Marks and Schrijver

Reports submitted on behalf of the VLCD European Industry Group to the SCOOP working group on very-low calorie diets between 1998 and 2001, consolidated 2001.

John Marks MA, MD, FRCP, FRCPath, FRCPsych Life Fellow, Girton College, Cambridge CB3 0JG

Jaap Schrijver . Manager Corporate Regulatory Affairs for foods for particular nutritional uses (PARNUTS) - Royal Numico NV

Preamble

Introduction

When the SCOOP Task 76.3 was first announced, the VLCD European Industry Group asked to submit a report which had been prepared by one of us (JM) in March 1998. The SCOOP Committee, during the first plenary meeting in Maastricht, The Netherlands on March 15^th and 16^th 2000 accepted this report. A request was made by the Committee that those sections of the report which were concerned with scientific and medical data be updated to early 2000 and submitted as a discussion paper for the next meeting. Subsequently a series of further papers was requested by the Committee and submitted in the years 2000 and 2001 by JM and JS.

The present document which is referred to in the SCOOP Report to the EU Commission of August 2001 as Marks J and Schrijver J (2001) is the summation of all these reports from March 2000 to July 2001. It has been edited to try to remove any overlap resulting from the need, during the various meetings of the Committee to explain the background to the further reports. In addition the information is not presented in strict chronological order but in relation to the topics that were covered.

These original documents were prepared by one or both of us as independent scientists and were not discussed with the European VLCD Group. However members of that group were very helpful in finding copies of overseas scientific papers not available in United Kingdom libraries and in providing background data relating to their own studies.

Neither of us is currently employed by any of the member companies of the European VLCD Group though John Marks has, in the past received a fee as Consultant to Cambridge Nutrition Ltd.. Over the period of the preparation of this report John Marks has been a Life Fellow of Girton College, Cambridge.

Jaap Schrijver has his expertise in biochemistry and nutrition. He is employed by Royal Numico NV since 1991. He holds the position of Manager Corporate Regulatory Affairs for foods for particular nutritional uses (PARNUTS). These foods include VLCD products although the company has currently not an interest in these products. As a representative of the Dutch association for PARNUTS foods, he participates in the regulatory activities of the Association of the Food Industries for PARNUTS (IDACE). The IDACE secretariat has its office in Paris.

I want to express my particular thanks to Dr Stephen Kreitzman and Valerie Beeson of Howard Foundation Research Ltd., who undertook a substantial proportion of the original research on which Section III, the 'Recent Scientific Studies' is based. Not only did they make available to us copies of the published work, but also shared with us much of the basic data so that we could convince ourselves that their results, which demonstrated substantial misunderstanding in much published metabolic work, could be thoroughly checked. On the basis of this, we were not only able to confirm the validity of the Kreitzman and Beeson studies, but from their bibliographies undertake cross checks of the errors or omission in the earlier work.

We want to make it quite clear that we found no evidence of deliberate distortion or deliberate misinterpretation in the early works. Most of the errors occurred because the biological scientists did not fully understand the assumptions involved, exactly what their indirect methods of determination meant or the extraneous factors that influenced their results and interpretations.

This report presents evidence for VLCDs collected since the Scientific Committee for Foods Report of 1990.

In 1990 the SCF Report was based largely on the experience of one (United States) group and ignored not only reports prepared by European Member States (UK and The Netherlands) but also extensive studies by European nutrition experts.

In addition to work which was not reviewed for the 1990 report, there is a large body of new evidence since 1990 (at least 177 published scientific studies on over 26,000 people) and 10 years of further extensive use in many countries. Most of this new information comes from conditions of free sale and is well documented.

In earlier reports it was suggested that studies of the safety of VLCD should be undertaken under conditions of use in the community. This information is now available from various studies and shows the considerable levels of safety of the modern nutritionally complete very low calorie (energy) diets.

During the SCOOP Committee meetings it was accepted that though the term very low energy diet is scientifically more accurate, the term very low calorie diet (VLCD) is so widely known and used that this is the term that should be adopted for the SCOOP Task 76.3 Report. In consequence we have also adopted this terminology.

Summary

This report reviews over 400 published scientific and clinical studies to early 2000, undertaken on VLCDs, on over 50,000 people. Thus it is likely that VLCDs are the most widely studied of all weight reducing diets. In addition, it records the main findings in a series of audit studies undertaken during the routine use of VLCD.

The vast majority of the studies identify the compositional standards and the length of administration and this document concentrates on those papers. In almost 20,000 people use was for more than four weeks, giving good evidence on safety of long-term use.

In addition current formula VLCDs have been used by well over 25 million people in the international community over a period of over twenty years.

In addition to this critical review of the available safety and efficacy data in clinical use, there have been a substantial number of recent experimental studies which have shown that some of the earlier research reached erroneous conclusions. This report reviews this data and highlights some important new scientific conclusions which have practical implications.

Overall conclusions

A modern nutrient-complete VLCD provides a highly effective and safe method of weight reduction. The use of VLCD has benefits on excess weight related disorders which appear to be superior to those of LCD or food based plans probably on the basis of the more rapid weight loss.

On the basis of monitored clinical experience coupled with recent body composition studies a scientifically based standard for composition and labelling can and should be established for VLCD.

In view of the undisputed need to help the very large number who need to lose weight, as many safe methods as possible should be made easily and readily available. This includes VLCDs, where the safety can be shown to be at least as good as diets in the >800kcal energy range. VLCDs should therefore be available on free sale on the same terms as diets of over 800kcals (see Commission Directive 93/5/EC).

The following more detailed summaries and conclusions were presented to the SCOOP Working Group:

Section I Overweight and obesity are rapidly and substantially increasing problems in all European Union Member States (Section 1).

Over the past decade the prevalence of excess weight has increased by some 50%. About 20% of the European middle aged are now obese and a further 30% or more are overweight (Section 1.1) Excess weightis now accepted as having reached epidemic proportions

Morbidity increases steadily from a BMI of about 24 (towards the upper range of normal) upwards. The problems associated with excess weight include not only serious diseases, but also psychological and social ills (Section 1.2)

Excess weight is strongly correlated with increasing mortality, so that at a BMI of 40 there is a greater threat to life than smoking 20 cigarettes per day (Section 1.3)

The economic cost of excess weight is substantial, with direct costs amounting to 1-5% of the health care costs in most first-world countries (Section 1.4)

The evidence supports the view that all effective and safe weight control methods should be readily available for all those who have excess weight.

