Updated: 3/16/2021

Lipid-Lowering Drugs

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Snapshot
  • A 45-year-old man presents for management of hypercholesterolemia. His past medical history includes type 2 diabetes, hyperlipidemia, and hypertension. A few months ago, he started a new medication for his elevated LDL cholesterol. On laboratory evaluation, he is found with elevated liver enzymes. He is switched to another medication in the same class, as it is the most effective medication for lowering LDL levels. (HMG-CoA reductase inhibitors)
Introduction
  • Key enzymes in lipid physiology
    • lipoprotein lipase (LPL)
      • degrades triglycerides (TG) that are circulating around the bloodstream in chylomicrons and very low-density lipoproteins (VLDL)
    • hormone-sensitive lipase
      • degrades TG stored in adipose tissues
    • HMG-CoA reductase
      • converts HMG-CoA into mevalonate, a precursor of cholesterol
    • peroxisome proliferator-activated receptor-α (PPAR-α)
      • activated during starvation and catabolizes fatty acids
      • increases synthesis of LPL, causing a reduction in TG
      • raises high-density lipoprotein (HDL)
  • Lipid-lowering agents
    • acts on the liver
      • HMG-CoA reductase inhibitors
      • PCSK9 inhibitors
    • acts peripherally
      • fibrates
      • niacin
    • acts on intestinal absorption
      • bile acid resins
      • ezetimibe
 
Relative Effects of Lipid-Lowering Agents on LDL, HDL, and TG
Drug LDL HDL TG
HMG-CoA Reductase Inhibitors
↓↓↓*
PCSK9 Inhibitors ↓↓↓
Fibrates ↓↓↓*
Niacin ↓↓ ↑↑*
Bile Acid Resins ↓↓
Ezetimibe ↑/-
↓/-
* = best therapy
 
HMG-CoA Reductase Inhibitors
  • Drugs
    • lovastatin, pravastatin, simvastatin, rosuvastatin, and atorvastatin 
  • Mechanism
    • prevents synthesis of mevalonate, a cholesterol precursor, by inhibiting HMG-CoA reductase
    • this is the rate-limiting step of cholesterol synthesis 
  • Clinical use
    • ↓ mortality in patients with coronary artery disease
    • primarily lowers low-density lipoproteins (LDL)
      • most effective drug for lowering LDL
    • statin therapy should be initiated in patients > 40 years of age with no history of cardiovascular disease (CVD), CVD risk factors, and a calculated 10-year risk of a CVD event ≥ 10%  
  • Toxicity
    • elevated AST/ALT  
    • hepatotoxicity
    • myopathy
      • especially when used in combination with fibrates & niacin
    • inhibitors of P450 can ↑ serum concentration 
PCSK9 Inhibitors
  • Drugs
    • alirocumab and evolocumab
  • Mechanism
    • these drugs are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9)
      • PCSK9 destroys LDL-receptor on hepatocytes, which results in decreases clearance of LDL
    • inhibition of PCSK9 improves clearance of LDL
  • Clinical use
    • primarily decreases LDL
  • Toxicity
    • myopathy
    • neurocognitive effects
      • delirium
      • dementia
Fibrates
  • Drugs
    • gemfibrozil, bezafibrate, and fenofibrate
  • Mechanism
    • activates PPAR-α and upregulates lipoprotein lipase
      • reduces levels of triglycerides
    • induces HDL synthesis
  • Clinical use
    • primarily decreases TG
      • most effective drug for lowering TG
  • Toxicity 
    • myopathy
    • cholesterol gallstones
    • can ↑ LDL so, so fibrates are not often used as monotherapy
Niacin (Vitamin B3)
  • Mechanism
    • inhibits hormone-sensitive lipase
    • inhibits hepatic VLDL synthesis
  • Clinical use
    • primarily increases HDL
      • most effective drug for increasing HDL levels
  • Toxicity
    • red and flushed face/upper body
      • thought to be due to a release of prostaglandins and histamine 
      • treat with non-steroidal anti-inflammatory drugs (NSAIDs) 
    • ↑ glucose
    • ↑ uric acid
    • acanthosis nigricans
    • pruritus
Bile Acid Resins
  • Drug
    • cholestyramine, colestipol, and colesevelam
  • Mechanism 
    • binds to bile acids and prevents reabsorption of bile acids in the distal ileum
      • this forces the liver to make more bile acids by using the available cholesterol in the body
  • Clinical use
    • primarily decreases LDL
  • Toxicity
    • gastrointestinal upset
    • malabsorption, especially of fat-soluble vitamins
Ezetimibe
  • Mechanism
    • inhibits sterol transporter at small intestine’s brush border, preventing the absorption of cholesterol
    • this decreases the liver’s stores of cholesterol
  • Clinical use
    • primarily decreases LDL
    • primarily used in combination with a statin
  • Toxicity
    • rare hepatotoxicity
      • when used in combination with statins
    • gastrointestinal upset

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