the prevalence of obesity and diabetes.6 This increase has been so
Anthony Colpo
large that some predict the steady rise in life expectancy enjoyed by
Americans during the last century may soon come to an end.7
Critical Importance of Cholesterol
The belief that low-density lipoprotein (LDL) cholesterol causes atherosclerosis and subsequent heart disease is a fundamental Cholesterol, contrary to its popular image as a potent enemy of precept of modern medicine. Therapies aimed at reducing serum health and longevity, is actually a crucial substance that performs LDL cholesterol are currently considered to be an essential element innumerable vital functions in the body. Cholesterol is needed for of any attempt to prevent coronary heart disease (CHD).
the synthesis of bile acids, which are essential for the absorption of While it currently enjoys widespread acceptance among health fats, and of many hormones such as testosterone, estrogen, authorities and medical practitioners, numerous lines of evidence dihydroepiandrosterone, progesterone, and cortisol.8 Together with
raise questions about the LDL hypothesis. Native LDL cholesterol is sun exposure, cholesterol is required to produce vitamin D.9
a vitally important substance and is not in any way atherogenic.
Cholesterol is an essential element of cell membranes, where it Statin drugs, the only LDL-lowering agents shown to have clinical provides structural support and may even serve as a protective benefit in reducing the incidence of heart disease, have been antioxidant.10,11 It is essential for conducting nervous impulses,
shown to exert their benefits via mechanisms totally unrelated to especially at the level of the synapse.12
A potential causative role in atherosclerosis and heart disease The False Dichotomy of “Good” vs “Bad” Cholesterol
has indeed been detected for oxidized LDL, but this form of LDLshows no correlation with serum levels of native LDL. Rather, Because cholesterol is water-insoluble, it must be transported individual antioxidant status appears to be a key factor influencing inside lipoproteins. Various types of lipoproteins exist, but the two serum concentrations of oxidized LDL.
most abundant are low-density lipoprotein (LDL) and high-densitylipoprotein (HDL). The main function of LDL is to transport Background
cholesterol from the liver to tissues that incorporate it into cellmembranes. HDL carries “old” cholesterol that has been discarded For the last four decades, the mainstream medical establishment by cells back to the liver for recycling or excretion.
has maintained that elevated serum cholesterol levels are a primary Recognizing that cholesterol serves a number of important instigator of atherosclerosis and coronary heart disease (CHD).
functions, purveyors of the cholesterol hypothesis have modified Millions of people worldwide have been convinced by extensive their theory to incorporate the “good cholesterol, bad cholesterol” promotional campaigns that that the key to avoiding CHD is to paradigm, in which LDL cholesterol forms “fatty deposits” in reduce cholesterol levels by using lipid-lowering drugs and diets arterial walls, which become plaques that grow, rupture, and low in saturated fats. This campaign has produced billions in profits stimulate the formation of artery-blocking blood clots. HDL for drug companies and the manufacturers of low-fat food products.
cholesterol, on the other hand, is the “heart-friendly” lipoprotein The world’s current top-selling pharmaceutical, for example, is that counters the action of LDL by removing cholesterol from the Pfizer’s cholesterol-lowering drug atorvastatin (Lipitor), which arteries and transporting it back to the liver for safe disposal. This amassed $10.9 billion in sales in a single year, 2004.1
paradigm is overly simplistic and not supported by the evidence.
While the war on cholesterol has proved to be extremely If LDL cholesterol “causes” atherosclerosis, logic dictates that lucrative for the food and drug industries, it has delivered no benefit there should be a strong correlation between blood levels of LDL to public health. CHD is still the leading cause of death in Western cholesterol and atherosclerosis. Proponents of the LDL hypothesis countries. While the number of deaths from CHD has indeed have repeatedly maintained that this is true. However, a review of decreased since the late 1960s, total incidence of CHD has not the available evidence suggests otherwise.
declined.2-5 If cholesterol reduction were effective in preventing
CHD, then it would surely lower both fatal and nonfatal CHD. This
The Composition of Atherosclerotic Plaques
has not happened. Modern medicine has made significant advancesin extending the lives of those who have already had heart attacks, Despite popular perception, atherosclerotic plaques are not but it has failed to help people avoid CHD in the first place.
