To the Editor: In the Ezetimibe and Simvastatin in HypercholesterolemiaEnhances Atherosclerosis Regression (ENHANCE) study by Kasteleinet al. (April 3 issue),1 the addition of ezetimibe to simvastatinboosted the decrease in levels of low-density lipoprotein (LDL)cholesterol from 39.1% to 55.6%. However, the greater decreasein LDL cholesterol in the combined-therapy group did not affectprogression of the carotid intima–media thickness. Someobservers have suggested that the results of the ENHANCE studyforce us to question the basic lipid hypothesis of atherogenesis.
No single study can possibly counter the extensive body of evidencethat lowering of plasma cholesterol levels decreases the riskof coronary heart disease. As pointed out by the investigatorsin the Coronary Primary Prevention Trial, a reduction in riskin the pre-1984 outcome trials correlated well with the decreasein plasma cholesterol levels, whether that change was effectedby means of diet, nicotinic acid, or cholestyramine.2 The statinresults fit rather well on the same straight line.3 In short,the prevention of coronary heart disease depends primarily ona reduction in LDL cholesterol, independently of the mechanismof LDL lowering. One negative study is surely not a sufficientbasis for challenging the lipid hypothesis, especially sincea number of factors could have readily accounted for the apparentnegative result in patients receiving ezetimibe, as pointedout in the commentaries accompanying the article.4,5
Daniel Steinberg, M.D., Ph.D. University of California San Diego La Jolla, CA 92093-0682 dsteinberg{at}ucsd.edu
References
Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-1443. [Erratum, N Engl J Med 2008;358:1977.] [Free Full Text]
The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-374. [Abstract]
Brown BG, Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in ezetimibe? N Engl J Med 2008;358:1504-1507. [Free Full Text]
Drazen JM, Jarcho JA, Morrissey S, Curfman GD. Cholesterol lowering and ezetimibe. N Engl J Med 2008;358:1507-1508. [Free Full Text]
To the Editor: Given the extremely high cholesterol levels reportedin the ENHANCE study, the results of this trial are not applicableto the general population and do not represent changes in plaquethat might have been seen in patients with less severe hyperlipidemia.Although there is some relationship between a change in theintima–media thickness and a reduction in cardiac events,1other mechanisms are important, such as plaque stabilizationand reduction in inflammation.
The results of multiple statin trials have shown a consistentassociation between levels of LDL cholesterol and C-reactiveprotein (CRP) and clinical events.2,3 In the ENHANCE trial,levels of LDL cholesterol and CRP were lower in the combined-therapygroup than in the simvastatin-only group, which suggests thatevent rates are likely to be lower when the clinical outcometrials are completed.
The media has created an undue panic in the general populationon the basis of a study that offers little insight into thebenefits or dangers of combination therapy with simvastatinand ezetimibe. Other drugs have had surrogate measures thatat first appeared to be adverse. Had we never used beta-blockersto treat heart failure because they initially reduce the ejectionfraction,4 we would have denied many patients a lifesaving therapy.
Eric J. Eichhorn, M.D. Cardiopulmonary Research Science and Technology Institute Dallas, TX 75230
References
Furberg CD, Adams HP Jr, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;90:1679-1687. [ISI][Medline]
Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q. [ISI][Medline]
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979. [Erratum, N Engl J Med 1997;337:356.] [Free Full Text]
Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with β-adrenergic blockade. J Am Coll Cardiol 1995;25:1154-1161. [Abstract]
To the Editor: The results of the ENHANCE study, which involvedpatients with familial hypercholesterolemia, are at first glanceperplexing. Greater lowering of LDL cholesterol levels after2 years of treatment did not improve the intima–mediathickness of the carotid and femoral arteries. However, atheroscleroticblockages in 45-year-old men change very slowly, as indicatedin a study of cholesterol turnover in human atheroscleroticarteries.1 The turnover time of cholesterol was 821 and 934days in the femoral and carotid arteries, respectively. Onewould not expect to see much change in the arteries of thesestudy patients after only 730 days.
In their accompanying editorial, Brown and Taylor suggest anadditional factor. The patients in the study had already beentreated with statin drugs for years. Most likely, the benefithad already occurred with the loss of lipids from atheroscleroticplaques. The resultant fibrotic, calcified lesions would notbe expected to change very much as levels of LDL cholesterolwere further lowered. It is reassuring that the safety of ezetimibewas demonstrated in these 338 patients and that ezetimibe alsoreduced the CRP level significantly.
