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Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia

2008; Lippincott Williams & Wilkins; Volume: 118; Issue: 6 Linguagem: Inglês

10.1161/circulationaha.107.753152

1524-4539

Daniel Steinberg, Christopher K. Glass, Joseph L. Witztum,

Health Systems, Economic Evaluations, Quality of Life

HomeCirculationVol. 118, No. 6Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBEvidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia Daniel Steinberg, Christopher K. Glass and Joseph L. Witztum Daniel SteinbergDaniel Steinberg From the Department of Medicine, University of California San Diego, La Jolla. , Christopher K. GlassChristopher K. Glass From the Department of Medicine, University of California San Diego, La Jolla. and Joseph L. WitztumJoseph L. Witztum From the Department of Medicine, University of California San Diego, La Jolla. Originally published5 Aug 2008https://doi.org/10.1161/CIRCULATIONAHA.107.753152Circulation. 2008;118:672–677The long-standing controversy over the validity of the lipid hypothesis of atherosclerosis has been settled.1–3 In several large-scale, 5-year trials, statins have reduced coronary heart disease (CHD) morbidity and mortality by ≈30%, and the magnitude of the protective effect mirrored the magnitude of the low-density lipoprotein (LDL) lowering.4 However, as has been quite correctly pointed out,5,6 some 70% of those expected to have an event (based on the number of events in the control group) went on to have one during the 5 years of the trial despite statin therapy. For example, in the Scandinavian Simvastatin Survival Study, 502 events occurred in the untreated group and 353 in the statin-treated group. The number of events prevented (n=149), as a percentage of the number expected, was 29.7% (149/502×100); the number of events in the statin group that were not prevented (353) amounts to 70.3% (353/502×100). Looked at this way, the results are admittedly not quite so impressive. In fact, some investigators are now taking the position that we can expect to achieve higher salvage rates only if we supplement LDL-lowering therapies with alternative interventions such as the use of antiinflammatory agents or immunotherapy. This may turn out to be true. However, it is much too early to reach that conclusion for reasons we discuss here. The search for alternative or supplementary therapies is already in full swing and should continue.6–8 We are confident that one day these additional therapies will take their place alongside cholesterol-lowering agents in our armamentarium. However, we believe that the results of the statin trials to date considerably underestimate the full potential of cholesterol-lowering strategies. It would be unfortunate if efforts to fully exploit that potential faltered because of a misplaced pessimism based on the statin results to date. Our current approaches may be a case of "too little, too late."5,9–14 How much further can we expect to decrease risk by treating dyslipidemia (ie, lowering LDL levels and/or raising high-density lipoprotein levels)?Why Do We Think We Can Do Better?One important line of evidence comes from a consideration of the Japanese experience. In 1952, mortality from CHD among Japanese men 55 to 64 years of age was <10% of what it was in the United States.15,16 Their total cholesterol levels at the time averaged ≈160 mg/dL (estimated LDL, ≈80 mg/dL). It is noteworthy that the Japanese enjoyed this relative immunity to CHD despite the fact that the prevalence of one of the major risk factors—cigarette smoking—was much higher in Japan than in Western countries,17 and another—-hypertension—was just as high.18 Even the diabetic population in Japan fares better than the diabetic population in Western countries. In 1985, almost 30% of British male diabetics but only ≈15% of the Japanese male diabetics had CHD.19 The implication is that if blood cholesterol levels are sufficiently low, the other dominant risk factors, including cigarette smoking, hypertension, and diabetes mellitus, constitute much less of a threat.Are these large differences in incidence between Japan and Western countries based primarily on genetic factors? No. Two cleverly designed epidemiological studies showed that the Japanese who had migrated and taken up permanent residence in Hawaii had higher blood cholesterol levels and a higher incidence of CHD than those who remained on the home island. For those who migrated even further, on to California, the differences were even more striking.20,21 This and other migration studies22 showed that the differences in CHD risk among different populations are certainly not entirely genetic. Which environmental factors are at play? A number of factors could be involved, but there is reason to believe that the major factors are changes in diet and exercise patterns that predispose to elevated blood cholesterol and obesity. Keys23 reported as early as 1957 that the fat content of the diet, as a percentage of total calories, rose from 10% to 15% in Japanese on the home island to ≈30% in Japanese migrants to Hawaii and to almost 40% in migrants to Los Angeles.A crucially important point needs to be noted here: For whatever reasons, the Japanese have their lower cholesterol levels for their entire lifetimes. Lowering the cholesterol level of a 50-year-old American for just 5 years, even if his cholesterol is successfully brought down to a Japanese-like level, is unlikely to convert his risk to a Japanese-like risk. At 50 years of age, he most likely enters the study with well-established, extensive arterial disease.24,25 It would be unreasonable to expect that all that damage could be reversed in just 5 years. The canonical 5-year trials have given us a minimum estimate of the impact of preventive management. Only after longer trials with younger subjects will we have some estimate of the maximum potential. We will return later to this key issue, the need for earlier treatment.How Much More Aggressive Should Treatment Be?In the 1940s, many clinical laboratories defined a total cholesterol level of 280 mg/dL as the upper limit of normal. That number has come tumbling down over the decades as epidemiological and clinical trial experience has accumulated. Currently, for individuals at high risk, the widely accepted rule is becoming "the lower, the better."4,11,26–31 The National Institutes of Health (NIH) now recognizes that an LDL of ≤70 mg/dL confers more benefit than the canonical 100 mg/dL originally recommended in the Adult Treatment Panel III 2001 guidelines.32,33 Careful analysis