simply big wads of fat and cholesterol that have stuck to the walls of In addition, the relentless drive to steer people to low-fat, high- arteries like mud inside a pipe. The growth of atherosclerotic plaques carbohydrate diets has been accompanied by a marked increase in takes place primarily inside the artery wall, between the inner and Journal of American Physicians and Surgeons
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outer layers.13 The plaques are complex entities with numerous
In Japanese patients undergoing surgery to remove plaque from components, including smooth muscle cells, calcium, connective their carotid arteries, blood levels of oxidized LDL were tissue, white blood cells, cholesterol, and fatty acids. Proliferation of significantly higher than those measured in healthy controls.
plaques may occur, not because of simple elevations in blood Advanced carotid plaques removed from these patients showed far cholesterol, but because of unfavorable physiological conditions that higher levels of oxidized LDL than neighboring sections of artery damage or weaken the structure of the arterial wall. These factors that were disease-free. Elevated oxidized LDL was also associated include nutrient deficiencies,14 poor glycemic control,15 cigarette
with an increased susceptibility of plaque rupture. However, there smoking,16 homocysteine,17 psychological stress,18 nitric oxide
was no association between oxidized LDL concentrations and total depletion,19 high iron levels,20 microbial infection,21,22 dietary trans
fatty acids,23 excessive refined carbohydrate intake,24 and excessive
Von Shacky and coworkers, in a 2-year double-blind trial in omega-6 fatty acid intake and/or deficient omega-3 fat intake.25 All
patients with CHD, found that daily fish-oil supplementation of these factors have been shown to exert an atherogenic effect increased the incidence of atherosclerotic regression, and unrelated to serum cholesterol elevation.
decreased the loss in minimal luminal diameter, as assessed by Damage to the arterial wall triggers an inflammatory state in quantitative coronary angiography. Fish-oil recipients also which the body recognizes injury and sets about to repair it.13 This
experienced fewer cardiovascular events. LDL cholesterol levels response-to-injury scenario is well accepted by the vast majority of tended to be greater in the fish-oil group.
cardiovascular researchers, although many of them continue to The lack of importance of total LDL levels was further promote the hypothesis that LDL cholesterol is involved in underscored by two recent trials that examined the impact of LDL- triggering or aggravating the inflammatory state that eventually lowering therapy on calcified coronary plaque progression. In the leads to heart disease or stroke. There is little evidence to support first of these studies, patients given aggressive LDL cholesterol- such a contention. In fact, cholesterol, like other components, may lowering treatment (statins plus niaicin) were compared with those be present in atherosclerotic plaque as part of the repair mechanism.
receiving less aggressive treatment (statins alone). Despite greaterLDL reductions in the former group, there were no differences in LDL and Oxidized LDL
calcified plaque progression as detected by electron beamtomography. The authors concluded: “… with respect to LDL It is imperative to distinguish between “standard” and cholesterol lowering, ‘lower is better’ is not supported by changes “modified” LDL cholesterol. The former is the type of LDL that the in calcified plaque progression.”36
body produces daily in normal metabolic function. The latter has In the Scottish Aortic Stenosis and Lipid Lowering Trial, undergone some sort of deleterious alteration; the most widely patients with calcific aortic stenosis were randomly assigned to studied example is “oxidized” LDL.
receive either 80 mg of atorvastatin daily or placebo. After 25 During the 1980s, some researchers began to recognize that months, serum LDL concentrations remained at an average 130 LDL itself was not a reliable independent risk factor for CHD; half mg/dL in the placebo group but fell significantly to 63 mg mg/dL in of those who suffer CHD have LDL levels within normal limits.
the atorvastatin group. Despite the fact that LDL levels were Among the 28,000-plus participants of the Women’s Health Study, reduced by more than half in the atorvastatin subjects, there was no for example, 46% of first cardiovascular events occurred in women difference in aortic-jet velocity or progression in aortic-valve with LDL cholesterol levels less than 130 mg/dL—the “desirable” calcification between the treatment or placebo groups.37
target for primary prevention set by the National Cholesterol
Education Program (NCEP).26
Plaque Rupture
Research in both animals and humans has shown that oxidized LDL is a better predictor of atherosclerosis and cardiovascular It is well-established that plaque rupture is a major trigger of disease than regular LDL cholesterol. Whether or not oxidized LDL acute coronary events.38 Analysis of the lipid portion of
is a direct contributor to the atherogenic process cannot be atherosclerotic plaques shows they contain a disproportionately determined with any certainty based upon the available evidence.
