MOUNT SINAI JOURNAL OF MEDICINE 75:143–147, 2008 143

CONTROVERSY

Making Sense of ENHANCE:Ezetimibe (Zetia) Lowers LDL Cholesterol

But Doesn’t DecreaseCarotid Intima-media Thickness

Donald Smith, MD, MPH

Lipids and Metabolism, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center,New York, NY, USA

On Monday, January 14, 2008, Merck andSchering & Plough released to the press an abstractbeing sent to the American College of Cardiology forpresentation at its annual scientific meeting in March.The study, Ezetimibe and Simvastatin in Hyper-cholesterolemia Enhances Atherosclerosis Regression(ENHANCE),1 compared simvastatin 80 (Zocor 80)with simvastatin 80/ezetimibe 10 (Vytorin 10/80)by using quantitative B-mode ultrasonographicchanges in carotid artery intima-media thickness(IMT) over a 2-year period. The design of thestudy, by a very skilled team in the Netherlands,duplicated that of an earlier study, atorvastatin versussimvastatin on Atherosclerosis Progression (ASAP)2

that compared aggressive LDL-cholesterol loweringusing atorvastatin 80 (Lipitor 80) with conventionalLDL-cholesterol lowering using simvastatin 40 (Zocor40) in a similar group of subjects. Both trialsenrolled in subjects with familial heterozygoushypercholesterolemia and a very high baseline meanLDL cholesterol greater than 300 mg/dL (mean USAlevels approximate 130 mg/dL).

Address Correspondence to:

Donald Smith, MD, MPHLipids and Metabolism

Zena and Michael A. WienerCardiovascular Institute

Mount Sinai Medical CenterNew York, NY

Email: donald.smith@mssm.edu

In ASAP, an LDL cholesterol of 155 mg/dLwith atorvastatin 80 resulted in significant regressionwhereas an LDL cholesterol of 192 mg/dL withsimvastatin 40 resulted in only a 2-year slowingof carotid artery IMT progression. ENHANCE, asurrogate imaging trial of LDL-lowering preventiveefficacy, enrolled double the number of patientsas ASAP and was expected to produce similarresults, which would bolster the proposed preventiveclinical efficacy of ezetimibe added to simvastatincompared with simvastatin alone. It did not, and theavalanche of publicity that followed became a horrorfor us physicians, worldwide, who were writingprescriptions for ezetimibe or simvastatin/ezetimibefor 5 million patients. If taking either of thesemedications or prescribing one of these, what inthe world is one to do?

HOW TO INTERPRET THE ENHANCESTUDY RESULTS

The subjects of the ENHANCE study were personswith familial heterozygous hypercholesterolemiarandomized to simvastatin 80 versus simvastatin80/ezetimibe 10 for 2 years. The primary endpointswere changes in mean combined carotid IMTmeasures (6 measures of distal-wall IMT–right andleft-in the common carotid artery, carotid bulb, andinternal carotid artery).1

To interpret these results, one must first examinethe data and second try to put them into the contextof previous trials. Table 1 shows results providedby Merck/Schering–Plough Pharmaceuticals in theirabstract on January 14, 2008, supplemented by the

A different version of this article was previously published electronically on May 23, 2008.Published online in Wiley InterScience (www.interscience.wiley.com).DOI:10.1002/msj.20031

2008 Mount Sinai School of Medicine

144 SMITH: CONTROVERSY–MAKING SENSE OF ENHANCE

Table 1. ENHANCE Study Results.

EfficacySimva 80/Ezet 10 Simva 80 p

Baseline LDL cholesterol (mg/dL)a 319 318 –Reduction after 2-yr treatment (%) 58 41 <0.01On-treatment LDL cholesterolb 134 188 <0.01Baseline mean carotid IMT (mm) 0.68 0.69 NSChange in mean carotid IMT after 2 yr (mm/2 yr) 0.0111 0.0058c 0.29Cardiovascular events

CV death 2/357 1/363 NSNonfatal MI 3/357 2/363 NSNonfatal stroke 1/357 1/363 NSRevascularization 6/357 5/363 NS

Adverse eventsConsecutive AST ≥3 ULN 2.8 2.2 NSCPK ≥10 ULN 1.1 2.2 NSCPK ≥10 ULN with muscle symptoms 0.6 0.3 NS

a After statin washout in 80% of subjects. Thus, prior, prestudy LDL cholesterol levelsunknown.b Calculated by present author.c Apparent difference most likely a chance effect. Patients on combination were noworse.

present author’s own calculations, which are shownin italics.

