Lipid-Lowering Drugs

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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.
Drug ClassPrimary TargetKey Effect(s)
StatinsHMG-CoA ReductaseLDL↓↓, HDL↑, TG↓
FibratesPPAR-α activationTG↓↓, HDL↑, LDL↔/↓
Niacin↓VLDL production, ↓LipolysisLDL↓, HDL↑↑, TG↓
Bile Acid SequestrantsBind bile acids (intestine)LDL↓, HDL↔, TG↑ (⚠️)
Cholesterol Absorp. Inhib.NPC1L1 (gut)LDL↓
PCSK9 InhibitorsPCSK9LDL↓↓

Statins - Plaque Busters

  • Mechanism (MoA): HMG-CoA reductase inhibitors.
    • Inhibit cholesterol synthesis (rate-limiting step).
    • Upregulate hepatic LDL receptors → ↑ LDL clearance. Lipid-Lowering Drugs: Mechanisms of Action
  • Pleiotropic Effects: Anti-inflammatory, plaque stabilization, improved endothelial function.
  • Key Statins & Doses:
    IntensityDrugHigh-Intensity Dose
    HighAtorvastatin40-80mg
    Rosuvastatin20-40mg
    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).

Lipid-Lowering Drugs: Sites of Action in Lipid Metabolism

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.

Practice Questions: Lipid-Lowering Drugs

Test your understanding with these related questions

Which among the following is the false statement regarding statins?

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Flashcards: Lipid-Lowering Drugs

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_____, Rosuvastatin and Pitavastatin have a long half-life and may be taken at any time of the day.

TAP TO REVEAL ANSWER

_____, Rosuvastatin and Pitavastatin have a long half-life and may be taken at any time of the day.

Atorvastatin

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