high concentration of the omega-6 fatty acid linoleic acid, and that The stronger association between oxidized LDL and cardi- plaque content of linoleic acid correlates with dietary intake.39,40
ovascular disease suggests, however, that a person’s antioxidant Higher plaque concentrations of linoleic acid are also associated status is a far more important determinant than LDL levels of the with an increased likelihood of plaque rupture.41 The major sources
risk of developing advanced plaques.
of linoleic acid in Western diets are “heart-healthy” In animal studies, administration of antioxidant drugs like polyunsaturated vegetable oils that have been heavily promoted probucol impairs LDL oxidation and arterial plaque formation, because of their clinically demonstrated ability to lower total and even when there is no change in blood cholesterol levels.27-31 In fact,
LDL cholesterol levels.42
administration of the antioxidant butylated hydroxytoluene (BHT)significantly reduces the degree of atherosclerosis in the aorta of Serum LDL vs Antioxidant and Fatty Acid Status
rabbits, even though it raises LDL cholesterol levels.30
A similar phenomenon is observed in humans. Among elderly In 1997 Swedish researchers published a comparison of CHD Belgians, higher levels of oxidized LDL were accompanied by a risk factors among men from Vilnius in Lithuania and Linkoping in significantly increased risk of heart attack, regardless of total Sweden. These two groups were selected because the former had a LDL levels.32,33
four-fold higher death rate from CHD than the latter. Very little Journal of American Physicians and Surgeons
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difference in traditional risk factors existed between the two group of patients; namely, middle-aged males with existing CHD.
groups, except that the men from CHD-prone Vilnius had lower Statins may also lower mortality in diabetic patients.47
Trials with men free of heart disease have not shown any According to common wisdom, the lower total and LDL consistent and significant mortality-lowering benefit from the use cholesterol of the Lithuanian men should have placed them at of statin drugs.48-52 In women of any age, statins have not been
reduced risk of heart disease. When the researchers probed further, shown to exert any reduction in cardiovascular or all-cause they discovered that the men from Vilnius had significantly higher mortality whatsoever when used for primary prevention, and no concentrations of oxidized LDL.43 They also displayed
reduction in all-cause mortality when used for secondary significantly poorer blood levels of important diet-derived prevention. The only study to date focusing on elderly subjects, antioxidants such as beta carotene, lycopene, and gamma the PROSPER trial, did find a reduction in cardiovascular deaths, tocopherol (a form of vitamin E).44 Blood levels of these particular
but this was negated by a similar increase in cancer mortality.
nutrients are largely determined by dietary intake, especially from Rarely mentioned are two studies showing that lovastatin was the consumption of antioxidant-rich fruits, nuts, and vegetables. So associated with increased all-cause mortality in healthy while the Lithuanian men had lower LDL levels, they were more hypercholesterolemic males and females.
prone to the formation of oxidized LDL owing to what appeared to In those trials showing decreased mortality with statins, the be a poorer intake of antioxidant-rich foods.
reduction in death rates are no greater than, and often inferior to, that This may well have explained their greater susceptibility to seen with other less toxic interventions, such as omega-3 fatty acid 45, 46, 55, 56
cardiovascular disease; in tightly controlled clinical trials, supplementation, fruit-and-vegetable-rich diets, and exercise.
discussed below, individuals randomized to increase their intake of Secondly, the claim that LDL reduction is responsible for any fruits and vegetables have experienced significant reductions in statin-induced reduction in cardiovascular events or mortality rates cardiovascular and all-cause mortality.
