Re: Atkins Research Results

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New Duke Findings Corroborate Earlier Studies Demonstrating Benefits of Low-Carb Diet

November, 2002

At the American Heart Association Scientific Sessions in Chicago held this month, Duke researcher, Eric Westman, M.D., M.H.S., presented preliminary results on his soon-to-be-published study, "Effect of a Low-Carbohydrate Ketogenic Diet Program on Fasting Lipid Subfractions". The two-arm randomized, controlled study examined a group of overweight individuals with elevated cholesterol and triglyceride levels who were put on either a low-fat, low-calorie, high-carbohydrate diet or a low-carbohydrate, ketogenic diet that was supplemented with a formula containing fish, borage and flaxseed oil. While both groups of dieters lost weight, the low-carbohydrate dieters outperformed the low-fat group by 5% in 24 weeks on the program.

Both programs benefited cholesterol levels by lowering the LDL (bad cholesterol), but only the low-carbohydrate program showed a major decrease in the ratio of triglycerides to HDL (good cholesterol), another documented risk factor for cardiovascular disease. The ratio was reduced by an impressive 53% in the low-carbohydrate group versus only 6% in the low-fat group.

Dr. Westman is the author of "Effect of 6-Month Adherence to a Very Low Carbohydrate Diet Program", published in the American Journal of Medicine, July 2002, which reported on a six month weight-loss study that monitored 50 subjects who were following low-carbohydrate, ketogenic program. Data gathered included the results of laboratory tests, weight/waist measurements, diet composition, symptoms and side effects. The results showed that low- carbohydrate, ketogenic program is not only effective in weight loss and management, but manifests significant improvement in a number of cardiovascular disease risk factors.



University of Connecticut Studies Indicate Ketosis is Safe

Volek, JS, et al.: A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men. Journal of Nutrition, July 2002.

Volek, JS, et al.: Body Composition and Hormonal Response to a Carbohydrate Restricted Diet. Metabolism, July 2002.

Two recently-published studies show that ketosis, the controversial metabolic process often associated with the Atkins Nutritional Approach(TM), may not only be harmless but may also be beneficial. One study demonstrated that subjects in ketosis, due to a controlled carbohydrate diet, experienced statistically significant improvement in blood markers that have been shown to predict coronary artery disease. This finding clearly refutes the claim that lipids improve solely as a result of weight loss. The second study found that people lost fat (an average of seven pounds), while actually gaining muscle (an average of two pounds) in only six weeks. In essence these individuals lost an average of five pounds not only preserving their muscle mass, but also increasing it. Both published studies come out of the University of Connecticut's Human Performance Laboratory and were conducted on normal-weight men with normal cholesterol levels.

The first study, "A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men", published in the July 2002 issue of the Journal of Nutrition, shows that ketosis is not only harmless but may actually improve the blood markers that have been shown to predict coronary artery disease. The results showed that fasting TG was decreased by 33%, post-meal lipids by 29%, LDL particle size increased, and fasting insulin concentrations by 34% after the ketogenic diet. LDL and total cholesterol were unchanged by the diet, HDL ("good" cholesterol) tended to be slightly increased, suggesting a favorable outcome in this predictor of improved cardiovascular risk.

The second study, "Body Composition and Hormonal Responses to a Carbohydrate Restricted Diet", published in the July 2002 issue of Metabolism, examined how the normal-weight body responds to six weeks of a carbohydrate restricted diet (8% carbohydrate, 61% fat, 30% protein) compared with a traditional diet (47% carbohydrate, 32% fat, 17% protein) that involved equal caloric intake. At week six, this study, with 12 subjects, found that people lost fat (an average of seven pounds), while actually gaining muscle (an average of two pounds). The average weight loss of five pounds was achieved while not only preserving muscle mass, but also increasing it. Because this positive change occurred in conjunction with lowered insulin levels (a hormone measured in the blood that is stimulated by carbohydrate intake and has been associated with the conversion of excess carbohydrate to body fat), it is postulated that the reduction in the hormone insulin was responsible for this.


Low-Carb Diet Beneficial for Men with Uncontrolled Diabetes

Gutierrez M, Akhavan M, Jovanovic L, Peterson CM.

