• Clinical science

Second-line lipid-lowering agents


Second-line lipid-lowering agents include fibrates, bile acid resins, niacin, and cholesterol absorption inhibitors. These drugs are used concurrently with statins for patients who have hypercholesterolemia that is inadequately controlled with statin monotherapy. They are also used as second-line agents for patients who experience persistent side effects from statins (e.g. myositis, myalgias, and/or myopathy). Each drug targets different steps in cholesterol and lipid metabolism pathway to treat hypercholesterolemia and therefore vary in their effectiveness at decreasing low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and decreasing triglycerides. Second-line lipid-lowering agents are rarely indicated for primary prevention of cardiovascular disease because they do not improve cardiovascular outcomes or mortality.

Overview of lipid metabolism and lipid-lowering agents

Fibrates (fibric acid derivatives)


Bile acid resins





  • Mechanism of action: : selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → LDL
  • Indication
  • Side effects (especially in combination therapy, otherwise rare): : liver enzymes, angioedema, diarrhea, myalgia
  • Contraindication: : coadministration with a statin during active liver disease


PCSK9 inhibitors

  • Drugs: alirocumab, evolocumab
  • Mechanism of action: monoclonal antibodies that inhibit proprotein convertase subtisilin kexin 9 (PCSK9), an enzyme that degrades the LDL-receptor → increased removal of LDL from the blood stream → ↓↓↓ LDL, HDL, triglycerides
  • Side effects
    • Myalgia
    • Neurocognitive defects (delirum, dementia)