Is it over for ezetimibe?

Is it over for ezetimibe? The short answer is no. The recent firestorm of controversy over the lack of benefit with ezetimibe in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial appears to have been fueled more by the delay in reporting the trial results rather than a careful sci-entific examination of the evidence.

Why were the results of ENHANCE different from earlier carotid intimal medial thickness trials?

ENHANCE found that adding ezetimibe to high-dose simvastatin therapy had no significant effect on carotid intima media thickness (CIMT) in 720 subjects with familial hypercholesterolemia (FH) [1]. While ENHANCE was similar in many ways to the earlier Effect of Aggressive Versus Conventional Lipid Lowering on Atherosclerosis Progression in Familial Hypercholesterolemia (ASAP) trial, which found that atorvastatin 80 mg resulted in CIMT regression compared with simvastatin 40 mg [2], there were several very important differences. In ASAP, FH subjects were selected to have a CIMT greater than 0.7 mm at baseline and had either received no prior therapy or had LDL-cholesterol (LDL-C) levels greater than 174 mg/dl (4.5 mmol/l). By contrast, 80% of subjects in ENHANCE had received prior statin therapy. Although lipid levels prior to entry into ENHANCE were not reported, following the publication of ASAP in 2001, these patients were most likely treated with high-dose statins and probably also with ezetimibe. Indeed, ENHANCE is a resounding success story for cholesterol-lowering treatment, with ENHANCE subjects having baseline CIMT levels 25% lower than observed in ASAP, which was commensurate with the CIMT of an average 32-year old male with an LDL-C of 134 mg/dl [3].

Long-term statin therapy has been shown to stabilize plaque by depleting lipid content without changing plaque volume [4]. Therefore, it was not surprising that ENHANCE failed to demonstrate a difference in CIMT when LDL-C was lowered by an additional 17% over a 2-year period. Moreover, these findings are similar to those in the ASAP trial after a further 2 years of follow-up [5]. Notably, in the 20% of ENHANCE subjects who were statin-naive at baseline, there was evidence of less CIMT progression in those receiving ezetimibe [1].

Does ezetimibe have a mechanism of action different from statins?

Ezetimibe selectively inhibits the absorption of cholesterol by blocking the Niemann–Pick C1-like (NPCL)1 protein DNA receptor at the intestinal wall, which decreases cholesterol return to the liver, very similar to bile acid sequestrants [6]. These two drugs, along with statins, all lower intracellular hepatic cholesterol levels and upregulate the LDL-receptor to enhance LDL-C clearance from plasma. Some have argued that the non-LDL-C, or pleiotropic effects, of statins provide additional benefits over LDL-C lowering alone. However, this is not supported by evidence from morbidity/mortality trials, in which statins, bile acid sequestrants, diet and ileal bypass surgery all exhibited a 1:1 relationship between percentage LDL-C lowering and CHD event reduction [7]. ENHANCE found that ezetimibe also lowered C-reactive protein by 26% when added to simvastatin 80 mg, providing further evidence that statins are not unique in their pleiotropic effects.

Ezetimibe has minimal systemic absorption, making an off-target effect less likely [6]. An editorial accompanying the publication of the ENHANCE results cited reduced ABCA1 expression in Caco-2 (an intestinal cell line) as a potential off-target effect of ezetimibe [8]. However, since intracellular cholesterol level influences ABCA1 expression, ABCA1 is also downregulated by statins [9]. Inhibition of NPCL1 additionally blocks uptake of plant sterols by 40–50% [6]. This is generally considered beneficial since patients with homozygous sitosterolemia, a recessively inherited disease caused by a mutation in the gene for either the ABCG5 or ABCG8 transporter protein, develop premature atherosclerosis.

Should we be using bile acid sequestrants, fibrates or niacin in preference to ezetimibe?

In those who have not achieved their LDL-C and non-HDL-cholesterol goals on statin therapy, some have advocated the use of agents other than ezetimibe until the results of ongoing morbidity/mortality trials have been completed [10]. Ironically, there is virtually no evidence that adding bile acid sequestrants, fibrates or niacin to statin therapy provides additional reductions in cardiovascular events over statin therapy alone, however several such trials are underway [11]. Although bile acid sequestrants and a 2-g dose of niacin also lower LDL-C by an additional 12–15% when added to statins, these drugs have significant adverse event profiles which limit their use [101,102]. Fibrates do not have a consistent effect on LDL-C, and may increase levels in some patients [11]. Concomitant use of statins and gemfibrozil substantially increases the risk of serious muscle complications, although fenofibrate appears to be safer in this regard.

How should ezetimibe be used in clinical practice?

Statins remain the foundation of cardiovascular risk reduction therapy. Extensive clinical trial evidence has shown that the magnitude of cardiovascular benefit is directly proportionate to the degree of LDL-lowering with statins, as well as with diet, bile acid sequestrants and ileal bypass surgery [7,12]. The majority of patients will require two or more drugs to achieve very aggressive cholesterol targets [11]. Therefore, in patients who have not achieved their guideline-defined LDL-C and non-HDL-cholesterol goals on statin therapy, it is reasonable to add ezetimibe. Ezetimibe is also an option for statin-intolerant patients. The ezetimibe–simvastatin coformulation (Vytorin^®) may provide some cost savings over adding ezetimibe to other statins. It should be noted that Vytorin 10/80 mg is approximately equivalent to adding ezetimibe to either atorvastatin 40 mg or rosuvastatin 20 mg [103].

Ongoing clinical trials will eventually provide evidence of the incremental benefit of adding ezetimibe (or niacin or fenofibrate) to statin therapy. In the meantime, it is reasonable to continue to include ezetimibe in our cardiovascular prevention armamentarium.

Financial & competing interests disclosure

In the past year, Jennifer Robinson has received research grants from Abbott, Bristol-Myers Squibb, Hoffman La Roche, Merck, Pfizer, Procter & Gamble, Schering-Plough, Aegerion, and Takeda. She has also received honoraria from Merck Schering Plough and is a consultant on the advisory boards of Astra-Zeneca and Merck Schering Plough.

Michael Davidson is on the speakers’ bureau of Abbott Laboratories, Astra Zeneca Pharmaceuticals, Kos Pharmaceuticals, Merck, Merck/Schering-Plough, Pfizer, Inc., Reliant Pharmaceuticals, Inc., Sankyo Pharma, and Takeda Pharmaceuticals. He is also a consultant for Abbott Laboratories, Astra Zeneca Pharmaceuticals, Kos Pharmaceuticals, Merck, Merck/Schering-Plough, Pfizer, Inc., Novartis, Reliant Pharmaceuticals, Inc., Roche Pharmaceuticals, Sankyo Pharma, Sumitomo Pharmaceuticals and Takeda Pharmaceuticals. He has also received grants and carried out research for Abbott Laboratories, Astra Zeneca Pharmaceuticals, Bristol-Myers Squibb, Kos Pharmaceuticals, Merck, Merck/Schering-Plough, Pfizer, Inc., Novartis, Reliant Pharmaceuticals, Inc., Roche Pharmaceuticals, Sankyo Pharma, and Takeda Pharmaceuticals.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.