- ACRONYMS AND DEFINITIONS
- ACC - American College of Cardiology
- ACS - Acute coronary syndrome defined as myocardial infarction or unstable angina
- AHA - American Heart Association
- CVD - Cardiovascular disease
- RCT - Randomized controlled trial
- ULN - Upper limits of normal
- DRUGS IN CLASS
- Sterol transporter inhibitors
- Ezetimibe (Zetia®)
- Combination products with statins
- Roszet® (ezetimibe + rosuvastatin)
- Vytorin® (ezetimibe + simvastatin)
- Combination products with bempedoic acid
- Nexlizet® (ezetimibe + bempedoic acid)
- FDA-APPROVED INDICATIONS
- Primary hyperlipidemia - as monotherapy or in combination with statins or fenofibrates
- Homozygous familial hypercholesterolemia (HoFH) - in combination with atorvastatin or simvastatin
- Homozygous sitosterolemia - as adjunctive therapy to diet
- MECHANISM OF ACTION
- Sterol transporter
- Sterol transporter (Niemann-Pick C1-Like 1 (NPC1L1)) is involved in the intestinal uptake of cholesterol and phytosterols
- Ezetimibe blocks this transporter
- Sterol transporter study
- Some genetic mutations in the genes that code for an enzyme will cause the enzyme to be less active. These mutations are called "inactivating mutations."
- A study published in the NEJM in 2014 evaluated the association of inactivating mutations in the NPC1L1 gene with cholesterol levels and the risk of coronary heart disease. The study found that subjects with an inactivating mutation of NPC1L1 had an average LDL level that was 12 mg/dl lower than subjects without a mutation. The risk of coronary heart disease was 53% lower in subjects with one inactivating mutation compared to subjects without. The authors concluded that the risk reduction for heart disease among patients with inactivating mutations was greater than would be expected based on lower LDL levels alone. [PMID 25390462]
- CHOLESTEROL EFFECTS
| Effect of ezetimibe on cholesterol in a 12-week trial | ||
|---|---|---|
| Ezetimibe 10 mg (N=1288) |
Placebo (N=431) |
|
| Total | -13% | 0% |
| LDL | -18% | +1% |
| Triglycerides | -8% | 0% |
| HDL | +1% | -2% |
| Effects of ezetimibe when added to statins in an 8-week trial | ||
|---|---|---|
| Ezetimibe + statin (N=379) |
Placebo + statin (N=390) |
|
| Total | -17% | -2% |
| LDL | -25% | -4% |
| Triglycerides | -14% | -3% |
| HDL | +3% | +1% |
- SECONDARY PREVENTION OF CVD
- Overview
- Two large trials evaluated the effects of ezetimibe on CVD outcomes. The IMPROVE-IT trial compared the addition of ezetimibe or placebo to simvastatin, and the RACING study compared moderate-intensity statin + ezetimibe to high-intensity statin. Both studies are detailed below.
- The IMPROVE-IT study enrolled 18,144 patients with acute coronary syndrome
Main inclusion criteria
- Age ≥ 50 years
- Hospitalized within previous 10 days for ACS
- LDL level ≥ 50 mg/dl
- LDL level ≤ 125 mg/dl (no treatment) or ≤ 100 mg/dl (with treatment)
Main exclusion criteria
- Planned CABG
- Using potent statin (equivalent to > 40 mg simvastatin)
- CrCl < 30 ml/min
- Active liver disease
Baseline characteristics
- Average age 64 years
- Average LDL - 94 mg/dl
- Previous heart attack - 21%
- Prior statin use - 34.5%
- Index event: STEMI - 29% | NSTEMI - 47% | Unstable angina - 24%
Randomized treatment groups
- Group 1 (9077 patients) - Placebo + Simvastatin 40 mg once daily
- Group 2 (9067 patients) - Ezetimibe 10 mg + Simvastatin 40 mg once daily
Primary outcome: Composite of death from cardiovascular disease, a major coronary event (heart attack, documented unstable angina
requiring hospital admission, or coronary revascularization occurring at least 30 days after randomization), or nonfatal stroke
Results
| Duration: 7 years | |||
| Outcome | Placebo | Ezetimibe | Comparisons |
|---|---|---|---|
| Primary outcome | 34.7% | 32.7% | HR 0.936, 95%CI [0.89 to 0.99], p=0.016 |
| Overall mortality | 15.3% | 15.4% | HR 0.99, 95%CI [0.91 to 1.07], p=0.78 |
| Any myocardial infarction | 14.8% | 13.1% | HR 0.87, 95%CI [0.80 to 0.95], p=0.002 |
| Any stroke | 4.8% | 4.2% | HR 0.86, 95%CI [0.73 to 1.00], p=0.05 |
| Average LDL level (median time-weighted) | 69.5 mg/dl | 53.7 mg/dl | N/A |
|
|||
Findings: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit.