Section II The experimental studies and clinical experience reviewed here demonstrate that products with an adequate and specified macronutrient and micronutrient composition but an energy content below 800kcals per day (VLCD) are at least as safe as those of higher energy content (LCD)

Special closely monitored clinical studies in over 50,000 people, many for prolonged periods with laboratory investigations and electrocardiographic monitoring show no evidence of pathological changes as a result of the use of VLCD. This confirms the practical experience of use of VLCD in over 25 million people during more than 20 years. (Sections 2.1& 2.3)

The studies reviewed here show that products with an adequate macronutrient and micronutrient composition, but an energy content in the range 400-800kcals per day (VLCD) are at least as safe as those of higher energy content LCDs at starting BMI levels down to 25 and finishing BMI levels in the normal range (20 to 25). (Sections 2.3 & 2.4)

NB. The figures do not total because some papers do not contain full information.

Several papers covering at least 500 subjects have been omitted because the full paper could not be examined.

A full listing of these studies is given as Appendix I and a full bibliography for them is given as Appendix II.

Despite the fact that no deaths with liquid protein diets (PLD) have been identified since 1977/1978, it is still being suggested that experience with these diets have relevance. The information relating to LPD was re-examined and confirmation given to the Working Group that these have no relevance to current VLCD. (Section 2.3.1 &2.2)

i)There are a negligible number of significant adverse reactions in the studies (over 50,000 dieters) or in routine use in several millions under free sale use (Section 2.3)

iv) Various other concerns expressed in the previous reports on VLCDs (consequences of rate of weight loss, additional difficulty in weight maintenance and weight cycling) are no greater than with LCD (Section 2.5 & 2.6)

v) The results with VLCD are as good, if not better than with the use of other methods of dieting (Section 2.6) In a group study in which there is good compliance, the rate of weight loss depends upon the energy level of the diet (Section 2.6).

vi) The only way to achieve long-term weight maintenance is by a fundamental change in lifestyle. However the results achieved by such change after weight reduction by VLCD are at least as good as with those other non-invasive methods (Section 2.7)

vii) Cholelithiasis is not a specific disorder of VLCD use and different formulations affect the incidence (Section 2.7). There is a requirement for essential fatty acids. If the essential fatty acids are derived from normal fat (which would require above 7g per day normal fats) this also provides sufficient fat to avoid cholelithiasis

Modern, nutritionally complete VLCDs are not only more effective than all other non-invasive methods of weight reduction but are at least as safe

Section III Many recent studies have been undertaken which have established a clear understanding of the properties of VLCD

1)A thorough examination of body composition estimation has indicated that there is substantial lack of reliability and reproducibility in most of the methods that have been used for weight loss studies. With the exception of neutron activation, which is expensive and not widely available, all the methods are indirect estimates. This implies that the estimate is influenced by variation in formulae which are used for converting the observation to the estimate (Section 3.1).

ii) Apart from technical errors in the estimation, attention is directed to physiological variations that can profoundly alter the results. Considerable attention to detail in the study is necessary (Section 3.1.5)

iii) In consequence it is inappropriate to compare in the same chart, data derived by different techniques (Section 3.2.1).

iv) The most widely used reasonably reliable indirect technique is hydrodensitometry and unless otherwise stated we have concentrated on data derived by this technique.(Section 3.1.5)

v) Unrecognised analytical variation may explain the conclusions of Forbes on compositional changes during weight loss (Section 3.2.1)

vi)..The Keys (1950) Minnesota study has been quoted as confirming that fat free mass (FFM) loss is greater in individuals with less fat, who diet by any means. Re-examination of the data indicates that while this may be true in those at BMI levels less than 20, at these levels dieting is in any case un-necessary and contraindicated. It is irrelevant down to the least level (about BMI 25) at which dieting is justified. (Section 3.3)

vii) The loss of lean body mass (protein) is inherent to any weight loss, regardless of energy intake, because weight gained is not 100% fat. There is no proportionately greater lean body mass loss with VLCD providing over 40g high quality protein per day than with LCD (Section 3.4 & 3.5)

viii) Re-examination of the old data and further new observations support the view peoposed by Garrow and others in the 1970s, that at all pre-dieting BMI levels between about 60 and 25, FFM represents about 25% of the weight loss (range about 20-30% probably depending on genetic factors). This is true for any energy value diets containing appropriate macronutrient levels (Section 3.5)

ix) Attention is directed to the fact that as loss of lean body mass is inherent in any weight loss, there is an obligatory nitrogen loss during weight loss. Hence excess nitrogen loss is only relevant if it is greater than the obligatory loss. At daily intake levels of 40-50g protein in the diet, loss in excess of that which is obligatory is unusual. (Section 3.7)

x) There is no clinical or valid experimental evidence which indicates that carbohydrate levels above those currently available and widely studied, i.e. about 40-45g per day (about 90% of the available clinical data) have any merits.(Section 3.8)

Compositional standards.

From examination of the extensive scientific work available (Appendices II & III), and consideration of the various national and international regulations and codes of practice, the compositional conclusions currently in force for VLCD are:

Protein

Range of minima between 40-50g with a minimum nutritional quality as defined by WHO/FAO (FAO, 1991)

Either no recommendation; or in some regulations a range of minima for available carbohydrate between 40-50g.

Fat

A minimum of 7g neutral fat per day which would provide not less than 3g linoleic acid and 0.5g linolenic acid with a linoleic/linolenic acid ratio between 5 and 15

Micronutrients

This has been the subject of separate consideration and these internationally agreed levels should be adopted.

Fibre

The fibre recommendation should allow for soluble fibres to be used. The minimum should be 10g per day. The available carbohydrate component of this should be included in the carbohydrate figure.

Energy

There is a range of minima between 400-450kcal. The energy value per se has no direct relevance and the minimum should be established based upon the energy provided by the defined minimum for the macronutrient recommendations.

Having re-examined the clinical and experimental evidence which we have submitted to the Working Group, we see no scientific reason for changing any of the above views about the compositional standards which we submitted in March 2000.

