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Journal of Lipid Research, Vol. 47, 1339-1351, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
Thematic Review |
Department of Medicine, University of California-San Diego, La Jolla, CA
1 Based in part on the author's book in preparation, The Cholesterol Wars. 
Published, JLR Papers in Press, April 3, 2006.
2 To whom correspondence should be addressed. e-mail: dsteinberg{at}ucsd.edu
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ABSTRACT |
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Supplementary key words inhibition of cholesterol biosynthesis • triparanol • compactin • lovastatin
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INTRODUCTION |
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DECREASING PLASMA CHOLESTEROL LEVELS BY INHIBITING ENDOGENOUS CHOLESTEROL BIOSYNTHESIS |
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That was the gist of the proposal put forward in the early 1950s by Jean Cottet and his collaborators in France (6, 7) and by Steinberg, Fredrickson, and Avigan in the United States (8, 9). However, neither group came up with an effective compound. The drug introduced by Cottet and coworkers (
-phenylbutyric acid) did slow the rate of incorporation of radioactive acetate into cholesterol, but it did not actually decrease de novo production of cholesterol molecules. That is because the compound inhibited the activation of free acetate to acetyl CoA (10) but none of the later steps in cholesterol synthesis. Actually, the activation of acetate is not essential for endogenous cholesterol biosynthesis, a point often lost sight of. The degradation of all major foodstuffs (fatty acids, carbohydrates, and some amino acids) generates acetyl CoA, not free acetate. The acetyl CoA deriving from any of these pathways can then serve directly as the starting point for cholesterol synthesis (i.e., without being first degraded to free acetate). Therefore, inhibition of the conversion of acetate to acetyl CoA would not necessarily compromise net cholesterol production, and indeed it did not. The reported cholesterol-lowering effects of Cottet's compound in animals and humans could not be confirmed (11–13).
Steinberg, Fredrickson, and colleagues, following up on observations made by Tomkins, Sheppard, and Chaikoff at Berkeley (14), confirmed that a close chemical relative of cholesterol, 
-4-cholestenone, could inhibit cholesterol synthesis and went on to show that it reduced blood cholesterol levels (9, 15). However, feeding the compound caused the accumulation of cholestanol (16), which was itself proatherogenic, and toxic side effects of the compound precluded clinical use (15). These early efforts failed to solve the problem, but they did at least spark interest in the possibility that cholesterol synthesis might be a legitimate pharmacologic target.
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THE MER/29 (TRIPARANOL) SCANDAL: A SETBACK IN THE QUEST FOR DRUGS INHIBITING CHOLESTEROL BIOSYNTHESIS |
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Worst of all, in addition to being relatively ineffective, the drug had serious toxic side effects. It was quickly found that it caused lens cataracts and hair loss in rats and dogs. Rats on high doses actually became blind. Investigators working on the mechanism of action of the drug were well aware of these toxic effects and called them to the attention of the drug company. A group at Merck, Sharp and Dohme formally notified Merrell of these toxic effects several months before the drug was approved by the Food and Drug Administration (FDA) and invited a team from Merrell to visit their laboratories and see for themselves. The invitation was accepted, and three Merrell people visited in January 1961. During the discussions, the Merrell representatives denied having ever encountered cataracts in their own studies but indicated that they would "try to confirm the Merck experiments." It later emerged that Merrell toxicologists had in fact already observed eye damage and even blindness in some of their rats and dogs but failed to include that information in the material they submitted to the FDA. This omission would turn out to be a major factor in the 1963 federal grand jury criminal indictment brought against the company and some of its employees. The company pleaded nolo contendere, which protected them against the use of the grand jury findings in subsequent civil suits. Several hundred such suits were filed, and these were settled by Merrell at a cost of 
$50,000,000. Hard data are not available, but it would not be surprising if the company netted that much during the year they kept the drug on the market, even in the face of the increasing evidence that patients were developing serious eye problems and that the drug was not really decreasing the concentration of blood sterols very much. See R.A. Fine's excellent history of this scandal (21) for more information.
