Ezetimibe (Zetia), FDA approved in 2002, reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine.

Ezetimibe is FDA-indicated for primary and mixed hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and homozygous sitosterolemia.

American College of Cardiology (ACC)/American Heart Association (AHA) guidelines prioritize statin therapy as the primary intervention for blood cholesterol level management, with an objective of reducing atherosclerotic cardiovascular disease risk (ASCVD). Statins, recognized for their potent LDL-C (low-density lipoprotein cholesterol) lowering effects, are considered first-line treatment for the prevention of coronary disease in high-risk patients. However, non-statin cholesterol-lowering therapy like ezetimibe may be used in high-risk patients who show a less-than-anticipated response to statins, who cannot tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant.¹

Ezetimibe, either as a monotherapy or in combination with an HMG CoA reductase inhibitor (statins), serves as an adjunct to diet for reducing elevated total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-HDL-C in patients with primary hyperlipidemia (heterozygous familial and non-familial). For homozygous familial hypercholesterolemia, ezetimibe can be co-administered with atorvastatin or simvastatin to reduce elevated TC and LDL-C, especially in situations where other lipid-lowering treatments are unavailable. In cases of homozygous familial sitosterolemia, ezetimibe may be provided as an additional therapy to diet to reduce elevated sitosterol and campesterol levels.

Primary recommendation for clinical ASCVD involves the use of statin therapy. However, if not viable, moderate-intensity statin therapy can be initiated. In cases where LDL-C levels remain ≥ 70mg/dL on maximally tolerated statin, the addition of ezetimibe may be considered. For very high-risk patients with multiple high-risk clinical factors, ezetimibe can be added to maximally tolerated statin therapy. Thus, coverage is extended to patients who have experienced an inadequate treatment response, intolerance, or contraindication to a statin or statin combination product.

The ACC/AHA guidelines should be routinely reviewed for the most updated recommendations. More information is available on the ACC website at https://www.acc.org/guidelines.

Definitions

• Cholesterol is a waxy, fat-like substance produced by the body, which is integral to cellular structure and function.
• Clinical atherosclerotic cardiovascular disease (ASCVD) refers to a group of conditions characterized by plaque buildup within the arterial walls. This can result in reduced blood flow and lead to cardiovascular events such as angina (chest pain), myocardial infarction (heart attack), and stroke.
• Homozygous familial hypercholesterolemia (HoFH) is a rare, genetically inherited disorder, with genes inherited from both parents, that leads to extremely elevated cholesterol levels. This can predispose individuals to premature cardiovascular disease, often manifesting as early as adolescence.
• Homozygous sitosterolemia is a rare, genetically inherited disorder where both parents contribute genes leading to altered sterol lipid metabolism from plant-based foods, causing elevated levels of plant sterols in the blood and tissues. Dietary therapy is often insufficient to control this disease due to the ubiquity of plant sterols in food.²
• Lipids refer to various types of fats present in the body, which play crucial roles in hormone production, vitamin D synthesis, and digestive processes.
• Low-density lipoprotein (LDL-C) is a type of lipid-carrying particle that transports fats around the body. Elevated levels of LDL-C, also known as "bad cholesterol," can contribute to the development of atherosclerosis.
• Statins are a class of medications used primarily to lower cholesterol and triglyceride levels. They work by inhibiting an enzyme (HMG-CoA reductase) involved in the body's cholesterol synthesis. Examples include atorvastatin, lovastatin, simvastatin, and rosuvastatin.

Medical Necessity Criteria for Authorization

The Plan considers ezetimibe medically necessary when BOTH of the following criteria are met:

1. The member is 10 years of age or older; AND
2. The member is unable to use, or has tried and failed ONE (1) of the following:
   • Atorvastatin; or
   • Fluvastatin; or
   • Lovastatin; or
   • Pravastatin; or
   • Rosuvastatin; or
   • Simvastatin.

If the above prior authorization criteria are met, ezetimibe will be approved for 12 months.

References

1. Arnette DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140:e596–e646.
2. Clauss S, Wall K, Kavey RW, et al. Ezetimibe treatment of pediatric patients with hypercholesterolemia. J Pediatr. 2009;154:869-872.
3. Grundy SM, Stone NJ, Bailey AL et al. 2018 ACC/AHA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. Published Nov 2018. Updated June 2019. Accessed 15 July 2021. doi:10.1016/j.jacc.2018.11.003
4. Rosenblit, PD. Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at "Extreme" ASCVD Risk. Curr Diab Rep 2019 Nov 21;19(12):146. doi:10.1007/s11892-019-1246- y.
5. Sitosterolemia. Medline Plus. Accessed at: https://medlineplus.gov/genetics/condition/sitosterolemia/. Last Updated August 2020. Accessed July 10, 2021.
6. Yeste D, Chacon P, Clemente M, et al. Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents. J Pediatr Endocrinol Metabl. 2009;22(6):487- 492.
7. Zetia (ezetimibe) [prescribing information]. Jersey City, NJ: Organon LLC; June 2021.

Clinical Guideline Revision / History Information

Original Date: 11/05/2020
Reviewed/Revised: 10/14/2021, 12/01/2021, 06/23/2022, 06/29/2023