Section IV There is substantial medical and scientific justification for modern nutrient complete formula diets with an energy value less than 800kcals per day :

i) It is widely accepted by scientists that formula diets are more effective than normal food based diets for compliance in weight reduction (Section 4)

ii) There is no perfect single weight reducing method and a variety of safe diets is desirable to suit differing desires and prejudices. VLCD can have a significant effect on motivation and compliance in some people. (Section 4)

iii) There is recent convincing evidence that the rapidity of weight loss confers additional positive health benefits independent of the weight loss in, for example, non-insulin dependent diabetes mellitus and hypertension (Section 4)

Modern nutrient-complete formula VLCD have an important place in weight reduction

Section V The precautions for VLCD use should be those which apply to any method for losing weight

i). The report endorses physiological and medical contraindications and precautions that have already been extensively published, but emphasises that these apply to all forms of effective weight reduction and not just to VLCD (Section 4.1).

ii).As with any weight loss diet, medical supervision is only necessary if there are medical complications (Section 4.2)

iii).Those with defined medical conditions, those dieting for prolonged periods and those receiving prescription drugs should seek medical advice and/or supervision – following the same advice as those using LCD.

iv) .Continuous use of VLCD to the desired weight is preferable to intermittent dieting for both physiological and psychological reasons, and has no disadvantages (Section 4.3)

· The need for any product claiming weight loss to demonstrate safety and efficacy.

· Minimum compositional standards for all diets, including those in official reports, and in the media.

· Advice that those dieting for more than three weeks by any method should seek medical advice.

SECTION I: OVERWEIGHT & OBESITY - THE NEED FOR EFFECTIVE SLIMMING PLANS AND PRODUCTS

1.1 The prevalence of excess weight

The increase in the incidence of obesity is so great in most developed countries that it can be regarded as a pandemic. Over the past decade obesity has almost doubled in many countries and the average adult is currently adding an estimated one gram per day to its weight. Since overweight (BM1 25 – 30) and obesity (BMI >30) are factors in both mortality and morbidity, there is a real need not only to prevent any further increase in the problem but also to reduce the weight of those who are already affected.

There is no dispute that the ideal approach to weight problems is to avoid them by a judicious change in the lifestyle of the population. This involves an increase in physical activity and a reduction in food intake, particularly foods high in fats. Such social change has so far proved impossible to achieve. However, even if it can be achieved in future, it will still be necessary to reduce the weight of the substantial proportion of the population which is currently overweight or obese.

1.2 Excess weight and morbidity

Numerous studies have shown that women are far more likely than men to become overweight and that there is a higher incidence of obesity in the lower social classes (both men and women) in most industrially developed countries. Since the early 1980s there has been a considerable increase in the prevalence of overweight and obesity in most western countries. Thus, for example, Gregory et al. (1990); White et al. (1993) and Cox (1993) all demonstrated that in the United Kingdom, the proportion of those who were overweight rose by some 50% for women and 30% for men over the decade of the 1980s. One of the recent British surveys (Central Statistical Office, 1996), showed that the average weight for both men and women had risen still further, such that the average BMI for each sex now lies in the overweight range (average BMI men 26.0; women 25.8). Over the 15 year period from 1980 to 1995 the prevalence of obesity almost doubled (from 8% to 15% - Wilding, 1997). At present, in the UK, 62% of adult women are either overweight or obese. And the proportion is forecast to further increase (estimate 25% women and 20% men obese early in the next millennium).

Nor is this confined to the UK. Recent studies (e.g. Seidell, 1991; WHO, 1997) have found similar increases in many countries. Thus in Europe some 15-20% of the middle-aged are obese (more in Eastern Europe, less in Scandinavia).

1.3 Weight increase and mortality

Excess weight is associated with a high level of morbidity, embracing a wide range of disorders which both produce ill health in the community and are a great burden on national health costs. These include cardiovascular problems, diabetes, liver disorders and gall bladder disease, some cancers, excess risk during surgery and a higher incidence of accidents (Table 1.1). Added to this, increased weight increases the morbidity in various chronic disorders (such as arthritis) and produces several serious social and psychological problems.

Table 1.1 The increase in morbidity and mortality associated with obesity (>30% overweight) in various medical conditions

It has been traditional to regard a BMI between 25 and about 30 as a mild and largely cosmetic problem of negligible health concern. This has been highlighted by the use of two different terms – “overweight” and “morbid obesity” for different excess weight ranges, though where the dividing line is placed differs from one authority to another. The studies quoted above demonstrate that there is a continuum of deteriorating health from about BMI 24. It must be concluded that the arbitrary division into a morbid condition of obesity and a benign condition of overweight is not only scientifically unjustified, but is a dis-incentive to drawing attention to the need to consider any excess weight as requiring action.

Thus all the information supports the view that all effective and safe weight control methods should be readily available for all those who are overweight

1.4Weight increase and mortality

Over several years there have been many studies which have examined the relationship between either the body mass index or other indications of obesity and mortality. Among recent studies are those of Garrow (1992), Pi-Sunyer (1993), Andres et al. (1993) and Manson et al. (1995). Each has shown that as the weight increases so does the mortality. Garrow (1992) has expressed it very vividly –“for example, a woman of height 1,58m would be in the desirable range of weight for her height if she weighed 63kg. If she weighs 100kg [BMI 40] … the mortality ratio is about 250% of that at [her desired weight]…so this degree of obesity is a greater threat to health than smoking 20 cigarettes a day.” (Figure 1)

However, while the relationship between major weight increase and mortality is clear, the picture is a complicated one if looked at in detail, because obesity is also associated with other disorders which give rise to a reduced life expectancy. Other factors can also change these related disorders and in consequence the relationship to weight is not linear throughout the whole obese group. However, “the overall increase in mortality is approximately 15% for every 10% that the person is above the normal weight” (Marks, 1997). Reduction in weight produces a significant reduction in the mortality risk. There is therefore every justification for those who are overweight to attempt to reduce towards the normal level.

Figure 1.1 The relative risk of premature death compares with the level of obesity/overweight (BMI). Based on Garrow (1981)

The relationship of weight and mortality is also strongly correlated with the distribution of fat. Obesity with the main increase of fat around the waist carries the highest risk, both for all cause mortality and for that associated with cardiovascular diseases. Recent studies (Cox & Whichelow, 1996; Ashwell et al., 1996) suggests that the ratio of waist circumference/height is a very good predictor of mortality and that this ratio is also a good predictor of reduction in risk when the weight is reduced. There is evidence that it is more reliable than the BMI in this respect

Recent studies (Iribarren et al.,1995; Byers, 1995; Manson et al., 1995) have demonstrated that overweight per se (i.e. any increase in weight beyond the normal) carries an increased risk and that it is greater when the overweight is associated with other disorders.