of the statin data makes it clear that further benefit is conferred when LDL is reduced even to 40 to 60 mg/dL.29 Although limited, data are available suggesting that patients with initial LDL levels <40 mg/dL show lower all-cause mortality after 2 years of statin therapy.34With combination therapy, it is now possible to reach these low LDL goals; they are not unrealistic.35 Yet, most patients outside specialty clinics are not reaching those goals, in part because of poor compliance but also in part because practitioners are still hesitant to be more aggressive. There continue to be concerns about safety and side effects despite the wealth of evidence that they are not serious problems in the vast majority of patients.36Do Adverse Effects Accompany Cholesterol Lowering?Is lowering LDL levels intrinsically dangerous? That possibility has been suggested in the past, but no hard evidence exists for such a concern, and a number of considerations make such an effect quite improbable.First, levels of intracellular cholesterol are jealously guarded by the wonderfully efficient LDL receptor homeostatic mechanism elucidated by Brown and Goldstein.37 Consequently, lowering plasma cholesterol levels does not decrease intracellular cholesterol levels. The LDL receptor has a very high affinity for its ligand, so much so that even at plasma LDL cholesterol concentrations of 10 mg/dL, the LDL receptors in peripheral tissues would still be 50% saturated and uptake would continue unabated.Second, we know that most mammalian species have LDL levels well below those reached in humans during even the most aggressive treatment of hypercholesterolemia (mean value, 42 mg/dL).38 Obviously, these animals' cells do just fine. In addition, cord-blood LDL levels in humans are <20% of adult levels,39 showing that growth and development of the fetus are just fine at LDL cholesterol levels <40 mg/dL.Third, in some kindreds with hypobetalipoproteinemia, LDL cholesterol levels can be 40%.Of course, children with familial hypercholesterolemia should be started very early in life on statins, and other agents if necessary, to lower their LDL to 50 mg/dL. Adults with existing CHD or multiple risk factors also should strive to lower their LDL to 50 mg/dL. In fact, on the basis of the accumulated evidence reviewed above, it would be reasonable to recommend that an "ideal" LDL cholesterol level should be defined as ≤50 mg/dL. That goal is currently attainable in many patients with the treatment regimens now available, which include statins alone or in combination with other hypolipidemic drugs, including bile acid sequestrants, niacin, fibrates, and ezetimibe. In the future, new agents should become available to help reach these lowered goals in almost everyone.The Ultimate Long-Term SolutionIf indeed the low pre-Westernization CHD rate in Japan was, as discussed above, due primarily to lifestyle differences (diet and exercise), then our long-term goal should be to alter our lifestyle accordingly, beginning in infancy or early childhood. Is such a radical proposal totally impractical? It would, of course, take generations to achieve and would require an all-out commitment of money and manpower to reeducate and modify the behavior of the nation. Is that impossible? No. We have already shown that even a frankly addictive behavior like cigarette smoking can be overcome (eventually) with the right combination of education, peer pressure, and legislation. Would it be safe? Data are now available to show that instituting a low-saturated-fat, low-cholesterol diet in infancy (7 months) is perfectly safe without adverse effects on growth, development, and sexual maturation.71,72The importance of early intervention is becoming apparent in another common chronic disease entity, type 2 diabetes mellitus. Early treatment has been shown to prevent progression of prediabetes to frank clinical diabetes.73–75 Interestingly, intensive intervention on lifestyle factors (ie, diet and exercise) was just as effective as or more effective than intervention with drugs (metformin). It is now considered best practice to anticipate the conversion of prediabetes (impaired glucose tolerance) to frank diabetes mellitus and to forestall that conversion by early intervention. In much the same way, it should become best practice to anticipate the conversion of the fatty streak to the fibrous plaque by treating hypercholesterolemia at a much earlier age.The NIH has already committed itself to "wars" on obesity and diabetes mellitus. The weapons for those wars—education and behavior modification—are the same as those needed for a war on CHD. The overlaps are obvious. A concerted national public health program might dramatically reduce morbidity and mortality resulting from these 3 major chronic diseases.SummaryWith the advent of the statins, enormous progress has been made in the management of hypercholesterolemia. However, some authorities point out, quite correctly, that statin treatment reduces event rates by "only" ≈30% and suggest that preventing the other 70% will require more than just control of hypercholesterolemia (eg, adjunctive use of antiinflammatory or immunologic interventions). This may discourage clinicians from pressing on to do the best that can be done with the interventional tools already at hand. This review has summarized the evidence, drawn from a variety of sources, that the results of the 5-year statin trials seriously underestimate the ultimate potential of cholesterol-lowering therapy. We suggest that this evidence mandates continuing and more aggressive use of lipid-lowering regimens and, even more important, intervention at an earlier stage in the development of the atherosclerotic lesion.DisclosuresDrs Witztum and Glass are on the Merck Speakers' Bureau. Dr Witztum is a consultant to AtheroGenics Inc. Dr Steinberg reports no conflicts.FootnotesCorrespondence to Dr Daniel Steinberg, Department of Medicine, BSB 1080, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093–0682. E-mail [email protected] References 1 Steinberg D. The cholesterol controversy is over: why did it take so long? Circulation. 1989; 80: 1070–1078.CrossrefMedlineGoogle Scholar2 Grundy SM. United States Cholesterol Guidelines 2001: expanded scope of intensive low-density lipoprotein-lowering therapy. Am J Cardiol. 2001; 88: 23J–27J.MedlineGoogle Scholar3 Steinberg D. The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. New York NY: Academic Press/Elsevier, Inc; 2007.Google Scholar4 Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. 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