LDLTheory on Trial
Effects of Statins
No tightly controlled clinical trial has ever conclusively Statin drugs exert their lipid-lowering effect by blocking 3-hyd- demonstrated that LDL cholesterol reductions can prevent roxy-3-methylglutaryl (HMG) coenzyme A reductase, an enzymein the liver that is involved in the early stages of cholesterol cardiovascular disease or increase longevity.
synthesis. Statins inhibit the synthesis not only of cholesterol, but of In the large GISSI-Prevenzione trial in Italy, the mortality many important intermediate metabolites, including, but not benefits of omega-3-rich fish oil appeared early on in the limited to, mevalonate pyrophosphate, isopentanyl pyrophosphate, study—as did an increase in LDL cholesterol levels. Mean LDL geranyl-geranyl pyrophosphate, and farnesyl pyrophosphate.
levels in the subjects given fish oil rose from 136 mg/dL at base- Inhibition of these compounds means that statins exert a plethora of line to 150 mg/dL after 6 months, before gradually returning to effects unrelated to cholesterol lowering. In vitro, animal and initial levels at 42 months. A similar pattern was observed in the human studies show that these pleiotropic actions possess control group. This extended period of elevated LDL levels did not beneficial cardiovascular effects that occur independently of prevent the fish-oil patients from experiencing significantly more cholesterol reduction.57,58 Some of these cholesterol-independent
favorable cardiovascular and mortality outcomes.45
In the Lyon Diet Heart Study, an experimental group advised to Impairment or reversal of atherosclerotic plaque formation:
increase consumption of root vegetables, green vegetables, fish, Statins reverse or impede the progression of atherosclerosis in fruit, and omega-3 fatty acids also experienced greatly improved rabbits, without any accompanying change in serum cholesterol.59,60
cardiovascular and survival outcomes. The study was originally Improvements in arterial function: In elderly diabetic patients,
intended to follow the patients for 4 years, but death rates diverged cerivastatin increased dilation of the brachial artery (improved so dramatically early on that researchers decided it would be blood flow) after only three days, before any change in cholesterol unethical to continue, and called an end to the trial. After an average levels had occurred.61 In healthy young males with normal
follow-up of 27 months, the all-cause death rate of the control cholesterol levels, improved endothelial function was observed group was more than twice that of the experimental group.
within 24 hours of treatment with atorvastatin; again, this One little-publicized finding from this well-known trial was improvement preceded any drop in serum cholesterol levels.62
that the total and LDL cholesterol levels of the treatment and Longer-term improvements in arterial function: In human
control groups were virtually identical throughout the study. Those volunteers with slightly elevated cholesterol, researchers found in the treatment group, however, did show significantly higher that 4 weeks of simvastatin therapy significantly enhanced forearm blood levels of omega-3 fatty acids and antioxidants.46
blood flow. The improvement increased with continuedadministration of simvastatin despite no further reduction in serum Statins and Mortality
cholesterol, and there was no relation between the decrease in
cholesterol and improvement in endothelial function.63
According to medical “opinion leaders,” recent trials with statin Anti-clotting effects: Statins have been shown to reduce
drugs have proven that LDL reduction is beneficial. Allegedly, these platelet production of thromboxane, an eicosanoid that encourages trials have also shown that the greater the LDL reductions, the better.
blood clotting. This effect was not seen with older drugs that First, it must be emphasized that statin drugs have only been lowered total or LDL cholesterol such as cholestyramine, shown to exert consistent mortality-lowering benefits in a select cholestipol, and fibrates.64 Puccetti et al. observed that simvastatin,
Journal of American Physicians and Surgeons
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atorvastatin, and fluvastatin reduced platelet reactivity before markedly increasing their collagen content. This effect was significant reductions in LDL cholesterol occurred.65,66
independent of cholesterol reduction; blood lipid levels in the Anti-inflammatory effects: In research with mice, statins
animals were kept stable by manipulating dietary cholesterol markedly reduce measures of both inflammation and intake.84 (Unlike in humans, dietary cholesterol levels can signif-
atherosclerosis, despite little change in serum cholesterol levels.67
icantly influence serum cholesterol concentrations in monkeys.)85
In humans, statin therapy produces significant reductions in C- Prevention of cardiac hypertrophy: Takemoto and coworkers
reactive protein, a marker of inflammatory activity that has demonstrated the ability of statins to prevent cardiac hypertrophy repeatedly been associated with increased cardiovascular risk. This in mice. This benefit occurred despite no change in serum statin-induced reduction in CRP levels is not correlated with any cholesterol levels. Research by these and other researchers decrease in LDL cholesterol levels.68-71 Statins also reduce the
suggests the antihypertrophic effect of statins may derive from effects of adhesion molecules and chemoattractants, which play a their antioxidant properties.86,87
key role in the inflammatory process and plaque formation by The numerous actions of statins unrelated to lipid lowering are promoting migration of leukocytes and their adherence to the no doubt a major reason why almost all of the major controlled, arterial wall plaque.72 Weitz-Schmidt and coworkers have shown
randomized trials with these drugs have shown no association that statins exert anti-adhesion properties in vitro. In an important between the degree of total or LDL cholesterol lowering and the experiment, this group produced a specially modified form of CHD survival rate.50, 88-92 In most of these studies, the risk of a fatal
lovastatin with no inhibitory effect on HMG-CoA reductase. This heart attack was similarly reduced whether total or LDL cholesterol “designer statin” still possessed potent anti-adhesive, anti- levels were lowered by a small or large amount.