Several of these studies have produced a clear picture of an increase of serious and life shortening diseases from a BMI of about 22 upwards. Typical charts for cardiovascular disease and cancer from the paper by Manson et al. (1995) are shown in Figures 1.2a and 1.2b. A study in a Finnish population (Rissanen, 1990) showed a highly significant (p = <0.0001) linear rise in the weight range BMI 20 – 32.5 for coronary heart disease and musculo-skeletal diseases, while in the United Kingdom Shaper et al. (1997) reported that the risk of cardiovascular disease associated deaths, heart attacks and diabetes all increased progressively from a BMI index of <20, even after age, smoking, social class, alcohol consumption and physical activity had all been adjusted for. Similar results have been reported by Manson et al. (1987); Linsted et al. (1991); Lee et al. (1993) inter alia.

Indeed it is now apparent that the ideal weight from the point of view of low mortality is about BMI 20 to 21. This implies that it is not enough to concentrate on the treatment of the obese, but that the management of those who are overweight, particularly when young, also require attention quite apart from the fact that there is a steady progression from overweight in youth to obesity in middle age

Figure 1.2 a) and b) Relative risk of death from cardiovascular disease (a) and cancer (b) according to Body Mass Index amongst women who never smoked (from Manson et all, 1995)

1.5The economic cost of obesity

Although studies in Northern Europe, particularly Finland (Rissanen et al., 1990) had identified that there were major direct economic costs associated with obesity, the first of the papers which attempted to quantify the costs, emanated from the United States (Colditz, 1992). He considered the direct and indirect health costs involved based upon 1986 cost levels. He reached a figure of some $39.3 billion representing some 5.5% of the total health care costs in the United States (Table 1.2). His figures only represented health care costs. The true economic costs would add considerable sums to the overall cost to the community.

Subsequently, these economic costs have been studied in Europe, the United States, Australia and New Zealand (Wolf & Colditz, 1994; Segal et al., 1994; Seidell,1995; Levy et al., 1995; Seidell, 1997). The direct costs, i.e. those costs which are related to the diagnosis and treatment of both obesity and diseases related to obesity amount to between 1 - 5% of the total national health expenditure in these countries. Seidell (1997) specifically draws attention to the fact that these only represent the costs of true obesity and to these should really be added those attributable to overweight, which with the greater number of patients likely to be involved would probably amount to at least the same level as those for obesity. To these must be added indirect costs to society (sick pay, pensions etc); loss of productivity from sick leave and early mortality; personal costs which arise from higher insurance premiums, job discrimination, adaptations to cope with disability etc. Thus the total costs, which have not yet been quantified, are very large - placing a major strain on the economy of even the most industrially developed country. These costs are likely to rise even more if safe and effective diets are not made readily available.

SECTION II: THE SAFETY OF VERY LOW CALORIE DIETS IN EXPERIMENTAL AND CLINICAL USE.

The literature on the management of obesity in general and the use of VLCD in particular abounds in ex cathedra statements unsupported by scientific data. To compound the misinformation available in the literature, these ex-cathedra statements are then further quoted as though they represented prime data, not only in other papers and reviews, but also in national and international expert committee reports.

The best way to break this vicious circle is to examine and report the actual findings in true prime data publications i.e. those that define the actual individual studies with enough information to assess their significance. An attempt has been made to identify and list for this discussion paper as much prime data as possible for nutritionally complete formula diets with an energy value below 800 kcals.

This policy of stressing the prime data also accords with the summary of the SCOOP 76.3 task "Collection of data on products intended for use in very low calorie diets (EU document C(2000)498)

It is accepted that there are accidental "sins of omission and commission" within this discussion paper, particularly caused by changes in formulations over the years, but it is submitted that these do not significantly affect the conclusions.

Special closely monitored studies in over 50,000 people who have received many different formulae all giving a daily intake under 800 kcals. A substantial proportion of these represent administration for prolonged periods and/or laboratory investigations and electrocardiographic monitoring. A summary of this data is given in Table 2.1.

NB. The figures in Table 1 do not always total because some papers either do not contain full information or the information indicates that a range of intakes used covers more than one category. Several papers have been omitted either because the full paper could not be examined or inadequate information is given on the content of the diet which was used. This is particularly true of several recent papers which just use the designation ‘very-low-calorie diet’, without describing even the calorie content. There are now several papers using a formula diet which provides 800kcal per day- So far as possible these have also been omitted This has not been easy, because the trade name of the diet is similar to that of an earlier version of lower energy value and some papers do not clarify which formula has been used

A full listing of these studies is given as Appendix I A full bibliography of them is given as Appendix II. This bibliography also gives a list of additional papers examined over the period 1987 to 2000 during the preparation of the various versions of reports and discussion papers on VLCD that have been prepared for different committees.

In addition to these published studies, there has been extensive free sale use of modern very low calorie diets of different formulations in many countries over a number of years.

This "free sale, predominantly not medically supervised" use now covers substantially over 25 million people world wide. It is submitted that the topic of dieting is so newsworthy in the general media, that though this does not represent hard data on safety, such a level of use with virtually no reported morbidity provides valid evidence that free sale is entirely appropriate given adequate labellng.

Despite extensive enquiry concerning the regular media as well as the scientific literature, we have not been able to find one single death which can validly be attributed to the use of VLCD within this medically compromised group in the past 22 years, despite extensive studies and free sale use by many millions of the population.

This can be contrasted with the extensive literature which accumulated rapidly and dramatically in the late 1970s and early 1980s during the brief period when "liquid protein diets" (which bear no relationship to current nutrient complete diets) were available. Although these tragic deaths associated with the use of liquid protein diets covered a period of only about 12 months in 1977, with no further problems after they were withdrawn from the market, they remain to this day a ‘spectre at the feast’. On several occasions matters relating to them have been raised by the Working Group and it is clearly important to put this spectre to rest.

Doubt has been cast from time to time on whether the daths in 1977 were indeed solely attributable to the use of liquid protein diets or whether some of these subjects had been provided with slimming diets of higher nutritional status. Accordingly at the request of the Working Group, an examination was made of all the available evidence relating to these liquid protein deaths in 1977 (Isner et al, 1979; the full report (dated 1979) of the bureau of Foods, Food and Drug Administration committee meetings (Contract FDA 223-75-2090), records of evidence submitted to the committee by the Center for Disease Control, 1979; Food and Drug Administration, 1977, Schucker & Gunn 1978, Sours et al, 1981; Federal Register, 1980; Federal Register, 1982; van Itallie, 1984) Additional to this we have examined the three papers which describe some of the original papers (Michiel et al, 1978; Singh et al, 1978; Brown et al, 1978): the papers which describe other deaths during therapeutic starvation for obesity (Cubberly et al, 1965; Kahan 1968; Spencer, 1968; Garnett, 1969) as well as the pioneer studies on PSMF in which there were no recorded deaths. We have also examined the various AACE Positions Statements on Obesity up to the 1998 revision in which, from time to time comments appear on this problem. From this wealth of data and conjecture the following information emerges:

- Despite the fact that there were over 200 commercial LPD in use in the 1976/1977 period in the USA which were used by a very substantial number of dieters in the BMI range 25-30 there were no deaths in this group.