For 3 days after the press release of ENHANCE,the New York Times and other media claimed that‘‘. . . the plaque actually grew almost twice as fast inpatients taking the combination.3’’ This interpretationwas most likely fostered by Steve Nissen, MD,Chief of Cardiology at the Cleveland Clinic andby the superb coronary intravascular ultrasoundinvestigator who has proven in elegant studies thatlower LDL cholesterol levels stop progression ofcoronary plaques, and even lower levels produceregression. He was quoted as saying the resultswere ‘‘shocking,’’ and ‘‘this is as bad a result forthe drug as anybody could have feared. Millions ofpatients may be taking a drug that does not benefitthem, raising their risk of heart attacks and exposingthem to potential side effects. Patients should notbe given prescriptions for Zetia unless all othercholesterol drugs have failed.’’3 On Heartwire, apopular internet news source for cardiologists, hewas quoted as saying ‘‘the data show no benefit forezetimibe on top of simvastatin. In fact, the dataon both the rate of progression of atherosclerosisand cardiovascular events are trending in the wrongdirection. This is a pretty clear failure. Physiciansshould now stop using ezetimibe or Vytorin exceptas a last resort.’’4 In fact, such small increases inrate of common-carotid far-wall IMT progression inother studies were not statistically significant andrepresented nonprogression.5

One of Dr. Nissen’s arguments for the null resultwas that ‘‘statins do much more than lower LDL. They

increase HDL, lower triglycerides, and reduce inflam-mation (as measured by ultrasensitive C-reactive pro-tein, (usCRP)). In the absence of any demonstrableeffect beyond LDL lowering, nearly one million pre-scriptions per week are written for ezetimibe. Is thisrational?’’4 It is true that ezetimibe by itself will notproduce the extra benefits provided by statins men-tioned above. But the combination of ezetimibe witha statin, in addition to an approximate 14%–21% fur-ther lowering of LDL cholesterol, enhances those veryextra effects produced by statins, ie., further loweringtriglycerides by 11%–13%, raising HDL-cholesterol(HDL-C) an additional 0.4%–1.7%, and further lower-ing usCRP, a marker of inflammation, 10%–17%.6–8

So this, in fact, was not a test of the absence of suchpleiotropic effects with the use of ezetimibe alonebut was a test of whether enhancing these statin-produced, extra-LDL cholesterol-lowering effectswould prove beneficial. Because the study demon-strated no differential beneficial imaging effects, wefeel it is more profitable to examine the peculiaritiesof the study that gave this null effect rather than tolook for negative or hazardous effects of ezetimibewhich simply to date have not been demonstrated.

This was a study in persons who were 30–75years of age, some with stable coronary heart dis-ease and some without. Eighty percent had beenon statins and thus had been at much lower levelsof LDL cholesterol for unknown periods before thewashout period. Did this group have significant base-line carotid IMT abnormalities? One study showedthat the risk of first myocardial infarction increaseswith carotid IMT ≥0.82 mm, and that a progression

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rate of the far-wall common carotid artery IMT of≥0.034 mm/year increases the risk of future clinicalevents.9 The group studied in ENHANCE had neithera baseline mean IMT this great (0.68 mm) nor a pro-gression rate this great (0.003–0.006 mm/year). Thebaseline mean IMT in ENHANCE was certainly lessthan that studied in ASAP (0.93 mm).2 This suggeststhat previous use of statins in subjects in this trial mayhave already decreased and stabilized carotid IMT.This phenomenon was demonstrated in the ASAPextension trial; after 2 years on atorvastatin 80 andsimvastatin 40 in ASAP, a 2-year extension ensuedthat kept the group on atorvastatin 80 on the samedrug for an additional 2 years but switched all thoseon simvastatin 40 to atorvastain 80. The previousincrease in IMT in the second year on simvastatin40 regressed to baseline after 1 year of switching toatorvastatin 80. However, after carotid IMT decreasedfor the first 2 years on atorvastatin 80, it remainedconstant for the next 2 years on the same dose.10