Sansum Medical Research Foundation, Santa Barbara, California 93105, USA.

OBJECTIVE: To determine if introduction of a low carbohydrate diet might be a useful option for type 2 diabetic patients who do not achieve glucose target levels despite conventional treatment. METHODS: Subjects with type 2 diabetes, either treated with diet alone (n=9) or second generation sulfonylurea agents (n= 19), which were discontinued, were placed on a diet based on ideal body weight and comprised of 25% carbohydrate. After a mean of 8 weeks, they were then switched to a caloricly equivalent diet, but composed of 55% carbohydrate.

RESULTS: Compared to baseline diet, after 8 weeks of a 25% diet, subjects showed significantly improved glycemia as evidenced by fasting blood glucose values (p<0.005) and hemoglobin A1c levels (p<0.05). Those previously treated with oral hypoglycemic agents showed, in addition, a significant decrease in weight and diastolic blood pressure despite the discontinuation of the oral agent. When then placed on a 55% carbohydrate diet, the hemoglobin A1c rose significantly over the ensuing next 12 weeks (p<0.05).

CONCLUSION: A low carbohydrate, caloricly-restricted diet has beneficial short-term effects in subjects with type 2 who have failed either diet or sulfonylurea therapy and may obviate the necessity for insulin. Our study also affirms the need for reassessing the role of diet whenever type 2 diabetic patients manifests hyperglycemia, despite conventional oral treatment or diet management.

Results of use of metformin and replacement of starch with saturated fat in diets of patients with type 2 diabetes

Hays JH, Gorman RT, Shakir KM.

Christiana Care Health Services, Inc., Cardiology Research, Newark, Delaware 19718, USA.,

OBJECTIVE: To improve glycemic control by substituting saturated fat for starch, to identify any adverse effect on lipids masked by the extensive use of metformin and lipid-lowering drugs, and to attempt to separate dietary effects from effects of multiple drugs.

METHODS: We undertook a retrospective review of medical records of patients who completed 1 year of follow-up after dietary prescription. The study subjects included 151 patients in the diet group (whose dietary instructions included high saturated fat but starch avoidance) and 132 historical control subjects (who were allowed unlimited monounsaturated fat but had restriction of starch in their diets).

RESULTS: Hemoglobin A1c (HbA1c) levels improved in both study groups (-1.4 +/- 0.2% [P<0.001]; 95% confidence interval [CI], -1.9 to -0.9). Use of metformin was associated with a decrease in HbA1c (-0.12 +/- 0.003%/mo [P<0.001]; 95% CI, -0.17 to -0.07). The diet group had an additional decrease of -0.7 +/- 0.2% (P<0.001; 95% CI, -1.1 to -0.3). Weight increase was associated with the use of insulin (+0.3 +/- 0.07 kg/mo [P<0.001]; 95% CI, 0.2 to 0.5), sulfonylurea (+0.18 +/- 0.06 kg/mo [P<0.01]; 95% CI, 0.05 to 0.30), and troglitazone (+0.7 +/- 0.2 kg/mo [P<0.005]; 95% CI, 0.3 to 1.2). Although not statistically significant, metformin therapy showed a trend for weight loss (-0.14 +/- 0.08 kg/mo; P = 0.07). An additional weight loss was noted in the diet group (-2.65 +/- 0.62 kg [P<0.001]; 95% CI, -3.87 to -1.44). Hydroxymethylglutaryl-coenzyme A reductase inhibitor use was associated with reduced total cholesterol level (-1.7 +/- 0.6 mg/dL per month [P<0.005]; 95% CI, -2.9 to -0.5). The diet group had an additional decrease of -13.0 +/- 4.5 mg/dL (P<0.001; 95% CI, -21.9 to -4.1). No significant effect of the diet on triglyceride, low-density lipoprotein, or high-density lipoprotein levels was detected.

CONCLUSION: Addition of saturated fat and removal of starch from a high-monounsaturated fat and starch-restricted diet improved glycemic control and were associated with weight loss without detectable adverse effects on serum lipids.