- There were more than 50 deaths attributed to LPD but only 17 of these were investigated. It is acknowledged that the other deaths may have had a different pathology – the situation of these is unknown.

- Among the investigated deaths the survival time is directly related to the BMI in the above 30 range.

- The fact that those in the 25-30 BMI range did not die is probably due to the relatively short use in those at the lower weight, but it can not be held that “fat is protective”.

- In the above BMI 30 group it must be remembered that the total body protein before dieting was also substantially above the normal. If one of the problems with the LPD was a shortage of one or more essential amino acids, it follows that those with the highest protein (hence amino acid) reserves would survive longest.

· It is not true that ‘high quality VLCD’ were being used as a significant protein source.

- Some PSMF type non-commercial formulae of variable content were under study but the studies which used these higher quality protein did not lead to any deaths, though it is clear that the number of patients studies for over 2 months was so few that deaths would not have been predicted on the basis of the estimate of the risk of mortality from LPD (estimate some 1/700).

- The dietary information within the quoted LPD reports was, by its nature all hearsay from relatives and friends and virtually none of it could be verified by independent evidence.

- There are several references to the fact that “most consumed daily calorie intakes provided by 85 to 200ml… of hydrolysed collagen or gelatin estimated to supply approximately 300Kcal”. One of the original papers indicated that one patient took just 15ml per day over the whole period.

- The amino acid analyses indicate that many of the tested products were virtually free of many of the essential amino acids.

- Three women “added high quality protein to their” liquid protein diet. The amount is never stated but examination of their rate of weight loss compared with the remaining patients showed that the increase in calories must have been small. The conclusion of the USA committee was that the exact cause could not be determined (inadequate essential amino acids; ? electrolyte disturbances), that some supplementation with casein may have undertaken by a few people, but this does not amount to “use of high quality VLCD”.

- There was only one man involved. The level of his use of the protein source (not a VLCD) other than LPD is far from clear. One report suggests that he merely supplemented – “all had used a LPMF diet as their sole source of calories for some months”, another says “he used a protein product that was reportedly of high quality”. It is of interest that this is the only autopsy that records “possible early infarct”.

- Starvation had previously been shown to produce deaths of the type seen with LPD.

- No less than 12 of the 17 patients whose deaths were examined were being treated by medical practitioners. It is frequently suggested – inaccurately that all were self-medicating.

- A substantial proportion were alleged to have had regular electrocardiograms while they were receiving the LPD.

· The deaths could not be attributed to protein losses in the heart being greater than those in other organs due to a more rapid protein turnover in that organ

- The “weight of the hearts….was decreased in proportion to the documented decrease in body weight”.

- There was no evidence of increased loss of heart muscle protein as a result of the different heart muscle turnover rate.

- From the 1980 FDA report and a further FDA report in 1982 it is clear that there were NO further deaths attributable to weight reduction once the liquid protein diets were no longer used despite the substantial free sale of a substantial number of properly formulated VLCD most at that stage with an energy content in the range 300 to 400 kcal per day.

Nevertheless from time to time it is suggested in official reports that "there has been a lack of vigilance in gathering such information". There is no evidence whatsoever to support this contention. Indeed quite apart from vigilance by the various companies monitoring adverse reactions reported in the medical and lay media, there have been several extensive audits undertaken during use in the community under health professional care. These include:

1. An audit of 500 obese women sequentially joining a modular (12 week) obesity management programme (formulation: protein 43g; carbohydrate 38/45g) in the United Kingdom, of whom 85% completed 1 month and 50% completed 3 months or more. No serious untoward events have been encountered during the ten years that the programme has been running-

2. Also in the United Kingdom, Lipotrim, a GP-based programme has been active since 1990. The data on the first four years has been mislaid but it did not contain any significant adverse reactions. Since 1993, some 31,000 patients have been treated and monitored by their own practitioners following this programme (formulation for women: protein 43 g; carbohydrate 38/45g: formulation for men: protein 57g; carbohydrate 33/60g). The average duration of treatment was 16 weeks and the vast majority have been followed for at least one year post diet. Many of the practices have submitted audit results from these clinics to their respective health authorities. Twenty five such audits were assembled in a paper presented at the Medical Research Society in the UK and at the European Obesity meeting in Barcelona (Beeson 1994). Full medical records show that there have been no serious adverse effects over the whole 10 years.

While these audits cover the generality of the adverse effects during the use of VLCD there is a possibility that they only represent studies in which the starting BMI was well above the 30 level. Moreover it might represent those who did not reach the lower level, which it has been suggested is particularly susceptible to adverse effects.

As a result it was decided to examine those papers in more detail in which it had been shown that there was a significant component of subjects in which the starting BMI was below 30.

· Two papers by Wadden (JAMA: January & June 1990) have been quoted frequently as information relating to safety aspects of the use of VLCD, particularly at BMI levels between 25 and 30. The following comments are relevant:

- In the USA in the early 1980s a rumour, based upon an FDA Talk Paper, circulated that some six deaths might have occurred using the Cambridge Plan International Diet. Emil Corwin for the U.S. Food and Drug Administration on February 21^st 1996 issued the following statement “no deaths have ever been attributed to the use of the Cambridge Plan International Diet”… “during the last five years, as many as 7 million persons have used Cambridge’s programs and products” (Newsday, February 22 1986, page 2)

· In 1989, Connolly, a general practitioner in Ireland reported a sudden death which he alleged was the result of the use of a VLCD. The heart muscle was examined by a British Home Office pathologist who reported that there was no evidence of the pathology associated with “liquid protein diets” and that there was no evidence that this was a death that should be attributed to the use of VLCD

· In 1993 Muller & Grossklaus reported “Autopsy studies performed on 16 persons whose death was considered to be related to the use of VLEDs showed that the weight of heart decreased in proportion to the decrease in body weight” This report was taken to represent recent deaths in Germany. In fact the reference he gives is to Isner et al (1979) and this refers to the “liquid protein diets”.