chemoattractant effects, despite complete disablement of its There are two exceptions to this phenomenon: the PROSPER cholesterol-lowering actions.73
trial, which recorded the highest survival rates in both the treatment Antioxidant effects: In animal studies, statins reduce various
and control groups among those with the highest LDL levels,54 and
measures of oxidative stress, even when cholesterol levels remain the Japanese Lipid Intervention Trial (J-LIT). In the latter, a 6-year unchanged.74-76 In humans, a mere nine days of atorvastatin
study of more than 47,000 patients treated with simvastatin, those administration (20 mg/day) significantly decreased platelet levels with a total cholesterol level of 200-219 mg/dL had a lower rate of of oxidized LDL. These changes were observed before any coronary events than those whose levels were above or below this noteworthy drop in LDL cholesterol was evident.69 In patients
range. The lowest all-cause mortality rate was seen in the patients randomly assigned to receive 10 mg of pravastatin or 20 mg of whose total and LDL cholesterol levels were between 200-259 fluvastatin for 12 weeks, significant reductions in oxidized LDL mg/dL and 120-159 mg/dL, respectively.93
occurred in both groups. The reduction was significantly higher inthe fluvastatin group than in the pravastatin group (47.5% vs Selective Citation and Contradictory Evidence
25.2%, respectively). Reductions in total and LDL cholesterol,
however, did not differ between the two groups.77
When confronted with nonsupportive evidence, the Inhibition of the migration and proliferation of smooth
anticholesterol mainstream typically engages a two-pronged muscle cells seen during plaque formation:
strategy. First, it simply ignores contradictory evidence. Second, it which is independent of lipid-lowering, was first confirmed when simultaneously seeks out supportive evidence, no matter how researchers observed that addition of mevalonate, geraniol, flimsy, and then embarks on an aggressive propaganda campaign to farnesol and geranylgeraniol, but not LDL, prevented the anti- “educate” as many people as possible about it. The end result is that proliferative effect of statins.80,81 Animal research also shows a
the public receives a distorted picture of the existing evidence.
disconnect between the lipid-lowering and anti-proliferative A classic example of this process occurred in April 2004, when effects of statins. When collars were placed around one of the the results of the Pravastatin or Atorvastatin Evaluation and carotid arteries in rabbits, treatment with lovastatin, simvastatin, Infection Therapy trial (PROVE-IT) were published. The PROVE- and fluvastatin significantly reduced intimal lesion formation, IT researchers randomized patients who had recently been despite no change in the animals’cholesterol levels.60
hospitalized for an acute coronary event to either 40 milligrams of Prevention of atherosclerotic plaque rupture: Plaque rupture is
pravastatin (Pravachol) or 80 milligrams of atorvastatin daily. Not believed to be the instigating factor in a significant portion of acute surprisingly, median LDL cholesterol levels were lowered to a coronary events.38 In patients with symptomatic carotid
greater extent on high-dose atorvastatin. After an average follow-up atherosclerosis, 40 mg/d of pravastatin reduced the lipid and of 2 years, the high-dose atorvastatin group enjoyed a 30% reduction oxidized LDL content but increased the collagen content of plaques in CHD mortality and a 28% decrease in all-cause mortality.94
as compared to control subjects. These changes are like those seen in In the media barrage about the trial, “medical opinion leaders” stable plaques that are less prone to rupture.82 In apolipoprotein
asserted that PROVE-IT finally “proved” that the lower the LDL E–deficient mice, simvastatin significantly increased serum level, the better. Actually, PROVE-IT proved no such thing.