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IMPACT OF THE TRIPARANOL DEBACLE ON THE WAR AGAINST CHOLESTEROL |
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THE BIRTH OF THE STATINS: AKIRA ENDO |
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In 1971, Dr. Akira Endo, working at the Sankyo Co. in Tokyo, speculated that the broths in which fungi were being grown in the hunt for new and better penicillins just might also contain natural inhibitors of cholesterol synthesis. There was at the time no direct evidence to support that speculation, but Endo states that he hoped that some microorganisms might "produce such compounds as a weapon in the fight against other microbes that required sterols or other isoprenoids for growth" (23). Parenthetically, it should be noted that Endo's interest in cholesterol metabolism dated back at least to 1965, when he applied for a fellowship to work at Harvard with Konrad Bloch. Unfortunately, Bloch had no fellowship openings available at the time and Endo went instead to New York, where he spent 2 years as a Fellow at the Albert Einstein School of Medicine working in the laboratory of Dr. Bernard L. Horecker. On returning to Tokyo, Endo and his associate at Sankyo, Dr. Masao Kuroda, began to test fungal broths for their ability to inhibit cholesterol synthesis from labeled acetate in a cell-free system. The assay was straightforward, fast, and cheap. Endo and his colleagues began testing in 1971. Week after week, month after month, they patiently applied their assay to these broths, but the results were uniformly and depressingly negative. Two years and >6,000 tests later, they finally came up with a real winner. The culture broth from Penicillium citrinium contained a remarkably potent inhibitor of cholesterol synthesis (26, 27), which they isolated and designated ML-236B. They showed that it inhibited the incorporation of acetate but not that of mevalonate into cholesterol. They pointed out that the ML-236B molecule included a domain homologous to hydroxymethylglutarate and thus the presumptive site binding it to the reductase. ML-236B, for historical reasons discussed below, was referred to in the early years as "compactin," and the name stuck. We shall continue to refer to it that way in this review.
So now Sankyo had a specific inhibitor working at the HMG-CoA reductase step. The next question was whether it would work in vivo and whether it would be tolerated at effective dosages.
Endo's first tests were done in rats using just single doses, probably because the amounts of compound available were limited. It seemed at first to work, but when given in repeated doses over a longer period of time there was no consistent effect on blood cholesterol levels (28). It looked as if 2 years of work and >6,000 tests had led nowhere. Fortunately, Endo and associates did not give up at this point, as they might have. They went on to try their compound in dogs, and there the results were quite different; now they saw a very significant and consistent decrease of blood cholesterol levels (29). They also showed that the drug worked in rabbits, hens, and monkeys (30). In retrospect, the reason for the initial "failure" in rats is clear. The drug does actually inhibit cholesterol synthesis in vivo in the rat, just as effectively as it does in other species, even though there is a compensatory increase in the amount of reductase enzyme. However, rats have extremely low LDL levels. Most of their plasma cholesterol is in the HDL fraction. Consequently, even a significant percentage reduction of LDL might not show up as much of a reduction in total cholesterol level, which is what was measured in these early studies.
Endo's results did not draw a lot of attention initially. Partly, this apathetic reception may have reflected the reaction to the triparanol fiasco reviewed above. There was no great enthusiasm in the pharmaceutical industry for another inhibitor of cholesterol biosynthesis in the 1970s. In 1977, Endo presented a paper in Philadelphia at a symposium on Drugs Affecting Lipid Metabolism, a triennial meeting to which all of the major pharmaceutical companies sent representatives. Surprisingly, his presentation was poorly attended. However, the exciting possibilities of compactin were not lost on Michael S. Brown and Joseph L. Goldstein at the University of Texas Southwestern Medical School (24). Within a month of the publication of Endo's first report on compactin, they had written to Endo to ask for a sample to use in their ongoing studies of the regulation of cholesterol biosynthesis. Endo sent the samples, and they invited him to visit them in Dallas after the Philadelphia meeting. They compared notes on their experiments done independently in Tokyo and in Dallas, found them to be concordant, and published the results jointly in a 1978 paper in the Journal of Biological Chemistry (31). This was an important paper because it described for the first time the huge increase in the amounts of the reductase enzyme induced in cells by statin treatment. Because the statins are competitive inhibitors, the inhibition, which is powerful at the drug concentrations reached within the intact cells, is largely lost when the tissue is homogenized and the cytoplasm greatly diluted for measurement of enzyme activity. These studies were done using human fibroblasts, but the same phenomenon was later reported in hepatocytes. A few years later, the Goldstein/Brown laboratory showed that this huge overproduction of reductase protein, representing an attempt by the cell to overcome the statin inhibition, is accompanied by a huge buildup of endoplasmic reticulum, the organelle in which the reductase resides (32). As a result, the cells look "abnormal," but of course they are not cancer cells. As discussed below, in retrospect, this may be what led the pathologists at Sankyo at a later date to conclude, incorrectly, that high doses of compactin were possibly carcinogenic.
