6 - Inhibitors of Cholesterol Absorption, Fibric Acid Derivatives, & Omega-3 Fatty Acids

Cholesterol absorption inhibitor agent

Ezetimibe

What is the MOA of ezetimibe?

inhibits intestinal absorption of cholesterol by inhibiting the transport protein NPC1L1, causing upregulation of LDL receptors and increase in hepatic cholesterol synthesis

What are the effects of ezetimibe on LDL alone compared to when used with a statin?

alone - 18% reduction

w/ statin - additional 25% reduction

What class of medications inhibits the absorption of ezetimibe?

bile acid sequestrants

How is ezetimibe eliminated?

unchanged in the feces

What are the ADE of ezetimibe?

well tolerated

What are the patient care considerations of ezetimibe?

can use with other lipid-lowering agents except bile acid sequestrants

What should be monitored when taking ezetimibe?

lipid panel

What are the fibric acid derivative ingredients?

fenofibrate, gemfibrozil

What is the MOA of fibrates?

stimulates peroxisome proliferator-activated receptor to:

• increase lipoprotein lipase to clear VLDL

• reduce TG synthesis

• increase HDL synthesis

What is the effect of fibrates on TG, HDL, & LDL?

↓↓↓TG

↓HDL

∅LDL

How is ezetimibe excreted?

as glucuronide conjugates in the urine, excreted impaired with renal failure

What are the ADE of fibrates?

• GI effects

• increased liver transaminases

• gallstones

What are the patient care considerations of fibrates?

• concomitant use with statins increases musculoskeletal effects

• monitor/reduce warfarin doses

• renal/hepatic failure contraindicated

What should be monitored when on fibrates?

• fasting lipid profile at baseline and 4-6 weeks after initiation

• baseline AST, ALT

• CK if muscle symptoms develope

What are the omega-3 fatty acid ingredients?

• fish oil/krill oil supplements

• EPA + DHA ethyl esters (lovaza)

• icosapent ethyl (vascepa)

What is the MOA of omega-3 fatty acids?

likely reduce VLDL synthesis in the liver and enhance TG clearance from VLDL

What are the effects of omega-3 fatty acids?

↓TG

↑↑LDL

↑HDL

What is the omega-3 fatty acid dose requirement for TG reduction?

4 g/day

Which omega-3 fatty acid is not associated with increased LDL?

icosapent ethyl

What are the ADE of omega-3 fatty acids?

• belching, dyspepsia, taste preversion

• increased LDL

• increased bleeding risk at high doses

• atrial fibrillation/atrial flutter

What are the patient care considerations for omega-3 fatty acids?

• drug interaction w/ antithrombotics

• refrigerate OTC supplements, take with meals

• caution with fish/shellfish allergy

What should be monitored when taking an omega-3 fatty acid?

• lipid panel at baseline and every 4-12 weeks

• ALT

What is PCSK9?

protease that binds to the hepatic LDL receptor and enhances its degradation, resulting in higher plasma LDL concentration

What is the MOA of PCSK9 inhibiting monoclonal antibodies?

bind free PCSK9 to prevent binding to the LDL receptor, increasing availability of LDL receptors to clear LDL from plasma?

What is the MOA of PCSK9 inhibiting small interfering RNA (siRNA)?

uses RNA interference to direct catalytic breakdown of the messenger RNA that is responsible for the production of PCSK9, increasing expression of LDL receptor and increasing LDL uptake from circulation

What are the monoclonal antibody PCSK9 inhibitor ingredients?

alirocumab, evolocumab

What are the effects of monoclonal antibody PCSK9 inhibitors on LDL & TG?

• inhibit pcsk9 activity for 2-3 weeks, then LDL begins to rise

  • monotherapy reduces LDL the most of any other single agent

  • can be complementary to statins

• slightly reduce TG

What are the dosage forms of monoclonal antibody PCSK9 inhibitors?

• SQ every 2-4 weeks

• autoinjectors

• high cost

• refrigerated, warm to room temp at least 30 minutes before injecting

What are the ADE of monoclonal PCSK9 inhibitors?

• injection site reaction

• flu-like symptoms

• neurocognitive effects

What should be monitored when taking a monoclonal antibody PCSK9 inhibitor?

lipid panel at baseline and 4-8 weeks after initiating therapy

What are the available siRNA agents?

inclisiran

How long do the effects of siRNAs last and what is the effect on LDL?

~6 months, reduces LDL by about 50%

How is inclisiran administered?

• given as SQ by a healthcare provider at initiation, at 3 months, and then every 6 months after

• combined with statin

• high cost

What are the ADE of inclisiran?

• injection site reaction

• joint aches

• UTI

• dyspnea

In what populations should inclisiran be used?

heterozygous familial hypercholesterolemia, clinical ASCVD

What should be monitored when on inclisiran?

lipid profile at baseline and 4-8 weeks after initiating therapy