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 the cholesterol and lipid metabolism pathways 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.

• Agents: : bezafibrate, fenofibrate, and gemfibrozil
• Mechanism of action: : activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride
• Indication: second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides
• Adverse effects
  • Dyspepsia
  • Myopathy, especially in combination with statins
  • Cholelithiasis: fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)
  • ↑ LFTs (reversible)
  • Mild decrease in hemoglobin, hematocrit, and WBC upon initiation; normally stabilizes with long-term therapy
• Contraindications
  • Renal insufficiency
  • Liver failure
  • Gall bladder diseases
• Interactions: enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450

• Drugs: cholestyramine, colestipol, colesevelam
• Mechanism of action
  • Ion exchange resin binds bile acids in the intestine; → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion); → lowers cholesterol pool and promotes synthesis of LDL receptors (↓↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides
• Indications
  • Combination treatment with statins in hypercholesterolemia
  • Digitoxin overdose
  • Pruritus associated with elevated bile acid levels (cholestasis)
  • Bile acid diarrhea
• Adverse effects
  • Gastrointestinal: nausea, abdominal bloating and cramping
  • ↑ LFTs
  • Myalgia
• Contraindications
  • Hypertriglyceridemia > 300–500 mg/dL
  • Hypertriglyceridemia-induced pancreatitis
  • Bowel obstruction
• Drug interactions: reduces absorption of warfarin, digoxin, and fat-soluble vitamins

• Mechanism of action: inhibits lipolysis and fatty acid release in adipose tissue through blockade of hormone-sensitive lipase and ↓ hepatic VLDL synthesis → ↓ triglyceride, ↓↓ LDL synthesis, ↑↑ HDL
• Indication: high LDL cholesterol and lipoprotein(a) levels (> 50 mg/dL) despite statin and ezetimibe therapy (or if statins are contraindicated) ^[4]
• Adverse effects
  • Flushing and pruritus: ↑ prostaglandin synthesis → peripheral vasodilation (pretreatment with aspirin or ibuprofen can minimize this side effect)
  • Hyperglycemia
  • Hyperuricemia and gout (e.g., podagra)
  • Paresthesias
  • GI upset (e.g., diarrhea, flatulence, abdominal pain)
  • ↑ LFTs
• Contraindications
  • Liver failure
  • Gout
  • Hemorrhage
  • Gastric ulcer
  • Cardiovascular instability

• Mechanism of action: selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → ↓↓ LDL; , little effect on HDL (slight ↑) and triglycerides (slight ↓)
• Indication
  • Monotherapy: in contraindications or statin intolerance
  • Combination therapy (statin and ezetimibe): in insufficient LDL cholesterol reduction by statins
• Adverse effects: rare, except in combination therapy
  • ↑ Liver enzymes
  • Angioedema
  • Diarrhea
  • Myalgia
• Contraindication: coadministration with a statin during active liver disease

• Drugs: alirocumab, evolocumab
• Mechanism of action: monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9), an enzyme that degrades the LDL-receptor → increased removal of LDL from the blood stream → ↓↓↓ LDL, ↑ HDL, ↓ triglycerides
• Indication: add-on therapy for patients who have both of the following ^[5]
  • LDL ≥ 1.8 mmol/l (70 mg/dL) despite maximally tolerated treatment with statins and ezetimibe
  • Presence of very high-risk atherosclerotic cardiovascular disease
• Adverse effects: myalgia ^[6]

Marine omega-3 fatty acids (fish oil)

• Mechanism of action: : most likely decreases transportation of free fatty acids to the liver and inhibits triglyceride-synthesizing enzymes → slight ↑ of HDL and LDL and (at higher doses) ↓ triglycerides
• Adverse effects
  • Fishy taste
  • Nausea

Lomitapide

• Mechanism of action: inhibits microsomal triglyceride transfer protein (MTTP) → ↓ VLDL, LDL, and chylomicrons
• Indications
  • Homozygous familial hypercholesterolemia
  • Abetalipoproteinemia (in combination with low-fat diet and other lipid-lowering medications)
• Adverse effects: gastrointestinal symptoms (nausea, vomiting), elevation of transaminases