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THE EARLY CLINICAL TRIALS OF COMPACTIN |
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AN INSTRUCTIVE FOOTNOTE TO THE DISCOVERY OF THE STATINS |
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MERCK ENTERS THE RACE: ALFRED W. ALBERTS AND P. ROY VAGELOS |
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6,000 broths before making a hit! Alberts's lovastatin had a structure differing by only one methyl group from that of compactin, and it had very similar biological properties. Preliminary clinical studies were begun in 1980, and the early results looked very promising indeed. But the whole Merck program was suddenly shut down in the fall of 1980. The story behind that is an intriguing one, but we need to preface it by going back to Japan and the early work of Endo.
In 1979, Endo was offered an Associate Professorship at Tokyo Noko University and left Sankyo. He continued his pursuit of reductase inhibitors, and in August of the same year he reported the isolation from cultures of a different fungus (Monascus ruber) of another highly effective inhibitor of cholesterol synthesis, which he named monacolin K. Its chemical structure was very similar to that of compactin, differing only by the addition of a single carbon atom on one of the rings. He applied for a patent in Japan in February 1979.
Meanwhile, Merck was plowing ahead with its own screening program and, as mentioned above, very quickly hit its first promising inhibitor, a compound secreted by a fungus (Aspergillus terreus) quite distinct from the one Endo had used. Merck named its compound mevinolin (later changed to lovastatin) and applied for the U.S. patent in June 1979. The remarkable fact is that the structures of Endo's monacolin K and Alberts's lovastatin turned out to be absolutely identical: precisely the same compound produced by two different microbes and discovered independently in two different laboratories almost simultaneously. Endo and his university originally held the patent on monacolin K/lovastatin in Japan but later sold it to Sankyo. Merck held the patent on lovastatin in the United States but did not have worldwide rights. Sankyo was now already quite far along with its clinical studies on compactin, had published several papers on its use in humans, and was probably going to market it any day. Merck was putting every effort into its lovastatin program and had already carried out a few clinical studies. The groundwork was now laid for a knock-down, drag-out race to see who would be the first to successfully bring a statin to market. But then something strange happened.
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HOW WE ALMOST LOST THE STATINS |
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$400 million) thanks to an innovative drug discovery plan that Vagelos had initiated. That plan had brought several "blockbuster" drugs to the market over the preceding few years. Still, Vagelos knew that maintaining Merck's leadership role required that there be a continuing input of new products into the "pipeline." As Vagelos puts it, "[that's] why we were all watching Mevacor [lovastatin] so closely and that's why we were all so upbeat about our research program. We thought Mevacor had the potential to become a billion-dollar-a-year product" (37). The day's discussions went well and spirits were high.
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What had been a warm and comfortable, even self-congratulatory, company retreat suddenly became something of a wake. Lovastatin differed in structure from compactin by only one carbon atom. If compactin was carcinogenic, it was likely that lovastatin would be also. On the other hand, the carcinogenicity that had allegedly been encountered might be related not to the cholesterol-lowering effect per se but to an unrelated effect of the compactin molecule. Conceivably, the one extra carbon on lovastatin might abolish any carcinogenic potential. However, that was a long shot. Merck was already carrying out studies on the effects of lovastatin in dogs and had not encountered any intestinal cancers, but its studies were of fairly short duration. Longer exposures might confirm the Japanese findings. Merck had already invested millions of dollars on this project. Halting it would mean losing months or years in the race to get its statin drug on the market. Alberts, who had discovered lovastatin, was devoting his energies full time to this project. Jonathan Tobert was well along with safety and efficacy testing in the clinic. Vagelos knew that this might be a real blockbuster drug and that his teams would be devastated if the project was junked. What to do?
Vagelos did the right thing. He would not take any chance of exposing even one patient to a potential carcinogen, no matter what it might cost Merck and even if it meant losing the race to be the first to bring a statin to market. He immediately called a halt to all clinical studies and asked investigators to return outstanding samples; he notified the FDA; and he decided to make an all-out effort to get to the bottom of the cancer rumors. At this point, only a small number of patients had received lovastatin and only at low dosages, but still Merck advised its physicians to check carefully for any signs of cancer. None was found, either at that time or later, even after many years of testing in many thousands of patients all over the world. But in the fall of 1980 at Absecon, New Jersey, none of this was known and the mood was somber.