Heart Disease Related to Glycemic Load

Simin Liu, Walter C Willett, Meir J Stampfer, Frank B Hu, Mary Franz, Laura Sampson, Charles H Hennekens and JoAnn E Manson

From the Departments of Epidemiology and Nutrition, the Harvard School of Public Health; the Channing Laboratory; and the Division of Preventive Medicine, the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.

Background: Little is known about the effects of the amount and type of carbohydrates on risk of coronary heart disease (CHD).

Objective: The objective of this study was to prospectively evaluate the relations of the amount and type of carbohydrates with risk of CHD.

Design: A cohort of 75521 women aged 38–63 y with no previous diagnosis of diabetes mellitus, myocardial infarction, angina, stroke, or other cardiovascular diseases in 1984 was followed for 10 y. Each participant's dietary glycemic load was calculated as a function of glycemic index, carbohydrate content, and frequency of intake of individual foods reported on a validated food-frequency questionnaire at baseline. All dietary variables were updated in 1986 and 1990.

Results: During 10 y of follow-up (729472 person-years), 761 cases of CHD (208 fatal and 553 nonfatal) were documented. Dietary glycemic load was directly associated with risk of CHD after adjustment for age, smoking status, total energy intake, and other coronary disease risk factors. The relative risks from the lowest to highest quintiles of glycemic load were 1.00, 1.01, 1.25, 1.51, and 1.98 (95% CI: 1.41, 2.77 for the highest quintile; P for trend < 0.0001). Carbohydrate classified by glycemic index, as opposed to its traditional classification as either simple or complex, was a better predictor of CHD risk. The association between dietary glycemic load and CHD risk was most evident among women with body weights above average [ie, body mass index (in kg/m2)

Conclusion: These epidemiologic data suggest that a high dietary glycemic load from refined carbohydrates increases the risk of CHD, independent of known coronary disease risk factors.

The low fat/low cholesterol diet is ineffective

Reprinted with permission from: European Heart Journal (1997) 18, 18-22

L.A. Corr, Guy's and St. Thomas' Hospitals, London, U.K.
M.F. Oliver, National Heart and Lung Institute, London, U.K.

Correspondence: Dr. Laura A. Corr, MB, BS, MRCP, PhD, FESC,
Consultant Cardiologist, Guys and St. Thomas' Hospitals,
St. Thomas Street, London SE1 9RT

Ask almost member of the general public about a diet which would reduce their chance of heart disease and the reply is the same: "a low fat diet". On closer questioning, this means a diet with a reduction in cholesterol and saturated 'animal' fats, i.e. less meat, butter, milk and cheese. Most national and international recommendations for the prevention of heart disease, whether for primary prevention of or for patients who have developed the clinical manifestations of coronary heart disease, have made dietary restriction of total and saturated fats and of cholesterol the primary advice and often the sine qua non in relation to all other forms of management. To this extent they are to be congratulated that the message seems to be so universally accepted. Unfortunately, the available trials provide little support for such recommendations and it may be that far more valuable messages for the dietary and non-dietary prevention of coronary heart disease are getting lost in the immoderate support of the low fat diet.

The origin of the 'low fat' diet

The international bodies which developed the current recommendations based them on the best available evidence[1-3]. Numerous epidemiological surveys confirmed beyond doubt the seminal observation of Keys in the Seven Countries Study of a positive correlation between intake of dietary fat and the prevalence of coronary heart disease[4] although recently a cohort study of more than 43,000 men followed for 6 years has shown that this is not independent of fiber intake[5] or risk factors. The prevalence of coronary heart disease has been shown to be correlated with the level of serum total and low density lipoprotein cholesterol (LDL) as well as inversely with high density lipoprotein. As a consequence of these studies, it was assumed that the reverse would hold true: reduction in dietary total and especially saturated fat would lead to a fall in serum cholesterol and a reduction in the incidence of coronary heart disease. The evidence from clinical trials does not support this hypothesis.

The evidence from clinical trials

It can be argued that it is virtually impossible to design and conduct an adequate dietary trial. The alteration of any one component of a diet will lead to alterations in others and often to further changes in lifestyle so it is extremely difficult to determine which, if any, of these produce an effect. Dietary trials cannot generally be blinded and changes in the diet of the 'control' population are frequently seen: they may be so marked as to render the study irrevocably flawed. It is also recognized that adherence to dietary advice over many years by large population samples, as for most people in real life, is poor and that the stricter the diet, the worse the compliance. Nonetheless, the evidence for a reduction in saturated fat from dietary trials for both primary and secondary prevention merits closer scrutiny.