William E. Connor, M.D. Oregon Health and Science University Portland, OR 97239 connorw{at}ohsu.edu
References
Jagannathan SN, Connor WE, Baker WH, Bhattacharyya AK. The turnover of cholesterol in human atherosclerotic arteries. J Clin Invest 1974;54:366-377. [CrossRef][ISI][Medline]
To the Editor: Kastelein et al. defend the precision of theircarotid ultrasonographic methodology on the basis of its "highintraclass correlation coefficient and . . . small standarddeviations." Although this precision is sufficient for measurementsof intima–media thickness of approximately 700 µm,as reported by the authors, the relative errors become substantiallymagnified for the much smaller derived differences representingthe operative primary outcome. According to our calculations,the difference in the mean (±SD) carotid intima–mediathickness was 6±66 µm in the simvastatin-only group,as compared with 11±68 µm in the group receivingsimvastatin plus ezetimibe. These large errors become magnifiedeven further for the resultant between-group differences —averaging (11–6) ± the square root of (662+682),or 5±95 µm (less than the width of a red cell),with a 95% confidence interval ranging from –181 to 192µm (the width of more than 50 red cells). These tiny differencesand large errors provide no information whatsoever for or againstthe study hypothesis or any of its putative corollaries. Nordo they say anything about the likely denouement of ongoingclinical-outcome studies. Simply stated, the absence of evidenceis not evidence of absence.
George A. Diamond, M.D. Sanjay Kaul, M.D. Cedars–Sinai Medical Center Los Angeles, CA 90048 gadiamond{at}pol.net
Dr. Diamond reports being a former employee of Merck (1995 to1996) and receiving lecture fees from Merck and Schering-Plough.No other potential conflict of interest relevant to this letterwas reported.
To the Editor: In their editorial, Brown and Taylor do not considerimaging methodology as a factor in the results of the ENHANCEtrial. Carotid–intima thickening suffers from a lack ofconsensus on measurement technique.1 Different techniques havea large effect on reproducibility, and error contributes significantlyto observed changes in longitudinal studies.1 Reproducibilityis greater for the distal common carotid artery than for thebulb or internal carotid.1,2 Accordingly, the common carotidartery alone has been studied in most major trials other thanthe ENHANCE and the Atorvastatin versus Simvastatin on AtherosclerosisProgression (ASAP) studies, including a trial cited by Brownand Taylor and by Kastelein et al., which showed a correlationbetween an increase in the intima–media thickness anda tripling of the cardiovascular risk.1,2,3
Since subjects in the ASAP study had grossly abnormal intimalthickening with "visible plaque," the methodology was less criticalin detecting regression.4 However, in the ENHANCE study, amonghealthy subjects in the simvastatin-only group who had progressionin the intima–media thickness of only 0.0058 mm at 2 years,the inclusion of the carotid bulb and the internal carotid arteryproduced a standard deviation between paired quality-controlmeasurements of 0.056 mm, which limits the statistical powerof the study. Notably, confining the analysis to the commoncarotid artery actually shows a trend in favor of ezetimibe.Although it emphasizes the primary role of statins, the studyis too limited to remove ezetimibe as an important adjunct.
James A. Blake, M.D. New York–Presbyterian Hospital New York, NY 10065
References
Kanters SD, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke 1997;28:665-671. [Free Full Text]
Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Venralis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106:2055-2059. [CrossRef][ISI][Medline]
Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262-269. [Free Full Text]
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-581. [CrossRef][ISI][Medline]
To the Editor: The editorial by Brown and Taylor addressingthe ENHANCE trial suggests that ezetimibe may trigger proatherogenicgene-regulatory mechanisms. The basis for this claim comes froman in vitro study involving Caco-2 (colon carcinoma cell line),in which crushed ezetimibe pills (10% ezetimibe and 90% non-ezetimibeformulation) caused the inhibition or gene down-regulation ofscavenger receptor B1 and ATP-binding cassette transporter A1.In contrast, numerous studies of tissues derived from ezetimibe-treatedanimals have shown no effect on the expression of these genes.1,2,3Studies of ezetimibe in a variety of species and in mice witha deletion of its molecular target, the Niemann–Pick C1-like1 (NPC1L1) enterocyte transporter, have consistently shown selectiveinhibition of cholesterol uptake from the intestine,3 withoutshowing off-target effects. Changes in gene expression reflectthis inhibition — for example, increased expression ofgenes encoding the LDL receptor and cholesterol biosynthesis.In animal models, ezetimibe treatment caused an inhibition ofatherosclerosis of more than 90%3 and extended lifespan.4 Thedeletion of NPC1L1 in apolipoprotein E–null mice causesnearly complete protection from atherogenesis.5 The data stronglysupport an antiatherogenic role of ezetimibe through its selectiveinhibition of NPC1L1-mediated intestinal absorption of cholesterol.
