Lipid-Lowering Drugs

Classification & Targets - Lipid Landscape

• Dyslipidemia Types:

  • Hypercholesterolemia: Elevated LDL-C
  • Hypertriglyceridemia: Elevated TG
  • Mixed Dyslipidemia: Elevated LDL-C & TG

• Lipoprotein Classes & Apolipoproteins:

  • Chylomicrons (CM): Transport dietary TGs; ApoB-48.
  • VLDL: Transports endogenous TGs; ApoB-100.
  • IDL: VLDL remnant; precursor to LDL.
  • LDL ("Bad"): Major cholesterol carrier to tissues; ApoB-100.
  • HDL ("Good"): Reverse cholesterol transport; ApoA-I.

Statins - Plaque Busters

• Mechanism (MoA): HMG-CoA reductase inhibitors.
  • Inhibit cholesterol synthesis (rate-limiting step).
  • Upregulate hepatic LDL receptors → ↑ LDL clearance.
• Pleiotropic Effects: Anti-inflammatory, plaque stabilization, improved endothelial function.
• Key Statins & Doses:

  Intensity	Drug	High-Intensity Dose
  High	Atorvastatin	40-80mg
  	Rosuvastatin	20-40mg
  Moderate doses: Atorvastatin 10-20mg, Rosuvastatin 5-10mg.

• ADRs: 📌 Statins: Hepatotoxicity, Myopathy, Glucose ↑ (New Diabetes).
  • Myopathy, rhabdomyolysis (monitor CK).
  • Hepatotoxicity (monitor LFTs).
  • New-onset diabetes mellitus.
• Contraindications (CIs):
  • Pregnancy (teratogenic).
  • Active liver disease.
• Interactions:
  • CYP3A4 inhibitors (e.g., macrolides, azoles) ↑ toxicity of simvastatin, lovastatin, atorvastatin.
  • Pravastatin, Rosuvastatin: Less CYP3A4 interaction.

⭐ Statins are best given in the evening/night as cholesterol synthesis is maximal then (except long-acting Atorvastatin/Rosuvastatin, which can be taken anytime).

Fibrates & Niacin - TG & HDL Tune-Up

Fibrates (e.g., Fenofibrate, Gemfibrozil)

• MoA: PPAR-α agonists → ↑LPL activity → ↓VLDL, ↑HDL.
• Use: Severe hypertriglyceridemia (TG >500 mg/dL) to prevent pancreatitis.
• ADRs: Myopathy (risk ↑ with statins), cholelithiasis (gallstones), GI upset.

  ⭐ Gemfibrozil + statin = higher myopathy risk vs. fenofibrate + statin.

Niacin (Vitamin B3)

• MoA: Inhibits lipolysis in adipose tissue → ↓hepatic VLDL synthesis.
• Effects: ↓LDL, ↓TG, ↑↑HDL (most potent HDL elevator).
• ADRs: Cutaneous flushing (PG-mediated; ↓ with aspirin/NSAID), pruritus, hyperuricemia (gout), hyperglycemia, hepatotoxicity.
  • 📌 Niacin ADRs: Nice And Hot (Flushing), HyperGlycemia, HyperUricemia.

Other Key Players - Lipid Diversifiers

• Ezetimibe
  • MoA: Inhibits dietary & biliary cholesterol absorption (NPC1L1 protein).
  • Use: Monotherapy or adjunct to statins.
  • ADRs: Generally well-tolerated; diarrhea, rare myopathy/hepatitis.
• PCSK9 Inhibitors (Evolocumab, Alirocumab)
  • MoA: Monoclonal antibodies, prevent LDL receptor degradation → ↑LDL clearance.
  • Use: Familial hypercholesterolemia, statin-intolerant, very high-risk ASCVD.
  • Route: Subcutaneous injection.
  • ADRs: Injection site reactions, nasopharyngitis.

  ⭐ PCSK9 inhibitors can achieve >50-60% additional LDL-C reduction when added to maximally tolerated statin therapy.

• Bile Acid Sequestrants (Resins) (Cholestyramine, Colestipol, Colesevelam)
  • MoA: Bind bile acids in intestine, prevent reabsorption → ↑hepatic conversion of cholesterol to bile acids, ↑LDL receptors.
  • ADRs: GI distress (constipation, bloating), ↓absorption of fat-soluble vitamins & other drugs (take other drugs 1h before or 4h after). May ↑TGs.
  • Colesevelam: Fewer GI effects & drug interactions, safe in pregnancy.
• Omega-3 Fatty Acids (Fish Oil) (EPA, DHA)
  • Use: Adjunct for severe hypertriglyceridemia (>500 mg/dL).
  • MoA: ↓TG synthesis, ↑TG clearance.
  • ADRs: GI upset, fishy aftertaste, bleeding risk (high doses).

High‑Yield Points - ⚡ Biggest Takeaways

• Statins (HMG-CoA reductase inhibitors) are first-line for ↑LDL; major side effect: myopathy.
• Fibrates primarily ↓ triglycerides by activating PPAR-α; risk of gallstones & myopathy with statins.
• Ezetimibe inhibits cholesterol absorption (NPC1L1); used with statins to further ↓LDL.
• Bile acid sequestrants (e.g., cholestyramine) cause GI distress and can ↑ triglycerides.
• Niacin causes cutaneous flushing (prostaglandin-mediated); effectively ↑HDL.
• PCSK9 inhibitors (evolocumab) are potent LDL reducers; injectable administration.