Could this be the reason why there wasno differential effect on carotid IMT between thesimvastatin/ezetimibe group with LDL cholesterol of134 mg/dL and the simvastatin-only group with LDLcholesterol of 188 mg/dL? If the 80% of the studygroup previously on statins had mean LDL cholesterollevels significantly less than 200 mg/dL before the6-week drug washout period and randomizationdate, then the reduction in IMT may have alreadyoccurred, and 2 years at these new levels of LDLcholesterol might not have provided enough time, orenough of a differential level in LDL cholesterol, tobegin seeing a differential effect on IMT. With moretime, such differential levels of LDL cholesterol mighthave produced differential IMT rates of progression.The carotid IMT progression rate in a previous trialin the placebo cohort was 0.031 mm/year.11 Theprogression rates in both groups in this trial were one-tenth of that (0.003 mm/year), suggesting that a majorstabilization of progression most likely had alreadyoccurred at the beginning of the trial and simplycontinued throughout the 2-year trial in both groups.

It has been shown by using quantitative coronaryangiography that patients with familial heterozygoushypercholesterolemia and a very high mean baselineLDL-cholesterol level of 285 mg/dL who are takingcombined bile-acid binders, niacin, and lovastatinand decreasing LDL cholesterol to only 175 mg/dLcan regress coronary stenoses.12 The stenoses, andthus plaques, of such hypercholesterolemic patientsare very responsive to lowering LDL cholesterol tolevels that are above average in the general pop-ulation. The foam-cell accumulation in the carotidarteries, the major pathological feature of increasedcarotid IMT,13 should be equally regressive at such

LDL-cholesterol levels. This at least makes plausi-ble the explanation that these unique patients mayalready have decreased IMT to a stable level beforethe study began. This is a much more plausible expla-nation of this null trial than (1) rejecting the notionthat further LDL-cholesterol lowering is ineffective inreducing IMT thickening or reducing clinical eventsafter more than 40 years of research consistentlyconfirming such hypotheses, or (2) suggesting thatalthough ezetimibe can lower LDL cholesterol, it pro-duces some unknown toxic effect that negates itsbeneficial LDL-cholesterol-lowering effect.

Statins lower serum LDL cholesterol predomi-nantly through hepatic inhibition of HMG CoA reduc-tase, an early enzyme used in the 26-step cholesterolbiosynthetic pathway. The hepatocyte has manymechanisms to maintain a steady intracellular choles-terol concentration. When statin-produced choles-terol synthesis is lowered, hepatocyte LDL receptorsynthesis and transport to the cell surface is increased,which results in reduced serum LDL cholesterol. Eze-timibe, on the other hand, localizes to enterocytesof the endothelium of the small intestine. It blocksthe Nieman–Pick C1-like 1 (NPC1L1) receptor neces-sary for cholesterol absorption from micelles in thesmall intestine.14 This block in intestinal cholesterolabsorption results in decreased uptake of choles-terol from the gut, decreased hepatocyte intracellularcholesterol with compensatory increased LDL recep-tor synthesis, and again results in reduced serum LDLcholesterol. It is hard to imagine by what mechanisma medication located predominantly in the enteroctyecould negate the cardiopreventive effects of its LDL-cholesterol lowering feature. Because the averagehuman body synthesizes 800 mg of excess cholesteroldaily, which cannot be biochemically catabolized, itis eliminated from the body through the liver viabile and ultimately into feces. As this 800 mg ofcholesterol passes daily through the small intestine,it will be partially absorbed. Ezetimibe, by block-ing the enterocyte NPC1L1-cholesterol receptor, canthus lower LDL cholesterol even in those vegetarianswhose dietary intake of cholesterol is zero.