Trials of low fat diets in primary prevention

There have been six randomized, controlled trials with the long-term follow-up designed to modify the development of coronary heart disease in healthy subjects [6-11]. Remarkably, no primary prevention trial of sufficient size or sensitivity to examine the effect of a low total and saturated fat diet alone has ever been conducted. All six primary prevention trials involved alteration of one or more other risk factors such as cigarette smoking, blood pressure and exercise.

Of the three smallest trials(approximately 300-600 subjects per group), two suggested a significant reduction in coronary events. In the Oslo Study[7], men at high risk were given dietary advice aimed at reducing saturated fat intake and modestly increasing polyunsaturated fat intake, and counseled to stop smoking. General advice was given to increase fish, whale meat, vegetable and fruit intake. Over 5 years the mean difference in serum cholesterol between the two groups was relatively large for a dietary trial - 13% and tobacco consumption was lower in the intervention group. There were fewer coronary events in the control group (P<0.028) but the study was not powered to show any difference in coronary or total mortality. The second small trial to show a benefit, the Finnish Mental Hospital Study[6], allocated test and control diets to the inmates of two separate institutions in a cross-over design lasting 12 years. Unfortunately the design was flawed since one-third of the inmates changed over the period of the study and again, although there was a reduction in coronary events, the study was not powered to show any difference in morality. Curiously, the third and most recent of these small studies actually showed a significant adverse effect on coronary and total mortality[8]. In this trial, 1222 businessmen with one or more risk factors were randomly allocated to intensive dietetic measures to reduce saturated fat and cholesterol intake. They were also given advice on physical activity and smoking and had drug treatment for hypertension and hyperlipidemia. After 5 years, the predicted risk of coronary heart disease had fallen by almost half in the intervention group (with a 6% fall in total cholesterol) but there were actually more non-fatal myocardial infarctions (P<0.01) and a trend towards more cardiac deaths. All the subjects were followed for a further 10 years after the end of the intervention period and all-cause mortality, cardiac deaths and deaths associated with violence were all significantly increased. No one has yet managed to rationalize these findings, but at least it should not be assumed that such interventions are automatically without risk when assessing possible cost-benefits.

The three remaining dietary trials for primary prevention were much larger (4000-25000 subjects in each group) and had sufficient power to examine overall mortality[9 , 11]. All of them were ineffective in reducing either coronary events or total mortality over the period of the trial. This is despite the fact that the Minnesota Coronary Survey trial[9] in seven mental hospitals managed to achieve similar reductions in serum cholesterol to the smaller trials above. A recently published follow-up of the MRFIT study[12] showed that deaths from acute myocardial infarction did become significantly lower in the original intervention group after 16 years although no data are available to indicate the compliance to the dietary advice over the years. Despite the size and long follow-up there was no significant reduction in overall mortality.

The message from these trials is that dietary advice to reduce saturated fat and cholesterol intake, even combined with intervention to reduce other risk factors, appears to be relatively ineffective for the primary prevention of coronary heart disease and has not been shown to reduce mortality.

Trials of low fat diets in secondary prevention

There have been two trials of the effect of a low saturated fat diet alone in patients with coronary heart disease. The MRC study[13] followed 252 men randomized to a very low fat diet or no change in diet over three years: the low fat diet was poorly tolerated but achieved a 10% reduction in cholesterol. There was no difference in the rate of reinfarction or death and the researchers concluded that the low fat has no place in the treatment of myocardial infarction. An Australian trial of 458 men substituted polyunsaturated margarine for butter and found a slightly lower 5 year survival in the intervention group (3.3% deaths per year) than in the control group (2.4% deaths per year) although multivariate analysis showed that none of the dietary factors was significantly related to survival[14]. Following the negative results of these trials, no further studies of a low saturated fat diet alone have been conducted.

Should we be recommending diet at all?

