Cardiology pharm – Lipid-lowering agents

1) Inhibition of HMG-CoA reductase (direct).

2) Upregulation of LDL receptor expression on hepatocytes (indirect).

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Statins (e.g., atorvastatin)

MOA of statins?

• Competitive, reversible inhibitors of HMG-CoA reductase (rate-limiting enzyme for cholesterol synthesis).
• This causes a compensatory increase in LDL receptor expression on hepatocytes (i.e., if hepatic cholesterol synthesis is inhibited, then it will try to pull more out of the blood to compensate).
• Students will memorize that statins are HMG-CoA reductase inhibitors, but sometimes the USMLE will simply have “increased LDL receptor expression” as the answer for the mechanism. So know both, despite the latter being the indirect effect of the enzyme inhibition.
• USMLE wants you to know that HMG-CoA reductase mRNA will increase as a result of giving a statin (i.e., if we inhibit the enzyme, then the cell will attempt to synthesize more enzyme to compensate).

USMLE wants you to know that HMG-CoA reductase mRNA will increase as a result of giving a statin (i.e., if we inhibit the HMG-CoA reductase enzyme, then the cell will attempt to synthesize more enzyme to compensate).

Non-diabetics 20-39: if LDL >190 mg/dL.

Diabetics 20-39: if LDL >100 mg/dL.

Anyone 40-75: if LDL >70 mg/dL.

Age <20: only consider if familial dyslipidemia with severely elevated LDL.

Age >75: discuss with patient lowering the dose or stopping it altogether (↑ risk of side-effects in elderly + benefit not proven age >75).

Hepatotoxicity (↑ LFTs); most common side-effect.

• Mild transaminitis is normal and expected when commencing hepatotoxic agents. Do not lower dose or discontinue if patient is asymptomatic and has mild elevation of ALT and/or AST.

Myositis (↑ creatine kinase); more common when combined with fibrates (e.g., fenofibrate).

• Students tend to remember myositis but don’t realize hepatotoxicity is more common. If the USMLE asks for the most common side-effect of statins, choose hepatotoxicity, not myopathy.
• A Step 1 NBME Q asks why myositis is more common when statins are combined with fibrates; answer = “inhibition of P-450 enzymes.”

Statins have an anti-oxidant effect on vascular endothelial cells that transcends the lipid-lowering effect.

Fibrates (e.g., fenofibrate, gemfibrozil)

Upregulate lipoprotein lipase (enables the movement of TGAs out of the blood and into the adipocytes).

TGAs cannot transcytose vascular endothelium. Lipoprotein lipase breaks down TGAs into monoacylglycerol and three fatty acids. The latter can then move into the adipocytes.

The upregulation of lipoprotein lipase occurs following stimulation of PPAR-α.

When TGAs are greater than 500 mg/dL.

Decrease TGAs more than any other agents.

A step 1 NBME Q has both LDL and TGAs elevated in a patient where TGAs are 550. Correct answer is the fibrate; statin is the wrong answer.

Similar to statins except carry the added side-effect of causing cholesterol gallstones (due to inhibition of 7α hydroxylase, which converts cholesterol to bile acids).

Hepatotoxicity (↑ LFTs); most common side-effect.

• Mild transaminitis is normal and expected when commencing hepatotoxic agents. Do not lower dose or discontinue if patient is asymptomatic and has mild elevation of ALT and/or AST.

Myositis (↑ creatine kinase); more common when combined with statins.

• Students tend to remember myositis but don’t realize hepatotoxicity is more common. If the USMLE asks for the most common side-effect of fibrates, choose hepatotoxicity, not myopathy.
• A Step 1 NBME Q asks why myositis is more common when statins are combined with fibrates; answer = “inhibition of P-450 enzymes.”

Bile acid sequestrants (cholestyramine, colesevelam, colestipol)

Prevent enterohepatic circulation of bile acids (i.e., bind to bile acids in the small bowel and prevent their reabsorption at the terminal ileum and return to the liver).

If the liver has an insufficiency of bile acids because it’s not receiving them via enterohepatic circulation, then it needs to synthesize more. The way it does this is by converting cholesterol into bile acids via 7α hydroxylase. As a result, more cholesterol is consumed intrahepatically, and in turn the liver will pull more cholesterol out of the blood to compensate.