Merck had only rumors to go on, and those rumors were unconfirmed and lacking in detail. How common were these tumors in dogs? At what dosage did they occur? How did that dosage compare with the dosage needed to treat human hypercholesterolemia? Alberts and some of the other Merck investigators wanted to continue at least the animal toxicity studies. A second group favored dropping the whole project and instead making every effort to find a different statin that would be totally "clean" with respect to carcinogenicity.
Vagelos tried every way he could to get more information about the findings that prompted Sankyo to drop its clinical trials, including letters and phone calls to the company's executives asking them to share the results of their safety assessment tests. Sankyo was unwilling to comment. Vagelos did get second-hand confirmation through an American pharmaceutical company that was working with the Japanese that the rumors might be true. So he and Barry Cohen, who was in charge of Merck's international businesses, went to Japan and visited Sankyo themselves. Vagelos offered a business deal: " If you help us solve this problem, we'll share Mevacor [lovastatin] with you in Japan and you can share your second-generation product with us when you're ready." The head of Sankyo smiled and said he would like to cooperate but that there were "others" who objected. Vagelos returned empty-handed, puzzled, and angry.
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THE IMPLICATIONS OF DROPPING LOVASTATIN |
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This line of argument was urged on Vagelos by a number of clinicians who had used lovastatin in early safety and efficacy trials, including Roger Illingworth of Portland and Scott M. Grundy, David Bilheimer, Joseph L. Goldstein, and Michael S. Brown of Dallas. Two members of Vagelos' Scientific Advisory Board, Jean Wilson from Dallas and Daniel Steinberg from La Jolla, made the same case. In his memoir, Vagelos remembers that "we needed advice from the type of authorities in their field whom the FDA would consult." After these meetings, Merck presented all of its data to the FDA and got a green light for additional clinical trials in high-risk patients. Merck was on its way to putting the first statin drug into the hands of clinicians (the outstanding team at Merck that saw this project to completion included Drs. Georg Alber-Schonberg, Carl Hoffman, James MacDonald, Richard Monaghan, and Arthur Patchett and Ms. Julie Chen).
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WAS COMPACTIN INDEED CARCINOGENIC? |
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200 times the dosage that would be used in patients. Still, the toxicologists at Sankyo felt obliged to counsel against continuing the use of even the small dosages being used in patients. Like most Japanese pharmaceutical houses, Sankyo was strongly tilted toward conservatism in the 1960s, partly because of several serious instances of postmarketing toxicity, including the tragic experience with thalidomide. This conservatism tended to be shared generally by the medical profession in Japan at the time. One prominent Japanese clinician warned that "powerful drugs, like a sharp knife, should be considered dangerous." Another warned students not to prescribe drugs at full dosage, thereby running the risk of toxicity, but whenever possible to use half the normal dosage. Another factor may have been the somewhat parochial approach of the pharmaceutical companies in Japan at that time, an unwillingness to openly exchange information with and seek advice from those outside the company "family" (Akira Yamamoto, personal communication). In any case, Sankyo dropped compactin and continued to hunt for other fungal inhibitors. In retrospect, we can now say with absolute confidence that neither lovastatin nor any of the other statin drugs on the market is carcinogenic, either in experimental animals or in humans. Clinical trials in which tens of thousands of subjects have received either a placebo or a statin have shown no change at all in cancer incidence. In the early 1980s, however, the level of anxiety at both Sankyo and Merck was high, and we came close to losing these wonder drugs.
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THE MIRACULOUS POWER OF THE STATINS TO PREVENT HEART ATTACKS AND SAVE LIVES |
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First, because the statins decreased blood cholesterol so much more than any of the existing diet or drug treatments, it suddenly became much easier to demonstrate the decrease in coronary heart disease events and to do so in a statistically significant, unarguable way. For example, in the groundbreaking 1984 NIH Coronary Primary Prevention Trial, using the drug cholestyramine (39, 40), total blood cholesterol in the treated group decreased by only 10% and LDL cholesterol by 20%. This was enough to reduce the heart attack rate, but only by 20%. The result barely reached statistical significance. By contrast, in one of the first large-scale statin trials, total cholesterol was reduced by 25%, LDL cholesterol by 35%, and coronary heart disease deaths by 42%. This reduction was highly significant (P < 0.00001). This trial, the so-called 4S study (for Scandinavian Simvastatin Survival Study) in Scandinavia (41), was done using simvastatin, the second Merck statin, which was discovered while the company was assessing the safety of lovastatin. The 4S study showed, for the first time in any cholesterol-lowering trial, a significant decrease in all-cause mortality. A new era in the treatment of hypercholesterolemia and coronary heart disease had arrived.