Harry R. Davis, Jr., Ph.D. Nicholas J. Murgolo, Ph.D. MichaelP. Graziano, Ph.D. Schering-Plough Research Institute Kenilworth, NJ 07033 harry.davis{at}spcorp.com
References
Repa JJ, Turley SD, Quan G, Dietschy JM. Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption. J Lipid Res 2005;46:779-789. [Free Full Text]
Telford DE, Sutherland BG, Edwards JY, Andrews JD, Barrett PHR, Huff MW. The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res 2007;48:699-708. [Free Full Text]
Davis HR, Veltri EP. Zetia: inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia. J Atheroscler Thromb 2007;14:99-108. [ISI][Medline]
Braun A, Yesilaltay A, Acton S, et al. Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-B1/apoE double knockout mice. Atherosclerosis 2008;198:77-84. [CrossRef][ISI][Medline]
Davis HR Jr, Hoos LM, Tetzloff G, et al. Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE–/– mice. Arterioscler Thromb Vasc Biol 2007;27:841-849. [Free Full Text]
To the Editor: Brown and Taylor recommend using drugs that haveshown clinical benefits when added to statins before using ezetimibewith statins. They reference studies demonstrating the clinicalbenefit of adding niacin to statins, but I am unaware of anystudy that shows a clinical benefit of adding fibrates or bileacid sequestrants to statins. Fibrates, bile acid sequestrants,and ezetimibe should be reserved for patients in whom individuallipid targets have not been reached with a statin and niacinor who do not tolerate this combination. One should choose amongthese three agents on the basis of efficacy, potential drug–druginteractions, side effects, and cost.
Todd Kaye, M.D. Palo Alto Medical Foundation Mountain View, CA 94040
Dr. Kaye reports receiving lecture fees from Merck–Schering-Plough.No other potential conflict of interest relevant to this letterwas reported.
The authors reply: For several decades, the lipid hypothesishas been universally accepted. Randomized, controlled trialswith statins, resins, or even partial ileal bypass have shownthat reductions in LDL cholesterol levels are accompanied bya clinical benefit as well as improvement in atherosclerosis,as assessed with imaging techniques.1,2 We share Steinberg'sposition that a small surrogate-marker trial such as ours doesnot carry the weight to challenge this hypothesis.3 Furthermore,Eichhorn states that in multiple statin trials, levels of LDLcholesterol and CRP were lowered in a manner similar to thatin our study. It is not far-fetched to expect that ezetimibe,like statins, might ultimately also reduce cardiovascular eventsin outcome trials, but this is by no means a certainty, giventhe results of our study. The unanticipated results of our studycould be caused by the extent of previous lipid-lowering treatment,the imprecision of ultrasonographic techniques, the short durationof treatment, or off-target effects of ezetimibe that offsetthe reduction in LDL cholesterol. A final conclusion must awaitthe results of the ezetimibe clinical-end-point study.
Connor points to the aggressive lipid-lowering treatment andthe ensuing "delipidation" of the arterial wall as a major reasonthat our trial did not show an effect of the addition of ezetimibe,and he might well be right. However, he also mentions "atheroscleroticblockages" and "atherosclerotic plaques." Although this maybe a mechanism in patients with more severe disease, in ourtrial, no patients had extensive carotid atherosclerosis: only24 of 642 patients (3.7%) had small plaques (defined as an intima–mediathickness 1.3 mm) in one or more of their carotid segments.As in many other trials studying carotid intima–mediathickness, most of the data from our study represent overallthickening, the stage that precedes plaque formation.
Diamond and Kaul state that "the absence of evidence is notevidence of absence," and if they mean that our results cannotbe interpreted as proof that ezetimibe has no clinical benefit,we agree. However, if their contention is that with respectto the primary efficacy outcome a beneficial treatment effectof ezetimibe could be "hidden" because of what they call tinydifferences and large errors, we strongly disagree. It is obviousthat the standard deviations for the measurement of intima–mediathickness are higher than the actually measured differences.4For this reason, a large study population is needed for trialsstudying intima–media thickness. Our study was underpoweredto detect significant differences in intima–media thicknessin the range of 6 to 11 µm. On the basis of the post hocpower calculation, we could measure significant differencesof only 15 µm. Despite this much-better-than-anticipatedprecision, no treatment effect of ezetimibe could be observed.