· In various places in the Wadden articles there is a statement about reduced safety at lower BMI levels. The references are always the same – i.e. the work of Forbes and the repetition of the Forbes views by others. I can not find any other evidence for the statements about safety. The accuracy of the Forbes work is examined elsewhere in this discussion paper (Section III)

- In this respect, we would draw attention to the recent paper by Professor Sir Colin Berry entitled “Bellmanism: the distortion of reason” (Berry, 2000). The views expressed here are very apposite and particularly on the “imperfect understanding and use of science, in particular in the evaluation of data. Studies which have been discredited are cited repeatedly… in relation to the precautionary principle.”

In some of the papers it is possible to establish what proportion of the data represented experience at a BMI under 30.

In order to make the necessary calculations it would be necessary to have adequate information to determine that not only is there good compliance on average within the cohort, but that the compliance is equally good across the weight range.

It is abundantly clear from the text in many of the clinical papers that a proportion of those studied have lost such substantial amounts (or proportions of their starting weight) that they have not only moved into the BMI <30 range (if they were not there at the start), but have achieved the normal BMI range. This is obvious if it is appreciated that the compliant VLCD dieter, loses on average between 1 and 2kg/week. For a woman of average current height, one BMI unit is equivalent to some 2.64kg. The published clinical papers indicate that on average over 80% of the dieters are women. For the men one BMI unit weight equivalent is more but the rate of weight loss is greater.

Thus with the average weight loss per week with the majority of the current commercial VLCD, there is a BMI change at the rate of between about one BMI unit each 2 weeks. For those who start at BMI 30, a BMI about 25 (i.e. down to the normal weight level) will be achieved in about 8-10 weeks, at least three-quarters of which will be below BMI 30. At start BMI 35 the average time to normality will be about 18 weeks, with about half that period below BMI 30.

There are 3 papers which provide enough information tobe able to calculate, with reasonable accuracy, the proportion of the VLCD dieting period which represents a BMI level below 30. The basis of the calculation is such that even for these three studies it is clear that it does not represent hard data. Nevertheless much of the data cross checks and is sufficiently representative to be useful, bearing in mind that there are no serious side effects in the whole series. The information covers several previously published smaller cohorts, but the three papers concerned are those of Kirschner et al (1988); Kanders et al (1989) and Bode (1999).

These cover observations using VLCD at 300, 420 and 770kcal per day, though it is not possible to establish with certainty the exact proportion at each intake because the formulation changed over time. One merit of all these studies is that they represent data for observations of at least 12 weeks VLCD dieting a long enough period for any major adverse effect to occur.

Table 2.2 Data on the three papers from which information on the safety of VLCD at lower BMI levels can be gauged.

· For those with a BMI above 35, dieting for at least 12 weeks is necessary before the BMI falls below 30

· In a major proportion of the USA literature, with a very high initial BMI level and a short period of VLCD use there is relatively little data at BMI levels <30

· On the other hand, in Europe, VLCD have been used at lower starting BMI levels and, in consequence there is greater evidence of safety in the range 25 to 30.

On the basis of this evidence a reasonable proportion of the VLCD dieting for these studies was at BMI < 30. Since these represented experience in a substantial number of dieters for a period of at least 12 weeks, there is substantial evidence of use of VLCD in the BMI range (i.e. 25 to 30) for which further information was required

Taking each of these papers (Kirschner et al 1988; Kanders et al 1989; and Bode 1999)in turn:

· Kirschner summarises his experience thus: “Complications of obesity i.e. hypertension, type II diabetes mellitus and hyperlipidemias were remarkably improved after weight loss. Complications of the VLCD including cardiac abnormalities, were minimal”

“Complications. A list of side-effects and complications is presented in Table 4.

The most common problems noted were early postural lightheadedness and tiredness, The most common late complaint was that of mild transient hair loss, occurring in approximately 10 percent of the population. Other complications included eight cases of acute gout, two cases of foot drop, (thought to be due to sciatic nerve compression from leg crossing during or after weight loss), and four cases of acute psychosis occurring in women and generally thought to be a form of sexual panic.

In view of the great concern regarding cardiac arrhythmias in patients on VLCDs we carefully screened for such occurrences. Over the 8-year period, we documented only one patient who developed a supraventricular tachycardia clearly related to hypoglycemia ans corrected with intravenous glucose supplementation. Two patients required hospitalisation for the development of palpitations associated with multifocal PVCs. To date, we have had no unexplained deaths in contrast to the experience with liquid protein diets.

Non-complications. In view of the genuine concern as to the overall safety of VLCDs there were several important non-complications to record, including: (1) coronary pypass surgery without complications in eight patients; (2) major breast surgery without complications in 12 patients; (3) pregnancies occurring while patients were on VLCD (without subsequent complications) in six women in whom the diet was subsequently discontinued.”

To put this paper in context it should be appreciated that this represented something in excess of 40,000 weeks dieting experience in 4026 patients at 420kcal/day with some 10% in the BMI range <30. The quoted paragraphs followed several that detailed the beneficial effects of VLCD on medical problems in this same patient cohort.

· The equivalent paper by Kanders et al (1989) gives a substantial amount of information about beneficial effects. The phrasing of the report suggests that side effects were not a problem but there is no specific reference to side effects throughout the whole paper. It is abundantly clear from the nature of the paper, that, had side effects been a problem, they would have been recorded.

· The same situation is true of the report by Bode (1999). He describes reasons for the subjects stopping the use of the VLCD but these are primarily social. There are no significant medical problems.

· We have also obtained access to the detailed information relating to Lipotrim^Ò a monitored VLCD programme (Kreitzman & Beeson, 1996). This provides an indication of the VLCD dieting pattern in the practical commercial area and moreover gives some indication of the post diet period, though not over a prolonged period.

This study by Kreitzman & Beeson (1996) was undertaken with trained independent medical observers. Again, no VLCD related adversa effects were reported.

An audit of 746 case records was made. This covers an overall period of total food replacement (TFR) by VLCD of 13,446 weeks; a total weight loss in the group of 15,657Kg representing an average weight loss for each dieter of 20.99kg at an average of 1.2kg per week.