- STUDY
- Design: Randomized, open-label trial (N=3780 | length = 3 years) in South Koreans with CVD
- Treatment: Rosuvastatin 10 mg + Ezetimibe 10 mg vs Rosuvastatin 20 mg
- Primary outcome: 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke
- Results:
- Primary outcome: Rosuvastatin + Ezetimibe - 9.1%, Rosuvastatin - 9.9% (absolute difference -0.78%; 90%CI [-2.39 to 0.83])
- Discontinuation or dose reduction of the study drug by intolerance: Rosuvastatin + Ezetimibe - 4.8%, Rosuvastatin - 8.2% (p<0.0001)
- Findings: Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.
- Professional recommendations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- Summary
- Ezetimibe had a modest effect on cardiovascular outcomes in the IMPROVE-IT trial. The authors note in their discussion that the effect is consistent with what would be expected based on the difference in LDL cholesterol (16 mg/dl) that was achieved between the groups. This supports the premise that LDL-lowering is the primary determinant of cardiovascular risk, and the method (statin vs other) of lowering is less important. The study excluded patients taking high-intensity statins. Based on current AHA guidelines, a high-intensity statin would have been recommended for all the patients in this study. It's unclear if ezetimibe would have improved outcomes had patients been treated in this manner.
- In the RACING study, combination therapy with moderate-intensity statin and ezetimibe was noninferior to high-intensity statin. The authors note that the combination therapy was tolerated better, but the study was open-label, so this finding is suspect.
- SIDE EFFECTS
- General
- Ezetimibe is well-tolerated
- In trials, side effects with ezetimibe occurred at an incidence similar to placebo
- Liver enzyme elevations
- When used by itself, ezetimibe does not appear to cause elevated liver enzymes
- When ezetimibe is combined with a statin, it may slightly increase the risk of elevated liver enzymes when compared to statins alone
| Consecutive liver enzyme elevations (≥ 3 X ULN) | |
|---|---|
| Ezetimibe monotherapy | 0.5% |
| Placebo | 0.3% |
| Ezetimibe + statin | 1.3% |
| Placebo + statin | 0.4% |
- Cancer risk
- A study called the SEAS study compared simvastatin + placebo to simvastatin + ezetimibe in patients with aortic stenosis. The simvastatin + ezetimibe group had a significantly higher incidence of cancer compared to the placebo group (11.1% vs 7.5%). [PMID 18765433]
- The results of the SEAS study led to concerns that ezetimibe may increase the risk of cancer. An analysis that combined patients from three ezetimibe trials (SEAS, SHARP, IMPROVE-IT) was then performed in 2008. It did not find an increased risk of cancer in ezetimibe-treated patients. [PMID 18765432]. The SHARP trial which included 4650 ezetimibe-treated patients was not completed until 2011. In the final analysis, the risk of cancer was not elevated in the ezetimibe group after a median follow-up 4.9 years. [PMID 21663949]
- The FDA reviewed data from these trials and determined that ezetimibe does not increase the risk for cancer
- Muscle toxicity
- In trials, there was no excess risk of myopathy or rhabdomyolysis in patients treated with ezetimibe when compared to control. The incidence of creatine phosphokinase (CPK) > 10 × ULN was 0.2% for ezetimibe vs. 0.1% for placebo, and 0.1% for ezetimibe coadministered with a statin vs 0.4% for statins alone.
