Ezetimibe: Safety and Efficacy

Ezetimibe is a non-statin lipid-lowering medication that inhibits absorption of dietary cholesterol by blocking the Niemann-Pick C1-Like 1 protein (NPC1L1). It has a half-life of approximately 22 hours due to enterohepatic circulation; it is metabolized in the small intestine and the liver – not via the cytochrome P450 system – and excreted back in bile as means of elimination.¹

Ezetimibe lowers low-density lipoprotein cholesterol (LDL-C) by 15-20% when used alone² as compared to 5-10% from doubling the dose of statin.³ A recent pooled analysis³ of 17 double-blind trials of patients who were already on a statin showed that the largest percent reductions in LDL-C were seen with adding ezetimibe.

Two previous outcomes trials, Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) and Study of Heart and Renal Protection (SHARP), studied ezetimibe-statin combination therapy versus placebo treatment. Lowering LDL-C levels by about 75 mg/dl and 32 mg/dl, they showed a relative reduction in major cardiovascular events of 22% and 17%, respectively. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is the first study powered for atherosclerotic cardiovascular disease (ASCVD) outcomes to show a benefit of a non-statin agent (ezetimibe) when added to a statin in patients post-acute coronary syndrome (ACS).⁴ Now clinicians have a clinically proven second-line agent that can be added to the highest-tolerated dose of a statin.

This option was notably safe in IMPROVE-IT over a median of 6 years with lower LDL-C levels among the ezetimibe-simvastatin group as opposed to the simvastatin alone group (median LDL-C values of ~54 vs. 70 mg/dL). Previous National Cholesterol Education Program-Adult Treatment Panel III guidelines and other landmark studies, such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial, have supported an LDL-C target of < 70 mg/dl for maximal CVD risk reduction.

The most recent IMPROVE-IT trial results reinforce the LDL-C hypothesis rather than the statin intensity hypothesis and suggest that an LDL-C closer to 50 mg/dl is even better. Ongoing outcomes trials are studying the effect of adding a PCSK-9 monoclonal antibody to statin therapy (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY Outcomes], Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER], The Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects [SPIRE-1], SPIRE-2) to attain similar or lower LDL-C levels.

Despite growing evidence supporting a lower-is-better approach for LDL-C, treatment with statin therapy alone may not be sufficient to achieve optimal LDL-C targets or percent reductions; IMPROVE-IT demonstrates that adding ezetimibe to a statin is safe and efficacious. Moreover, based on a recent unique analysis of the IMPROVE-IT trial, ezetimibe reduced additional and total cardiovascular events over the course of the study, not only the first occurring event as trials are traditionally designed to assess.⁵ This provides clinicians with more data to assuredly utilize ezetimibe in their clinical practice whenever applicable.

Ezetimibe Reduces Total Cardiovascular Events: Does It Matter?

The 2013 American Heart Association and American College of Cardiology (AHA/ACC) cholesterol treatment guideline focused on lowering ASCVD risk through LDL-C lowering.⁶ The guideline emphasized the importance of lifestyle modification and maximizing statin therapy, with attention to adherence, prior to adding non-statin therapy. The expert panel stated that non-statin therapies were an important consideration in high-risk patients when a less-than-anticipated LDL-C lowering was observed.

Priority was placed on agents shown to provide net clinical benefit; however, questions lingered. How low can we go with LDL-C? Is ezetimibe safe? Does adding ezetimibe help protect patients against recurring or additional ASCVD events? These questions have now been addressed by the IMPROVE-IT trial.

The IMPROVE-IT trial investigators adopted a novel and clinically relevant analytic approach to further understand ezetimibe's impact on clinical events. The analysis addresses the fact that patients with a nonfatal, first cardiovascular event are at risk of developing additional events. Due to the long duration of follow-up in IMPROVE-IT, 13% of the participants had recurrent cardiovascular events. The investigators now report that adding ezetimibe to simvastatin reduces not only first cardiovascular events, but also additional and total cardiovascular events during the entire study period (relative risk reductions of 6%, 11%, and 8%, respectively) correlating with persistent lower LDL-C levels throughout the study period.⁵

In other words, approximately 11 total cardiovascular events (MI, stroke and revascularizations) can be prevented for every 100 patients treated for 10 years with ezetimibe and simvastatin, which is essentially double the number of first cardiovascular events prevented. Therefore, providing this data on recurrent and total events helps clinicians, insurers, and patients better understand long-term benefits.

There are costs linked to recurrent events, including costs of the hospitalization itself, new medications, any follow-up testing and additional physician follow-up appointments. As such, understanding ezetimibe's impact on recurrent events helps derive better estimates of the costs associated with a patient's morbidity and mortality risk over the next decade. The IMPROVE-IT trial investigators are in the process of studying the health economics of the ezetimibe-simvastatin strategy, which will provide us with more insight into its cost-effectiveness at the population level. Importantly, generic ezetimibe is expected later this year.

As for now, clinicians can consider ezetimibe in the management of high-risk patients who are already on a maximally tolerated dose of a statin.

Conclusion

Ezetimibe is a safe and efficacious non-statin LDL-C-lowering agent particularly in high-risk patients, such as those post-ACS. Clinicians now have randomized clinical trial evidence to support the prescription of ezetimibe as an add-on agent or alternative therapy in statin intolerant patients or among those with suboptimal LDL-C reductions on a statin monotherapy, incremental to lifestyle modifications. Furthermore, until further evidence is available, targeting at least 50% reduction in LDL-C levels and down to about an LDL-C of 50mg/dl seems to be an efficacious and safe strategy for utilizing ezetimibe in our clinical practice for better ASCVD outcomes in persons with recent ACS.

The distinctive analysis of total cardiovascular events conducted by Murphy et al. in the IMPROVE-IT trial presents a model for ongoing and future outcomes studies, such as the PCSK-9 inhibitors trials, that will help clinicians make more informed decisions on potentially efficacious emerging medications.

References

1. Phan BAP, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag 2012;8:415-27.
2. Battagia A, Alberto D, Font M, Molteni D, Galvano A. Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoint: systematic review and meta-analysis of randomized controlled trials. PLoS One 2015;10:e0124587.
3. Ambegaonkar BM, Tipping D, Polis AB, Tomassini JE, Tershakovec AM. Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Atherosclerosis 2014;237:829-37.
4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
5. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total cardiovascular events with Ezetimibe/Simvastatin post-acute coronary syndrome. J Am Coll Cardiol 2016;67:353-61.
6. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;65(25 Pt B):2889-934.

Keywords: Acute Coronary Syndrome, Aortic Valve Stenosis, Atherosclerosis, Azetidines, Bile, Cholesterol, Cholesterol, Dietary, Cholesterol, LDL, Cytochrome P-450 Enzyme System, Enterohepatic Circulation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intestine, Small, Liver, Myocardial Infarction, Pravastatin, Risk, Risk Reduction Behavior, Simvastatin, Stroke

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