Of the 746 dieters 140 started below BMI 30. The average BMI before dieting was 28.54 and that at the end of the TFR period 24.06 (12.16kg) achieved on average in 78.84 days (11.2 weeks) at an average of 1.08kg per week. All these spent their whole TFR at BMI <30 representing 1,568 weeks TRF. As a matter of interest the average follow up for this group after re-feeding was 35 weeks and at that stage 79% had maintained all their lost weight with the average regain under 0.9BMI unit.

The remaining 606 dieters started at average BMI 34.6. They lost 23.03kg weight on average at an average of 1.18kg/week (total weight loss in this group 13,955kg). Their average number of days on TFR was 137.10 days (19.6 weeks), achieving an average BMI at the end of the TFR period of 26.08. Their total TFR period was 11,878 weeks of which 5,465 was under BMI 30.

This means that in this whole group, out of 13,446 weeks VLCD use, no less than 7,033 weeks (something over 50%) represented experience at BMI <30. In no dieter at any stage was there any serious or worrying side effect.

It was also considered important to examine the prime data in more detail to determine whether the information provided covered the broad range of the energy and carbohydrate levels (rather than just high carbohydrate levels providing energy levels close to 800kcals.

Table 2.3 A further split of the original data into Table a) <400kcal, 400-600kcal, 600-800kcal and b) carbohydrate levels 30-40g, 40-45g, 45-50g and >50g..

It should be noted that these figures differ slightly from those in Table 1 – some categories were not represented and for some a more detailed analysis was not feasible.

Nevertheless, the further analysis demonstrates not only that a major proportion of the data was derived from VLCD with an energy value less than 600kcals, but that over 90% of the subjects were receiving a daily carbohydrate level below 50g.

Several of the published clinical studies have investigated laboratory parameters of organ change (eg cardiac, haemopoietic, hepatic, renal) on a regular basis. Many more have undertaken spot laboratory checks. These have demonstrated evidence of improved health due to the weight loss but no adverse effects from the use of these diets.

It was suggested in some of the earlier reports that even if there appeared to be no overall excessive loss of protein during the use of VLCD, there might be specific extra and dangerous protein loss from the heart or other vital organs. However, as mentioned previously, clinical observations and laboratory investigations over a period in excess of 20 years, on more than 50,000 subjects using a very wide range of products of different composition with an energy content under 800kcal, have not demonstrated that any such problem exists. Nor is there any theoretical reason why damage to specific organs should occur.

Specifically there is extensive electrocardiographic evidence of cardiac integrity.

Obesity itself can produce cardiac changes (Hinkle et al 1969; Eisenstein et al, 1982; Frank et al, 1986; Carella et al 1996; Quaade et al 1996),). Indeed it has been calculated that an obese cohort subjected to surgery has 40 times the risk of sudden death compared to a normal weight cohort (Drenick & Fisler, 1988). Because the use of the seriously nutritionally deficient liquid protein diets in the early 1970s (which bear no relationship to the modern VLCD) led to fatal cardiomyopathies (FDA 1979; Sours et al 1981; Isner Sours et al 1981; Van Itallie et al 1984, random electrocardiographic recordings and regular Holter monitoring have been an important feature of studies on the modern very low energy diets in order to confirm that they do not have similar adverse effects.

The 12 formal studies (summarised in Table 2.4) all confirm that well formulated very low calorie

Table 2.4 Studies which examined the electrocardiograph by Holter monitoring at intervals during the use of VLCDs

diets produce no evidence of adverse effects on cardiac function. Additionally Linet (1983) ans Singer (1981) found no abnormality in food based diets (with added vitamins and minerals) at energy levels below 600Kcals/day.

Indeed calculations demonstrate that the incidence of sudden death in those being treated with VLCD well below the level which would be predicted from their age and weight

Examination of the "liquid protein diet" data on the 17 deaths that were studied (FDA 1979; Sours et al 1981; Van Itallie et aI 1984) show that the shortest period to any cardiac abnormality was several weeks. As Meuller and GrosskIaus wrote ( 1993) :

"Electrocardiographic changes do not become evident before 4-6 weeks of hypocaloric dieting" and "In subjects on VLEDs electrocardiograms are usually negative up to 4-6 weeks" and "a well supplemented VLED has fewer adverse effects on the electrical activity ofthe heart" (In fact examination of the original data suggests that the figure is more like 8 weeks than 4-6 weeks)

Hence the 12 ECG studies quoted here are not as valuable as they would appear at first sight because most cover the period before electrocardiographic changes wouId be expected. It must however be stressed that since 1978 there is no confirmed evidence of electrocardiographic changes at any stage.

This raises the whole question of the suggestion made by some authorities that regular routine electrocardiographic examination should be undertaken (even as frequently as weekly) on all those using VLCD. This suggestion has no validity-.-.

· The data indicates that the only reliable method for determining changes is by Holter continuous monitoring which is clearly impracticable. Thus in a study by Lantigua et al (1980) 3 out of the 6 subjects deliberately subjected to a hydrolysed collagen diet with added tryptophan showed cardiac conduction abnormalities, of which none were detected by 12-1ead ECG, only by continuous Holter monitoring.

· In six of the 17 who died in the liquid protein tragedy, normal ECGs had been found while they were taking the liquid protein diet.

· There is no agreement about the predictive relevance of any electrocardiographic features that might be found.

One recent widely publicised study (Greenway et al 1994) purports to demonstrate changes (particularly in the Q-T segment) related to the energy rather than the protein content but the changes reported are those seen commonly in untreated obese people and have no significance relative to the safety of VLCD (Quaade, 1996). Moreover Hinkle et al ( 1969) pointed out that " disturbance of heart rhythm and conduction occur in apparently healthy people with high frequency" while in the study by Carella et al ( 1996) between 41% and 53% (depending upon the method of determination) of obese people showed a prolongation of the Q-T interval before any dietary intervention.

It has also been postulated that since the protein turnover of myocardial proteins differs from that in skeletal muscle, this may produce a failure of protein conserving mechanisms in the heart and greater risks to that organ. Mueller & Grossklaus (1993) have pointed out that there is no failure of protein-conserving mechanisms in the heart for " the weight of the heart decreased in proportion to the decrease in body weight" and "Myocardial wasting...is not necessarily associated with reduced functional capacity" and "A 24-week of semi-starvation resulted in a weight loss of 15-20kg...but not circulatory insufficiency or heart failure" and "These data suggest a normal myocardial fiber performance in response to semi-starvation". These views expressed by Mueller & Grossklaus are in accord with the earlier observations of Smith (1928) and Amad et al (1965) that the weight loss in the heart during starvation is proportional to that lost in the rest of the body .