Selectively inhibits the absorption of cholesterol through the brush border of the small bowel wall.

Niacin (vitamin B3)

Increases HDL more than any other agent.

Decreases hepatic synthesis and export of VLDL (therefore ↓ TGAs); also inhibits hormone-sensitive lipase.

Facial flushing (redness); caused by prostaglandin, not histamine (makes sense, since aspirin treats the flushing, and aspirin inhibits prostaglandin synthesis).

Hyperglycemia (insulin resistance).

Gout (hyperuricemia).

• Vignette will give a guy with a big cardiovascular history and also a history of podagra (big toe gout), then ask which drug is contraindicated in this patient; answer = niacin.

Rarely used clinically because of its negative effects on blood glucose (i.e., worsens diabetes, and pushes people who are pre-diabetic into diabetes).

Evolocumab, alirocumab

• PCSK9 inhibitors.
• Proprotein convertase subtilisin/kexin type 9 is an enzyme that breaks down LDL receptor.
• LDL receptor is necessary for pulling LDL out of the blood.
• So if we inhibit the enzyme that breaks down LDL receptor, then more cholesterol can be pulled out of the blood.
• Some PCSK9 inhibitors have been shown to so drastically lower LDL (i.e., to 10-30 mg/dL), that longer term studies are needed to determine safety.

Not prescribed as medication, but scientifically proven to lower triglycerides (merely be aware they can have this effect on blood lipids).

Orlistat

MOA of orlistat?

• Pancreatic lipase inhibitor.
• Can be used for obesity.
• Can lower TGAs.
• Can cause diarrhea.

Fibrates (e.g., fenofibrate, gemfibrozil)

• Answer when TGAs are greater than 500 mg/dL.
• Decrease TGAs more than any other agents.
• A step 1 NBME Q has both LDL and TGAs elevated in a patient where TGAs are 550. Correct answer is the fibrate; statin is the wrong answer.

Fibrates (e.g., fenofibrate, gemfibrozil)

MOA of fibrates?

• Upregulate lipoprotein lipase (enables the movement of TGAs out of the blood and into the adipocytes).
  • TGAs cannot transcytose vascular endothelium. Lipoprotein lipase breaks down TGAs into monoacylglycerol and three fatty acids. The latter can then move into the adipocytes.
  • The upregulation of lipoprotein lipase occurs following stimulation of PPAR-α.

When do we use fibrates?

• When TGAs are greater than 500 mg/dL.
• Decrease TGAs more than any other agents.
• A step 1 NBME Q has both LDL and TGAs elevated in a patient where TGAs are 550. Correct answer is the fibrate; statin is the wrong answer.

Bile acid sequestrants (cholestyramine, colesevelam, colestipol)

MOA of bile acid sequestrants?

• Prevent enterohepatic circulation of bile acids (i.e., bind to bile acids in the small bowel and prevent their reabsorption at the terminal ileum and return to the liver).
• If the liver has an insufficiency of bile acids because it’s not receiving them via enterohepatic circulation, then it needs to synthesize more. The way it does this is by converting cholesterol into bile acids via 7α hydroxylase. As a result, more cholesterol is consumed intrahepatically, and in turn the liver will pull more cholesterol out of the blood to compensate.

Ezetimibe

MOA of ezetimibe?

• Selectively inhibits the absorption of cholesterol through the brush border of the small bowel wall.

Evolocumab, alirocumab

MOA of evolocumab, alirocumab?

• PCSK9 inhibitors.
• Proprotein convertase subtilisin/kexin type 9 is an enzyme that breaks down LDL receptor.
• LDL receptor is necessary for pulling LDL out of the blood.
• So if we inhibit the enzyme that breaks down LDL receptor, then more cholesterol can be pulled out of the blood.
• Some PCSK9 inhibitors have been shown to so drastically lower LDL (i.e., to 10-30 mg/dL), that longer term studies are needed to determine safety.

Orlistat

MOA of orlistat?

• Pancreatic lipase inhibitor.
• Can be used for obesity.
• Can lower TGAs.
• Can cause diarrhea.

A Step 1 NBME Q asks why myositis is more common when statins are combined with fibrates; answer = “inhibition of P-450 enzymes.”

Cholesterol gall stones.

Both, however, can cause hepatotoxicity (most common) and myositis.