Fatima Akdim, M.D. Eric de Groot, M.D. John J.P. Kastelein,M.D., Ph.D. Academic Medical Center 1105 AZ Amsterdam, the Netherlands j.j.kastelein{at}amc.uva.nl
References
Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46:1855-1862. [Free Full Text]
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-581. [CrossRef][ISI][Medline]
Steinberg D. The pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy. V. The discovery of the statins and the end of the controversy. J Lipid Res 2006;47:1339-1351. [Free Full Text]
Bots ML, Evans GW, Riley WA, Grobbee DE. Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 2003;34:2985-2994. [Free Full Text]
The editorialist replies: Connor proposes that substantial changesin carotid intima–media thickness would be unlikely in2 years. However, thinning has occurred with intensive statintherapy. In 2001, in the ASAP trial, and in 2003,1 patientsin these studies who received 80 mg of atorvastatin or 80 mgof simvastatin during a 2-year period had a reduction in carotidintima–media thickness of 31 µm and 53 µm,respectively. But in 2007, in the Rating Atherosclerotic DiseaseChange by Imaging with a New CETP [Cholesteryl Ester TransferProtein] Inhibitor (RADIANCE 1) trial and in 2008, in the ENHANCEtrial, in which identical drugs were used in the same laboratory,patients in the same clinical population had minimal intima–mediathickening (an increase of 5 µm and 6 µm, respectively)during a 2-year period. These findings had nothing to do withezetimibe; rather, they reflect a fundamental change in thelaboratory or in its patients. This newly observed lack of responseto intensive statin therapy appears to be best explained bythe observation that lipid-lowering therapy primarily depletescore lipid deposits and lipid-rich macrophages2 but not elastin,collagen, smooth muscle, or calcium.2,3 In the ENHANCE study,81% of patients had received standard-of-care statins for manyyears in the expert centers that enrolled patients with familialhypercholesterolemia in this trial. In the remaining 19% ofpatients, the treatment history was unknown. A decade of intensivelipid therapy literally depletes the human carotid plaque oflipid.3 Thus, these patients, having undergone long, effectivetreatment, were probably lipid depleted and could not respondwith further intimal thinning and were similarly depleted ofmacrophage-derived inflammatory or growth factors, thus remainingin a quiescent progression mode.
Blake points out that different segments of the carotid bifurcationhave different variances in measurement. And Diamond (with whomI would never argue about statistics) and Kaul interpret thelarge variance in the change in carotid intima–media thickness(e.g., 6±66 µm) as an "error" in measurement. Iview this variance as largely a population variance. Nevertheless,the thin baseline carotid intima–media thickness and theabsence of significant between-group differences in carotidintima–media thickness, on the basis of seven averagingapproaches, convince me that the observed absence of intimalresponse to either of the treatments is entirely credible. TheENHANCE study neither rules out nor establishes a clinical benefitof ezetimibe in a population that has not undergone previoustherapy.
Kaye requests evidence that fibrates or resins add to risk reductionwith statins. He points out that there are no trials of fibratesplus statins, although the Fenofibrate Intervention and EventLowering in Diabetes (FIELD) study4 is seen by many as showinga strong favorable trend. The benefits of lovastatin plus colestipolin the Familial Atherosclerosis Treatment Study (FATS) far exceededthe established expectations for lovastatin alone.5
Davis and colleagues make a number of salient and supportivepoints regarding cell and tissue models of the action of ezetimibe.The model of choice is the human clinical model. We await itsevidence.
B. Greg Brown, M.D., Ph.D. University of Washington School of Medicine Seattle, WA 98195-6422
References
Nolting PR, de Groot E, Zwinderman AH, Buirma RJ, Trip MD, Kastelein JJ. Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin. Arch Intern Med 2003;163:1837-1841. [Free Full Text]
Small DM, Bond MG, Waugh D, Prack M, Sawyer JK. Physiochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis. J Clin Invest 1984;73:1590-1605. [ISI][Medline]
Zhao X-Q, Yuan C, Hatsukami TS, et al. Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler Thromb Vasc Biol 2001;21:1623-1629. [Free Full Text]
The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-1861. [Erratum, Lancet 2006;368:1415, 1420.] [CrossRef][ISI][Medline]
Brown BG, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:1289-1298. [Abstract]
1.3 mm) in one or more of their carotid segments. As in many other trials studying carotid intima–media thickness, most of the data from our study represent overall thickening, the stage that precedes plaque formation. 
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