- Postmarketing cases of myopathy and rhabdomyolysis have been reported in patients receiving ezetimibe monotherapy, but causality is unknown
- CONTRAINDICATIONS
- The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained, persistent liver enzyme elevations
- Known hypersensitivity
- Nursing mothers
- Women who are pregnant or may become pregnant [1]
- PRECAUTIONS
- Kidney disease
- No dose adjustment necessary
- Liver disease
- Child-Pugh B or C: not recommended
- Do not give with concomitant statin in patients with active liver disease or unexplained transaminase elevations
- Gallstones
- Ezetimibe may increase cholesterol excretion into the gallbladder
- Patients with suspected gallbladder disease should not take ezetimibe until their condition is evaluated
- Fibrates can also increase cholesterol excretion into the gallbladder
- When fibrates are taken with ezetimibe, the risk of gallstones may be increased (see drug interactions below)
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Ezetimibe
- Bile Acid Sequestrants (Questran®, Welchol®) - bile acid Sequestrants may block the absorption of ezetimibe. Ezetimibe should be taken ≥ 2 hours before or ≥ 4 hours after a bile acid sequestrant [1]
- Cyclosporine - blood levels of both cyclosporine and ezetimibe are increased when taken together. Caution should be used when combining.
- Fibrates (gemfibrozil, fenofibrate, etc.) - both ezetimibe and fibrates may increase cholesterol excretion into the bile. This may increase the risk of gallstones in susceptible patients. Gemfibrozil and fenofibrate both increase blood levels of ezetimibe. The significance of this interaction is unknown.
- Warfarin (Coumadin®) - ezetimibe may affect warfarin levels. Monitor INR levels when adding ezetimibe to warfarin. [1]
- Metabolism and clearance
- Ezetimibe (Zetia®)
- Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation
- Ezetimibe undergoes minimal cytochrome P450 metabolism
- P-glycoprotein - substrate [8]
- OATP - substrate [9]
Ezetimibe (Zetia®)
Dosage forms
Tablet
- 10 mg
Dosing
High cholesterol
- 10 mg once daily
- May take without regard to food
Generic / Price
- YES/$Ezetimibe + simvastatin (Vytorin®)
Dosage forms
Tablet
- Ezetimibe - Simvastatin
- 10 mg - 10 mg
- 10 mg - 20 mg
- 10 mg - 40 mg
- 10 mg - 80 mg
Dosing
High cholesterol
- Starting: 10/10 - 10/20 mg once daily in the evening
- Maintenance: 10/10 - 10/40 mg once daily in the evening
- Max: 10/40 mg once daily
- For patients requiring > 55% LDL reduction, recommended starting dose is 10/40 mg/day
- Due to increased risk of myopathy, the 10/80 mg dose should be restricted to patients who have been taking 10/80 mg chronically (> 12 months) without evidence of muscle toxicity
- May take without regard to food
Generic / Price
- YES/$$-$$$Roszet® (rosuvastatin + ezetimibe)
Dosage forms
Tablet
- Rosuvastatin - Ezetimibe
- 5 mg - 10 mg
- 10 mg - 10 mg
- 20 mg - 10 mg
- 40 mg - 10 mg
Dosing
High cholesterol
- Dosing: 5/10 mg - 40/10 mg once daily
- Asian patients: starting dose should be 5/10 mg once daily. Consider risks/benefits of doses > 20/10 mg. Exposure to rosuvastatin is higher in Asian patients (see statins in Asian patients for more).
- Kidney disease:
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: recommended starting dose is 5/10 mg once daily. Do not exceed 10/10 mg once daily.
- May take without regard to food
- Do not crush, dissolve, or chew tablets
Generic / Price
- NO/$$$$Bempedoic acid + Ezetimibe (Nexlizet®)
Dosage forms
Tablet
- Bempedoic acid - Ezetimibe
- 180 mg - 10 mg
Dosing
High cholesterol
- 180/10 mg once daily
- May take without regard to food
- Swallow tablet whole
- Check lipids 8 - 12 weeks after starting
- Nexlizet should be taken with with maximally tolerated statin therapy
Generic / Price
- NO/$$$$- LONG-TERM SAFETY
- Ezetimibe was FDA-approved in 2002
- It appears to be safe during long-term use
- BIBLIOGRAPHY
- 1 - Zetia PI
- 2 - PMID 19915217
- 3 - PMID 18765433
- 4 - PMID 15871634
- 5 - PMID 18765432
- 6 - PMID 21663949
- 7 - PMID 18376000
- 8 - PMID 16513445
- 9 - FDA drug development and drug interactions
- 10 - PMID 26039521