1. LDL ↓ (~18%)

Uses

1. Add-on to statin
2. Statin intolerance

Key Point

1. Synergistic with statins

4. PCSK9 INHIBITORS

Examples: Alirocumab, Evolocumab

Mechanism

1. Inhibit PCSK9 → prevent LDL receptor degradation
2. ↑ LDL receptor recycling → ↑ LDL clearance

Effects

1. LDL ↓↓↓↓ (50 to 60%)

Uses

1. Familial hypercholesterolemia
2. High-risk ASCVD
3. Persistent LDL despite therapy

Adverse

1. Injection site reactions

5. FIBRATES

Examples: Fenofibrate, Gemfibrozil

Mechanism

1. Activate PPAR-α
2. ↑ lipoprotein lipase → ↑ TG clearance
3. ↑ Apo A-I, Apo A-II → ↑ HDL

Effects

1. TG ↓↓↓
2. HDL ↑
3. LDL variable (may ↑ if TG very high)

Uses

1. Severe hypertriglyceridemia

Adverse

1. Myopathy (↑ with statins, especially gemfibrozil)
2. Gallstones

6. BILE ACID RESINS

Examples: Cholestyramine, Colesevelam

Mechanism

1. Bind bile acids → ↓ reabsorption
2. ↓ hepatic cholesterol
3. ↑ LDL receptors

Effects

1. LDL ↓
2. HDL ↑ (mild)
3. TG may ↑

Uses

1. Statin intolerance

Adverse

1. GI upset
2. ↓ absorption of fat-soluble vitamins

7. NIACIN

Mechanism

1. ↓ hepatic VLDL synthesis → ↓ LDL
2. ↑ HDL via ↓ Apo A-I clearance

Effects

1. HDL ↑↑
2. TG ↓

Note

1. Rarely used

Adverse

1. Flushing
2. Hyperglycemia, gout
3. Hepatotoxicity

8. OMEGA-3 FATTY ACIDS

Example: Icosapent ethyl

Mechanism

1. ↓ VLDL production
2. ↑ TG clearance

Effects

1. TG ↓ (20 to 50%)
2. LDL may ↑ (with DHA-containing products)

Uses

1. Severe hypertriglyceridemia
2. Cardiovascular risk reduction

Note

1. Pure EPA does not raise LDL

9. BEMPEDOIC ACID

Mechanism

1. Inhibits ATP citrate lyase
2. ↓ cholesterol synthesis → ↑ LDL receptors

Effects

1. LDL ↓ (~15 to 20%)

Uses

1. Statin intolerance
2. Add-on therapy

Adverse

1. Hyperuricemia
2. Tendon rupture

10. EXAM PEARLS

1. Most potent LDL lowering: PCSK9 inhibitors
2. First-line therapy: Statins
3. Severe hypertriglyceridemia: Fibrates, Omega-3
4. Niacin ↑ HDL most but rarely used
5. Avoid resins if TG elevated
6. Statin + fibrate → myopathy risk
7. Statin intolerance: Ezetimibe, Bempedoic acid, PCSK9