The blocking of hepatic cholesterol synthesiswith statins (HMG CoA reductase inhibitors) not onlyupregulates hepatocyte LDL receptor synthesis as acompensatory mechanism for stabilizing intracellu-lar hepatocyte cholesterol concentration, but it alsoupregulates cholesterol absorption in the intestine.Similarly, blocking the cholesterol NPC1L1 recep-tor with ezetimibe in the intestine and decreasingintestinal cholesterol absorption upregulates choles-terol synthesis in the liver.15 Hence, 2 drugs takensimultaneously such as a statin and ezetimibe, whichblock both cholesterol synthetic and absorptive

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146 SMITH: CONTROVERSY–MAKING SENSE OF ENHANCE

mechanisms, work extremely well together and arevery potent in reducing LDL cholesterol levels.14 Sim-vastatin 10 plus ezetemibe 10 taken together areas powerful in lowering LDL cholesterol as simvas-tatin 80 by itself.8 Hence, patients stopping Zetiacombined with a statin or Vytorin, based on a nullinterpretation of this study, will have to take muchhigher doses of the most powerful statins to attain thesame low LDL cholesterol goal. Such an augmenta-tion of statin dose risks a small (1%–2%), but definite,increase in risk of experiencing statin side effects,such as reversible increases in serum transaminaselevels or uncomfortable myalgias.

CONCLUSION ANDRECOMMENDATIONS

ENHANCE is the first unfortunate imaging trial thattested whether ezetimibe added to high-dose statincould add additional benefit to carotid artery IMTthickening in persons with familial heterozygoushypercholesterolemia. Unfortunately, 80% of thesubjects had been on statins for unknown periods oftime, which might have already resulted in regressionof IMT thickness to baseline levels less than thoseseen in other trials, in turn resulting in nonprogressiveIMT thickening in both groups. Despite implicationsin the public media, the study showed no harm inadding ezetimibe to simvastatin, rather it showedonly a lack of differential imaging efficacy. This is aninadequate trial of the efficacy of ezetimibe-loweredLDL cholesterol levels used to produce beneficialimaging and clinical effects. We still must wait for

Table 2. National Cholesterol Education Program AdultTreatment Panel Guidelines.

Number ofrisk factorsa or

medical conditionLDL cholesterolgoal (mg/dL)

0, 1 risk factor <160Two or more risk factors <130Diabetes, hypertension <100Coronary heart diease, stroke or

peripheral vascular disease<70

a Risk factors to be counted:• Hypertension history or use of antihypertensivemedications• Cigarette smoking• Age: Men ≥45 years; women ≥55 years orpostmenopausal• Early family history of coronary heart disease:Father, brother ≤55 years; Mother, sister ≤65 years• HDL cholesterol <40 mg/dL.Subtract one risk factor for HDL cholesterol >60 mg/dL.

results in ongoing clinical efficacy trials that will bereported in 2 years.

In the meantime, clinicians should focus onlowering LDL cholesterol to the proper goal, asestablished by the National Cholesterol EducationProgram (NCEP) (Table 2).

If necessary to achieve the appropriate NCEPgoal comfortably, clinicians should use ezetimibeor simvastatin/ezetimibe. Indeed, we should useany and all means studied, which lower LDLcholesterol including bile-acid binders, diets, ilealbypass, and statins, have shown coronary heart-disease preventive effects. This should be true ofezetimibe as a single agent or in combination with astatin. The combination with a statin is more effectivein LDL-cholesterol lowering, triglyceride lowering,usCRP lowering, and HDL-C raising than a statinalone.

The NCEP has always suggested beginningLDL-cholesterol lowering with a statin; this shouldbe continued. If a clinician has attained an LDLcholesterol goal with the use of ezetimibe alonewithout ever having tried a statin and becomesconcerned about the results of the ENHANCE study,the clinician could change to statin therapy or themore expensive, bile-acid binding resins.

For the time being, the ENHANCE study maypush us more in the direction of increasing statindosage than in adding ezetimibe to a statin to reachdifficult NCEP LDL cholesterol goals. But in manycases, LDL cholesterol goals cannot be reached withstatins alone, and with higher dose statins, patientsoccasionally experience intolerable side effects. Insuch cases, this one study in this unusual populationshould not undermine our attempts to reach NCEPLDL-cholesterol goals. Our policy for the moment,and until more results come in from clinical trials,is to attain NCEP LDL-cholesterol goals by anymeans possible including the use of ezetimibe andsimvastatin/exetimibe where necessary.

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