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Tuesday, August 19, 2025

Antihyperlipidemic agents


Introduction

Antihyperlipidemic agents are drugs used to correct abnormalities of lipid metabolism, including elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and reduced high-density lipoprotein cholesterol (HDL-C). These abnormalities, collectively known as dyslipidemias, are strongly associated with atherosclerotic cardiovascular disease (ASCVD), which includes coronary artery disease, ischemic stroke, and peripheral arterial disease.

Lifestyle modifications (diet, exercise, weight management) remain the foundation of lipid management, but pharmacologic therapy is often required in patients at high or very high risk, those with familial hypercholesterolemia, or patients who fail to achieve lipid targets through lifestyle measures alone.

Classification of Antihyperlipidemic Agents

1. HMG-CoA Reductase Inhibitors (Statins)

  • Generic names: atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin

  • Mechanism of action: Inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This upregulates hepatic LDL receptors, enhancing clearance of LDL-C from plasma.

  • Lipid effects: LDL-C ↓ 20–60, HDL-C ↑ 5–10, TG ↓ 10–30.

  • Uses: First-line therapy in primary and secondary prevention of ASCVD, familial hypercholesterolemia, mixed dyslipidemia.

  • Adverse effects: Myopathy, rhabdomyolysis, elevated liver enzymes, new-onset diabetes (rare).

  • Contraindications: Active liver disease, pregnancy, breastfeeding.

2. Cholesterol Absorption Inhibitors

  • Generic name: ezetimibe

  • Mechanism: Inhibits Niemann-Pick C1-like 1 (NPC1L1) transporter in the intestinal brush border, reducing dietary and biliary cholesterol absorption.

  • Lipid effects: LDL-C ↓ 15–25.

  • Uses: Added to statins when further LDL-C reduction is required; used in statin intolerance.

  • Adverse effects: Diarrhea, abdominal pain, mild liver enzyme elevations.

3. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

  • Generic names: evolocumab, alirocumab

  • Mechanism: Monoclonal antibodies that inhibit PCSK9, preventing degradation of LDL receptors and enhancing clearance of LDL-C.

  • Lipid effects: LDL-C ↓ 50–60 beyond statins/ezetimibe.

  • Uses: Familial hypercholesterolemia, very high-risk ASCVD, statin-intolerant patients.

  • Adverse effects: Injection site reactions, flu-like symptoms, rare neurocognitive effects.

  • Contraindications: Hypersensitivity reactions.

4. ATP Citrate Lyase Inhibitors

  • Generic name: bempedoic acid

  • Mechanism: Inhibits ATP citrate lyase, upstream of HMG-CoA reductase in cholesterol biosynthesis.

  • Lipid effects: LDL-C ↓ 15–25.

  • Uses: Alternative for patients intolerant to statins; often combined with ezetimibe.

  • Adverse effects: Hyperuricemia, gout, tendon rupture (rare).

5. Bile Acid Sequestrants

  • Generic names: cholestyramine, colestipol, colesevelam

  • Mechanism: Bind bile acids in the intestine, preventing reabsorption; liver increases bile acid production from cholesterol, upregulating LDL receptors.

  • Lipid effects: LDL-C ↓ 15–25, may ↑ TG.

  • Uses: Hypercholesterolemia, safe in pregnancy, adjunct to statins.

  • Adverse effects: Constipation, bloating, GI discomfort, impaired absorption of fat-soluble vitamins and drugs.

6. Fibric Acid Derivatives (Fibrates)

  • Generic names: fenofibrate, gemfibrozil, bezafibrate

  • Mechanism: Activate peroxisome proliferator-activated receptor alpha (PPAR-α), increasing lipoprotein lipase activity and enhancing TG clearance.

  • Lipid effects: TG ↓ 30–50, HDL-C ↑ 10–20, LDL variable.

  • Uses: Hypertriglyceridemia, mixed dyslipidemia, prevention of pancreatitis in severe TG elevation.

  • Adverse effects: GI upset, gallstones, myopathy (risk increased with statins, especially gemfibrozil).