A recent meta-analysis of 14 statin trials with an astonishing total of 90,056 individuals randomized (using lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin) showed that the decrease in coronary events was best predicted by the absolute decrease in LDL levels. The incidence of major vascular events was reduced by 20% for each 1 mm/l (40 mg/dl) decrease in LDL cholesterol (42). Thus, an individual starting with an LDL of 280 mg/dl whose level decreased to 200 mg/dl on therapy (a 29% decrease) would be predicted to have a 40% decrease in risk over a 5 year period.
Second, the large-scale statin studies laid to rest the lingering concerns that decreasing blood cholesterol levels might be intrinsically dangerous. This concern arose originally because in the European clofibrate trials there were indeed more deaths in the drug-treated group than in the controls, although the difference was marginal (43). In retrospect, this difference was probably attributable not to the decreased cholesterol level per se but to a toxic effect intrinsic to the clofibrate molecule and unrelated to its cholesterol-lowering activity. The second-generation fibric acids (e.g., gemfibrozil and fenofibrate) have not shared the toxicity of clofibrate (44, 45). Concerns that decreasing blood cholesterol levels might be intrinsically dangerous were misplaced a priori 1) because levels of intracellular cholesterol are jealously guarded by the LDL receptor homeostatic mechanism (46), and 2) because most animal species have LDL levels well below those reached during even the most aggressive treatment of hypercholesterolemia (47). Obviously, these animals' cells do just fine. Nevertheless, this had been a concern and deterred some physicians from treating hypercholesterolemia vigorously. The large-scale statin trials showed that even decreasing LDL levels to <100 mg/dl was not only safe but actually decreased overall mortality significantly (41, 42, 48–52).
Third, there had been concern that although treating hypercholesterolemia might reduce coronary heart disease risk, it might at the same time lead somehow to increases in mortality from other causes, not necessarily because of the decreased cholesterol levels per se but possibly from metabolic dysfunctions arising from other properties of the cholesterol-lowering agents. Indeed, in the Coronary Primary Prevention Trial, there had been a statistically significant decrease in coronary heart disease mortality and yet no decrease in all-cause mortality. Of course, as was pointed out at the time, the study was not designed to have the power to show a decrease in all-cause mortality; that would have required a larger number of subjects (39, 40). Nevertheless, much was made of a small, statistically nonsignificant increase in the category of "violent deaths," which included suicides, homicides, and traumatic deaths (e.g., automobile accidents). (How homicides could be made more likely by the victim's cholestyramine intake was never made clear.) In any case, as first shown in the 4S trial using simvastatin (41) and borne out in the meta-analysis of >90,000 subjects in 14 statin trials (42), statins decreased all-cause mortality.
One cause for concern about the safety of decreased cholesterol came from prospective epidemiologic studies. These showed that individuals with low blood cholesterol levels when initially surveyed (e.g., <160 mg/dl) were more likely to die during the next 5 years than those with average cholesterol levels. In retrospect, this was probably attributable to the fact that a number of potentially life-threatening diseases are characterized by low blood cholesterol levels in the early, preclinical stages. This is true, for example, in many forms of cancer and in cirrhosis of the liver. In other words, the poor prognosis in the group with initially low cholesterol levels might be accounted for by the fact that some fraction of them entered the study already ill. The NIH in 1990 convened a panel of experts to discuss the possibility that decreasing cholesterol levels might be intrinsically dangerous. The panel concluded that the evidence did not justify such a finding, but with the data available at that time neither could it be ruled out absolutely (53). The large-scale statin studies settled the issue. It is now clear that the marginal effects on all-cause mortality seen in the early trials were attributable in part to the small sizes of the populations studied and in part to the modest decreases of cholesterol levels.
Fourth, the large-scale statin studies made it clear for the first time that statin treatment benefits 1) women as well as men, 2) the old as well as the young, 3) those with low initial LDL levels as well as those with high initial levels, and 4) diabetics as well as nondiabetics. None of the earlier studies had been large enough to make these benefits evident.
Women
Women before the menopause have a much lower risk of coronary heart disease than men of the same age. However, after menopause, their risk increases, and over a life span coronary heart disease takes just as great a toll in women as in men. Nevertheless, there had been a tendency for physicians to regard women as "immune" and to undertreat their hypercholesterolemia. The statin studies have clearly shown that women benefit just as much from treatment as do men.