The overwhelming importance of coronary heart disease in terms of morbidity, mortality and economic cost in the Western world made dietary advice, which was perceived to be cheap and safe, very attractive to Governments and their Health Departments. Vast sums of money have been invested in nutritional programs, dietary advice and nurse counseling to promote low saturated fat, low cholesterol diet--yet the trials to date for both primary and secondary prevention suggest that these diets do not work. However, this does not mean that all dietary interventions are futile. Other trials of secondary prevention have to a greater or lesser extent tried to alter the quality of the dietary fat intake and other components in patients with coronary heart disease, rather than restrict the quantity of saturated and total fat, and the results are more encouraging.

Trials of diets not dependent on fat reduction

Vegetable oil supplements were used in four of these trials[15-18]. In the LA Veterans Administration study, increasing ingestion of corn, safflower, soyabean and cottonseed oils significantly reduced total cardiovascular events after eight years[15]. The study by Rose et al, found no evidence of clinical benefit in patients given a low fat diet and supplements of olive or corn oil[16]. Similarly, the MRC group added soyabean oil as a supplement to the diet and found no difference in the incidence of death or myocardial infarction compared to men taking their normal diet[17], but a similar study from Oslo did show a significant reduction in pooled coronary heart disease relapses after 5 years and fewer fatal myocardial reinfarctions by 11 years[18]. However, none of these produced a significant difference in total mortality.

Saturated fat reduction, vegetable oil supplements and lifestyle changes in keeping with the current recommendations of the American Heart Association were advised for both the intervention and control groups in a study of Indian patients randomized within 48 h of a suspected myocardial infarction, but in addition the intervention group received a diet high in dietary fiber, omega-3 fatty acids (from fish and nuts), antioxidant vitamins and minerals[19]. The intervention group achieved remarkable wide-ranging and sustained changes in their nutrient intake associated with a modest reduction in serum cholesterol and weight loss. Cardiovascular events were reduced in the intervention group after only 6 weeks and after 1 year there was a significant reduction in myocardial infarction, a 42% reduction in cardiac deaths and a 45% reduction in total mortality compared to the control group on the standard 'low fat' diet. The study does not seem to have been continued beyond on year.

The first successful dietary study to show reduction in overall mortality in patients with coronary heart disease was the DART study reported in 1989[20]. The three-way design of this 'open' trial compared a low saturated fat diet plus increased polyunsaturated fats, similar to the trials above, with a diet including at least two portions of fatty fish or fish oil supplements per week, and a high cereal fibre diet. No benefit in death or reinfarctions was seen in the low fat or the high fibre groups. In the group given fish advise there was a significant reduction in coronary heart disease deaths and overall mortality was reduced by about 29% after 2 years, although there was a non-significant increase in myocardial infarction rates. The reduction in saturated fats in the fish advice group was less than in the low fat diet group and there was no significant change in their serum cholesterol.

Finally, the more recent Lyon trial[21] used a Mediterranean-type of diet with a modest reduction in total and saturated fat, a decrease in polyunsaturated fat and an increase in omega-3 fatty acids from vegetables and fish. As in the DART study there was little change in cholesterol or body weight, but the trial was stopped early following a 70% reduction in myocardial infarction, coronary mortality and total mortality after 2 years.

The most effective diet for secondary prevention is therefore not reduction of saturated fats and cholesterol but appears to be an increase in polyunsaturates of both omega-6 and omega-3 fatty acids. Unfortunately, the design and conduct of these trials are insufficient to permit conclusions about which polyunsaturates and other elements of these diets are the most beneficial. The long term effects of these trials[20,21] and the compliance with the dietary regimes remain to be seen. But the mechanism of any benefit of the omega diets would appear not to be associated with reduction in the total or LDL cholesterol levels and may be more related to reduction of a thrombotic tendency.

The case for recommending similar changes in diet in primary prevention is less clear cut. Although the benefit of olive oil receives strong epidemiological support from several Mediterranean countries, particularly Crete, and short-term studies of diets rich in oleic acid (the principle monounsaturate in our diet) have demonstrated a reduced LDL susceptibility to oxidation, no formal randomized long-term trial of monounsaturates has yet been attempted. There is no consensus from population or cohort follow up surveys about the protective effects of increased fish consumption on coronary mortality. The recently published report from the physicians Health study[22] found no evidence of an inverse association between the intake of fish or fish oils and the risk of myocardial infarction and, while the highest coronary mortality was found among men who ate no fish, the risk did not decrease with increasing fish intake. At present, there does not appear to be any dietary advice which is effective in primary prevention.

