Lipid Lowering Drugs

Snapshot

• A 40-year-old man presents to his primary care physician for high cholesterol levels. Six months ago, at his last clinic visit, he was found to have high levels of LDL cholesterol. Since then, he has tried to change his diet and exercise more frequently but admits that this has been difficult for him. He reports recently starting a “natural” treatment for high cholesterol and that it is “a healthy vitamin.” Since starting this treatment, however, he reports having a flushed face. (Niacin)

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 
    • increases LDL receptors 
• Clinical use
  • ↓ mortality in patients with coronary artery disease
  • primarily lowers low-density lipoproteins (LDL)
    • most effective drug for lowering LDL 
• Toxicity 
  • hepatotoxicity
  • myopathy
    • especially when used in combination with fibrates and niacin
• inhibitors of P450 can ↑ serum concentration 

PCSK9 Inhibitors

• Drugs
  • alirocumab and evolocumab
• Mechanism
  • 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 the small intestine brush border, preventing the absorption of cholesterol
    • this decreases the hepatic 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