cholesterol levels, but induced a 49% reduction in the frequency of Neither did TNT (Treating New Targets), the vigorously promoted intraplaque hemorrhage and a 56% reduction in the frequency of study published in March 2005, which also allegedly proved the calcification—both markers of advanced and unstable value of aggressive LDL lowering. In this study, 10,001 CHD atherosclerotic plaques.83 Compared to controls, adult male monkeys
patients with LDL cholesterol levels of less than 130 mg/dL were fed an atherogenic diet and given pravastatin or simvastatin showed randomly assigned to either 10 or 80 milligrams of atorvastatin significantly reduced inflammatory activity in plaques, while daily. In those receiving low-dose atorvastatin mean LDL Journal of American Physicians and Surgeons
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cholesterol levels were reduced to 101 mg/dL, compared to 77 The change in CRP levels associated with pravastatin treatment was mg/dL in those taking the high dose.
not correlated with the reduction in LDL cholesterol levels.98
After a median follow-up of 4.9 years, 2.5% of the low-dose In the Effects of Atorvastatin vs Simvastatin on Atherosclerosis group had died from coronary causes, compared to 2% in the Progression (ASAP) study, baseline CRP values were similar high-dose group, a 20% reduction in relative risk (RR).95 Again,
among patients given either simvastatin (40 mg/d) or atorvastatin leading proponents of the lipid hypothesis dominated the (80 mg/d), but declined over the next 2 years to a greater extent in subsequent extensive media coverage, enthusiastically hailing the latter group. A significant correlation was found between the these results as triumphant confirmation of the PROVE-IT decrease of CRP and reduction in intima media thickness (IMT) of findings. According to these prestigious commentators, the carotid artery segments. No correlation was observed between “lower is better” era of LDL reduction had officially arrived. The fact that all-cause mortality did not differ between the twogroups, owing to an increase in noncardiovascular deaths among Conclusion
the high-dose subjects, evidently escaped notice.
The concept that LDL is “bad cholesterol” is a simplistic and Explaining Favorable Cardiovascular Outcomes
scientifically untenable hypothesis.
The inordinate focus on cholesterol, a perfectly natural That statins exert a whole host of biochemical effects beyond substance that performs many crucial functions in the body, has mere lipid lowering is beyond question. It is entirely possible, taken and continues to take valuable resources and attention away therefore, that the statins’ pleiotropic effects—and not LDL from factors more closely related to heart disease.
lowering—produced the favorable cardiovascular outcomes seen Independent-thinking practitioners must look at the readily in PROVE-IT or TNT. To claim otherwise, especially when little available evidence for themselves, instead of relying on the attempt was made to measure the impact of these lipid-independent continual stream of anticholesterol propaganda emanating from “health authorities.” By doing so, they will quickly realize that the C-reactive protein (CRP) has gained much attention since a LDL hypothesis is aggressively promoted for reasons other than large study published in 2002 suggested that it was a significantly better predictor of future cardiovascular events than LDL Anthony Colpo is a certified fitness consultant. E-mail:
cholesterol.26 While it is not yet clear whether CRP itself is directly
atherogenic, it is well-known that CRP serves as a marker forinflammation.
In January 2005, the New England Journal of Medicine 1 Pfizer. 2004 Financial Report. Available at:
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4 Lampe FC, Morris RW, Walker M, et al. Trends in rates of different forms of
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5 Sytkowski PA, Kannel WB, D’Agostino RB. Changes in risk factors and the
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importance of inflammation, and to show a disconnect between 7 Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life ex-
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Barres BA, Smith SJ. Cholesterol—making or breaking the synapse.
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15 Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism
37 Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive
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Journal of American Physicians and Surgeons
Volume 10
Fall 2005


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