Is drug treatment better?

An important aspect of the lipid-lowering dietary trials is that on average they were only able to achieve about a 10% reduction in total cholesterol. The results of recent drug trials have demonstrated that there is a linear relation between the extent of the cholesterol, or LDL, reduction and the decrease in coronary heart disease mortality and morbidity, and a significant effect seen only when these lipids are lowered by more than 25%[23].

Until 1994, the trials with lipid lowering therapy for primary and secondary prevention had been as disappointing and confusing as the trials with diet. They tended to show a reduction in coronary events, including deaths from myocardial infarction, but no reduction in overall mortality. Even though an excess of deaths from cancer and suicide was not shown to have any casual relationship with the treatment, there was no widespread acceptance of lipid lowering therapy.

This changed in 1994 with the publication of the seminal 4S study on secondary prevention of coronary heart disease in 4444 patients with cholesterol levels greater than 5.5 mmol . 1-1 who were randomized to treatment with simvastatin or placebo in addition to 'usual care' including dietary advice[24]. The 4S study showed highly significant (30%) reduction in cardiac events and deaths from myocardial infarction and, for the first time, in overall mortality. The benefits were apparent after 18 months and the difference between the treated and the control groups continued to increase over the five years of follow-up. The more recent CARE study showed a similar outcome with a 28% reduction in reinfarction using pravastatin in 4159 patients following myocardial infarction despite the fact their cholesterol levels before treatment were not high (mean 5.4 mmol . 1-1)[25]. As part of their usual care, patients in this study also received high levels of antiplatelet agents and beta-blockers and 55% had undergone revascularization with angioplasty or bypass surgery. There was no change in coronary heart disease deaths or in all-cause mortality. Over 5 years of follow-up in both these statin trials the treatment was extremely well tolerated with around 90% compliance and no serious effect, indeed there was almost no difference in the side-effect profiles between the statins and the placebo.

With primary prevention the results of treatment with the statins appears equally encouraging. The West of Scotland Coronary Prevention study treated over 6000 healthy men (aged 44-65 years) who had total cholesterol levels greater than 6.5 mmol . 1-1 with either pravastatin or placebo[26]. Again the trial was continued for 5 years, and normal advice was given to both the intervention and the control groups. The risks of death from coronary heart disease and non-fatal myocardial infarction were reduced significantly in the pravastatin group by 31%, and there was a non-significant but favourable trend for all-cause mortality (-22%) with no adverse effect on non-cardiovascular mortality.

The cost effectiveness of treatment with the statins has been assessed at current prices for both primary and secondary care. It varies greatly according to the risk, being obviously more efficient for those at the highest risk, but has been shown to be greater than drug treatment for mild-to-moderate hypertension which is widely endorsed and used in general practice. For those at lower risk, diet should be able to provide a cheaper regimen but at present none has proved sufficiently beneficial.

Conclusions

The commonly-held belief that the best diet for the prevention of coronary heart disease is a low saturated fat, low cholesterol is not supported by the available evidence from clinical trials. In the primary prevention, such diets do not reduce the risk of myocardial infarction or coronary or all cause mortality. Cost-benefit analyses of the extensive primary prevention programmes, which are at present vigorously supported by Governments, Health Departments and health educationalists, are urgently required.

Similarly, diets focused exclusively on reduction of saturated fats and cholesterol are relatively ineffective for secondary prevention and should be abandoned. There may be other effective diets for secondary prevention of coronary heart disease but these are not yet sufficiently well defined or adequately tested. The circumstantial evidence of benefit from oils, particularly olive oil, vegetables, fruit and fish is strong.

For those at high risk, drug therapy, with the statins provides effective primary and secondary prevention and should be considered, with or without a diet, in the same way as drug treatment for mild or moderate hypertension.

L.A. Corr, Guy's and St. Thomas' Hospitals, London, U.K.

M.F. Oliver, National Heart and Lung Institute, London, U.K.

References

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