The elderly
Until recently, physicians were somewhat reluctant to treat hypercholesterolemia in elderly patients. "Why bother them with yet another pill when they don't have much longer to live?" Only with the statin studies completed in the past few years has it become apparent that even patients older than 75 years benefit from treatment, in relative terms, as much as younger people. Because the chances of heart attack are much greater in the elderly, the absolute number of heart attacks prevented by treating 70 year old men is even greater than that prevented by treating men a decade or two younger.
In these days when life expectancy has increased to 75 years in men and 80 years in women, the number of good years of life conferred by treatment is large and the treatment is eminently worthwhile.
Patients with near-normal LDL levels
The question of "how high is high" is a complicated one (54). The 2001 Adult Treatment Panel III guidelines for physicians advised intensive treatment of very high-risk patients (e.g., those with established coronary heart disease or with high risk as a result of diabetes), treatment designed to decrease their LDL to 100 mg/dl (55). Some earlier studies had suggested that there was no significant reduction in risk for patients with an initial LDL level of 125 mg/dl or less (51). However, in the British Heart Protection Study, using simvastatin, subjects with initial LDL levels of <100 mg/dl, the "goal" by then current standards, showed a significant further reduction of LDL levels and a further significant reduction of coronary heart disease risk with statin treatment (48). Some epidemiologic studies, particularly studies in Chinese populations, had previously shown that coronary heart disease risk decreased with cholesterol levels even when the total cholesterol levels were in the 120–160 mg/dl range (i.e., LDL levels of 60–100) (56). However, the Heart Protection Study was the first to demonstrate directly that decreasing LDL levels even below the 100 mg/dl level, previously considered to be ideal, does indeed confer additional benefit. The percentage reduction in risk was approximately the same as that in subjects with higher initial LDL levels. Very recently, using high doses of statins, it was shown that decreasing LDL to a mean of 79 mg/dl arrested progression (measured by intravascular ultrasound), whereas decreasing it only to a mean of 110 mg/dl still allowed further progression (57).
Overviews of the statin trials (42, 52) show clearly that the lower the plasma LDL on treatment, the lower the incidence of major end points (Fig. 4 ). Almost certainly, these findings will result soon in a further reduction in the "goal LDL levels" recommended by the National Cholesterol Education Program.
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WHAT CAN WE EXPECT IN THE FUTURE WITH THE STATINS? |
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1) First, except for some very recent studies, the dose of statins used in clinical trials has been less than the maximum and less than optimal. Nor were adjuvant antilipid therapies included in an effort to obtain the maximal LDL decrease. Even this less than ideal intervention has reduced event rates dramatically. For primary prevention (Fig. 4), the prediction from extrapolation is that with an on-treatment LDL level of 57 mg/dl, there might have been no events (52). We recognize that extrapolations like this are not really justified, and we have tongue firmly in cheek. Still, the data suggest that we may not yet have reached the limit of what can be achieved just by decreasing LDL. With simultaneous attention to other causative factors, the impact should be even greater.
2) Second, these studies have for the most part lasted for only 5 years. Percentage reduction in event rate might be significantly greater after 10 or 15 years of treatment.
3) Third, almost all of the trials to date have been done in subjects with an average age of 50–60 years. We know that the arteries of these subjects harbor well-developed lesions even if they have no clinical manifestations of atherosclerosis. What, then, if intervention was started at age 40 or even 30, when the lesions are fewer and smaller? By how much would such early intervention further reduce the event rates? In individuals at unusually high risk, treatment should be started even earlier, even in childhood. A randomized, double-blind study of children ages 8–18 years has demonstrated a significant slowing of intimal thickness in the carotid artery and no adverse effects on growth, hormone levels, sexual maturation, or liver function (59). In short, the impact of the statins may ultimately exceed considerably that demonstrated in the clinical trials to date. However, if we hope to reach our goal of zero tolerance for myocardial infarction, we are probably going to have to start treatment earlier and also combine LDL-lowering with equally vigorous attention to the other treatable risk factors. New modes of intervention under intensive current study include 1) increasing HDL or otherwise favoring reverse cholesterol transport (60), 2) inhibiting cholesterol absorption from the intestine (61, 62), and 3) attacking the inflammatory and immune processes contributing to the arterial lesion (63–65).
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WHY DID THE CHOLESTEROL CONTROVERSY LAST SO LONG? |
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 TOPABSTRACTINTRODUCTIONDECREASING PLASMA CHOLESTEROL...THE MER/29 (TRIPARANOL) SCANDAL:...IMPACT OF THE TRIPARANOL... |
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ABSTRACT
INTRODUCTION