  • Contraindications: Severe renal or hepatic disease, gallbladder disease.

7. Niacin (Nicotinic Acid)

  • Generic name: niacin

  • Mechanism: Inhibits hepatic VLDL synthesis, lowering LDL-C and TG, and raising HDL-C.

  • Lipid effects: LDL-C ↓ 10–20, TG ↓ 20–40, HDL-C ↑ 15–35.

  • Uses: Previously used in combined dyslipidemia; now limited due to lack of outcome benefits and adverse effects.

  • Adverse effects: Flushing, hyperglycemia, hyperuricemia, hepatotoxicity.

8. Omega-3 Fatty Acid Derivatives

  • Generic names: icosapent ethyl, omega-3-acid ethyl esters

  • Mechanism: Reduce hepatic VLDL-TG synthesis and enhance clearance of TG-rich particles.

  • Lipid effects: TG ↓ 20–50; icosapent ethyl shown to reduce cardiovascular events.

  • Uses: Adjunct in hypertriglyceridemia and ASCVD risk reduction.

  • Adverse effects: Dyspepsia, fishy aftertaste, bleeding risk with anticoagulants.

9. Other Agents and Emerging Therapies

  • Inclisiran: siRNA that inhibits PCSK9 synthesis, administered twice yearly, LDL-C ↓ 50.

  • Evinacumab: Monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3), for homozygous familial hypercholesterolemia.

  • Mipomersen/Lomitapide: Target apoB production, reserved for severe familial hypercholesterolemia due to safety concerns.

Combination Therapy Strategies

  • Statin + Ezetimibe: Enhances LDL-C lowering; widely used in high-risk ASCVD.

  • Statin + PCSK9 Inhibitor: Profound LDL-C reduction, especially in familial hypercholesterolemia.

  • Statin + Bempedoic Acid: For statin intolerance or as add-on therapy.

  • Statin + Fibrate or Omega-3: Used in patients with persistent hypertriglyceridemia.

  • Triple Therapy: Statin + ezetimibe + PCSK9 inhibitor in very high-risk patients.

Clinical Uses

  • Primary prevention: High-risk patients with elevated LDL-C, especially diabetics and those with multiple cardiovascular risk factors.

  • Secondary prevention: Established ASCVD patients, post-myocardial infarction, or ischemic stroke.

  • Familial hypercholesterolemia: Often requires multiple agents (statin, ezetimibe, PCSK9 inhibitor).

  • Severe hypertriglyceridemia: Fibrates or omega-3 derivatives to prevent pancreatitis.

Contraindications and Precautions

  • Statins: Contraindicated in pregnancy, breastfeeding, and active liver disease.

  • Fibrates: Avoid in severe renal impairment and gallbladder disease.

  • Niacin: Avoid in uncontrolled diabetes, active liver disease, gout.

  • PCSK9 inhibitors & Inclisiran: Caution in hypersensitivity.

  • Bile acid sequestrants: Avoid in hypertriglyceridemia (>400 mg/dL).

Adverse Effects Summary

  • Statins: Myopathy, elevated liver enzymes.

  • Ezetimibe: GI upset, rare hepatotoxicity.

  • PCSK9 inhibitors: Injection site reactions.

  • Bempedoic acid: Hyperuricemia, tendon rupture.

  • Fibrates: Myopathy, gallstones.

  • Niacin: Flushing, hepatotoxicity, hyperglycemia.

  • Omega-3s: GI effects, bleeding risk.

  • Bile acid sequestrants: GI intolerance, drug interactions.

Drug Interactions

  • Statins + Gemfibrozil: Increased risk of rhabdomyolysis.

  • Statins + CYP3A4 inhibitors (e.g., azoles, macrolides): Increased toxicity risk.

  • Niacin + Statins: Increased risk of hepatotoxicity and myopathy.

  • Bile acid sequestrants: Reduce absorption of warfarin, digoxin, fat-soluble vitamins.

  • Omega-3 fatty acids + Anticoagulants: Additive bleeding risk.




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