Comment on: Clinical benefits of ezetimibe: absence of proof is just that

In 2012, I wrote a review of ezetimibe for the journal Expert Opinion on Pharmacology where I gave my opinion as ‘Ezetimibe alone or in the presence of simvastatin lowers LDL cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice' [1].

An editorial in the journal argued that ‘Clinical benefits of ezetimibe use: is absence of proof, proof of absence?' [2]. In my response, I argue that the absence of proof is just that. Thus, four clinical trials (ARBITER 6-HALTS, ENHANCE, VYCTOR and SANDS) have failed to detect any effect of ezetimibe on carotid intima-media thickness (cIMT). In ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol 6 – HDL and LDL Treatment Strategies), no significant reduction of carotid-intima thickness was observed with ezetimibe after 14 months [3]. In ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study, the primary outcome measure of IMT of the carotid artery was increased and ezetimibe had no effect [4]. SANDS (Stop Atherosclerosis in Native Diabetic Study) showed a similar reduction of carotid-intima thickness with simvastatin alone and simvastatin in combination with ezetimibe [5]. SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) did not demonstrate any effect of ezetimibe on cardiovascular events or aortic-valve replacement, and SHARP (Study of Heart and Renal Protection) did not demonstrate a reduction in major atherosclerotic events [1].

In 2013, another study has failed to show a beneficial clinical outcome with ezetimibe. Thus, ezetimibe, in the presence of a statin, did not reduce all-cause mortality in 3827 subjects with cardiovascular disease [6]. In conclusion, the absence of proof of any beneficial clinical outcomes is mounting for ezetimibe.

Declaration of interest

This letter was written independently. No professional writer was involved. I Gouni-Berthold has received honoraria from Genzyme, Novartis, Pfizer, Otsuka, Bayer Health Care and IPSEN. DP Mikhailidis has given talks and attended conferences sponsored by Merck, Sharp & Dohme and Abbott. M Rizzo has given lectures, received honoraria or research support, and participated in conferences sponsored by AstraZeneca, Bracco, Bromatech, Chiesi Farmaceutici, Kowa, Novartis, Novo Nordisk, Rikrea and Servier.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this article.

Bibliography

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Author's response

Ioanna Gouni-Berthold¹

Dimitri P Mikhailidis^†2

Manfredi Rizzo^3,4

^aUniversity of Cologne, Center of Endocrinology, Diabetes and Preventive Medicine, Cologne, Germany

^bUniversity College London (UCL), University College Medical School, Royal Free Hospital Campus, Department of Clinical Biochemistry, (Vascular Prevention Clinic), London, UK

^cUniversity of Palermo, Department of Internal Medicine and Medical Specialties, Via del Vespro, 141 90127, Palermo, Italy [phone]; [phone]; [email protected]

^dEuro-Mediterranean Institute of Science and Technology, Italy

Dr Doggrell adds another study to her previous comments on the suitability of ezetimibe for the treatment of hypercholsterolaemia [1,2]. This new study has several limitations as pointed out by its authors [3]. For example, ‘the study did not include lipid values following administration of ezetimibe' [3]. Thus, the benefits of low-density lipoprotein cholesterol (LDL-C) reduction could not be demonstrated [3]. Also, this is a retrospective single-center study [3]. If such studies are to be selected to support definitive statements, then perhaps 2 other studies [4,5] that have similar limitations as the one cited by Dr Doggrell [1] but report a clinically relevant benefit following ezetimibe administration should also be considered.

Regarding the other trials mentioned by Dr Doggrell [1], we and others have commented on their limitations [6,7], and we will not repeat this exercise. However, a few comments may be worthwhile. Doggrell cites [1] the SANDS study [8] in support of her argument. Yet, these authors conclude that reducing LDL-C to aggressive targets resulted in similar regression of carotid intima-media thickness (cIMT) in patients who attained equivalent LDL-C reductions from a statin alone or a statin plus ezetimibe [8]. Therefore, how could that happen if ezetimibe cannot decrease cIMT? It is no surprise that the authors of the SANDS study [8] concluded that ‘in the interim, ezetimibe remains a viable therapeutic option for patients who fail to reach their LDL-C target on a statin alone'. Regarding the VYCTOR trial [9] (another cIMT study) also cited by Dr Doggrell [1], the arguments are similar. This is probably why the authors state that ‘this study is one of the first providing evidence that dual therapy has a beneficial effect on a surrogate marker of atherosclerosis (i.e., cIMT)' [9].

It is of interest that the most recent guidelines (Aug 15, 2013; in press; Consensus Statement of the European Atherosclerosis Society) that we could find mention ezetimibe as a treatment option [10].

We maintain our conclusions [6]. There is no clinical event-based evidence supporting ezetimibe monotherapy. However, it is relevant that this drug is to be used in combination with a statin. The only exception would be if patients cannot tolerate a statin. Clinicians will need to decide regarding the use of ezetimibe on the basis of the current evidence (for or against ezetimibe). Making definitive comments on the basis of nondefinitive evidence may disproportionally influence busy clinicians who do not have time to evaluate the details of several trials.