The relationship between heart weight and body weight also applied to those who died in the 1977 liquid protein diet tragedy (Sours et al 1981, Isner, Sours et al 1981 and Van Itallie et al 1984) while none of these 17 dieters showed untoward evidence of heart muscle insufficiency.

2.5 Data on side effects

A relatively small proportion of those taking VLCD experience side effects. The risk of side effects is greater if the dieter does not follow the directions given on the diet pack or by any adviser (particularly of strict compliance to the diet and to drink substantial quantities of water while taking the VLCD). The vast majority of these side effects are minor and easily corrected. They occur at two distinct phases - either within the first few days of starting the diet or after several weeks of VLCD use. The main early side effects are shown in Table 2.5

The minor and non-dangerous nature of these side effects is clear. Perhaps the only one which might require some further attention is gout, but throughout the whole period during which one of us (JM) was advising VLCD to dieters during the early trials, He did not encounter a single episode of gout. We have also discussed this with others with extensive VLCD experience who confirm that in practice they have never seen a case of VLCD generated gout.

It is clear that the major cause of the early side effects is that the advice about the need for strict diet compliance and a high fluid intake during the use of VLCD have not being followed.

A list of the main later side effects is given in Table 2.6 All these side effects may be found with any successful weight loss process, including surgery. Reassurance is normally all that is required.

For well over 50 years it has been known that there is an increased incidence of cholelithiasis, particularly cholesterol stones, with obesity (Gross, 1929) and this has been confirmed by many recent epidemiological studies- These demonstrate that the incidence of gall bladder disease in the morbidly obese varies from 28% to as high as 45%, while over 80% show histological abnormalities in the gall bladder (Williams et aI., 1977; AmaraI & Thompson, 1985; Maclure et al, 1989; Bennion & Grundy, 1975; Bennion & Grundy, 1978; Tudevant et al, 1973; Kucio et al, 1988. Everhart, 1993; Sichieri et al, 1991; Thijs et al, 1992; inter alia)

It is also known that changes in food intake in the normal or obese, by whatever means (total parenteral nutrition (Roslyn et al. 1983; Messing et al 1983), isocaloric cholesterol lowering diets, traditional weight reducing diets (Everhart 1993), jejuno-ileal bypass, gastroplasty (Shiffman et al 1993), VLCD) resuIt in an increase of cholelithiasis. Moreover other factors, which have no relationship to weight loss can also cause an increase in gallstone formation in the obese These include multiple parity (Grodstein et al, 1994, though this is disputed by Maclure et al 1989), high energy intake (Maclure et al, 1989), cigarette smoking (Grodstein et al 1994), and current and long-term use of oral contraceptives (Grodstein et al,1994)- In contra-distinction to these a moderate alcohol intake as opposed to abstinence is reputed to reduce the gallstone incidence in the risk population (Maclure et al 1989; Grodstein et al 1994).

Thus there are many confounding factors which may play a role in any studies of the effects of diet on the genesis of gallstones. The picture has been further confused by the fact that many of the recent studies compare modem ultrasound measurements during VLCD dieting or surgical intervention with previous studies based entirely on clinical examination incidence. The extent of the difference between the symptomatic and ultrasonographic incidence is clear from the Shiffman et al, (1993) study. Following bariatric surgery in 230 patients, he found an incidence of gaIlstones of 37% by ultrasonography aIthough only 10% showed any symptoms.

It has been suggested, particularly in the 1980s and the first half of the 1990s that a rapid loss of weight, such as that produced by the use of VLCD or following jejuno-ileal bypass and gastroplasty leads to a higher incidence of gallstones than that which results from a slower loss of weight (e.g. that which results from a 1200kcal diet). A careful examination of recent studies of the reputed lithogenic effect of VLCD shows no clear evidence that this method of weight reduction leads to any greater incidence of gallstones than other methods which produce the same overall weight loss (Sturdevant et al, 1973; Mok et al, 1979; Schlierfet al, 1981; Wattchow et al, 1983; Messing et al, 1983; Roslyn et al, 1983; Anderson et al., 1984; Amaral & Thompson, 1985; Bolondi et al., 1985; Broomfield et al 1988; Jacob et al., 1989; Janowitz et aI., 1989; Liddle et aI., 1989. Yang et aI, 1990; Marks et al., 1991; Little & Avramovic, 1991; Shiffman,1991; Hoy et al., 1991; Mazzella et al., 1991; Shiffman et al., 1992; Karnrath et al., 1992; Heshka et al; 1992; Yang et al, 1992; Dammbach et al, 1993; Everhart, 1993; De Filippo et al., 1993; Festi et al 1993; Spirt et aI 1995; Gebhard et al 1996).

Examination of the literature shows that, with very rare exceptions, claims of increased incidence of cholelithiasis with rapid weight loss are American. The European literature is devoid of such reports and conversations with those European experts who have used VLCD extensively confirm that gallstone formation has not been a problem. Perhaps even more importantly, in those papers in which the details of the weight loss programme are recorded, the majority stem from two commercial weight loss products widely used in the USA but not in Europe.

If instead of just taking the total energy intake, one examines the energy sources involved, the picture becomes more clear (Table 2.7). Unfortunately no formal study has been undertaken with the equivalent of the typical European diets (under 600kcals with about 7g fat per day) although there is substantial evidence from adverse effect incidence in large scale studies in Europe- One of the best studies is that of Festi et aI, 1998. They compared two VLCD with very similar energy content but 9glday difference in the fat content. The number of patients in each group was small, but there was a significant difference (p= <0.01) in the incidence of new gallstones.

Table 2.7 Relationship of fat intake per day to percentage of cholelithiasis.

Probably due to the number of confounding factors, the relationship between the fat intake and the gallstone incidence is not quite uniform, but there is a very strong indication that it is the level of fat in the diet rather than the calorie level per se, which is of prime importance. The mechanism involved would appear to be the extent of biliary wall motility and regular gall bladder emptying (Kucio et al, 1988; Marks et al, 1991; Mazzella et al, 1991; Festi et al 1992; Shiffman et al 1995; Marks et al 1996)-

The available data, particularly the fact that cholelithiasis is virtually unknown as a complication with the widespread use of European commercial VLCD, suggests that a daily intake of about 7g fat is necessary to ensure that gallbladder contraction is normal. This fits in well with the observation that United States diet programmes are associated with a higher incidence of gallstones than European. It also explains why, when one United States commercial formula was changed, with the addition of extra fat per day, the incidence of reports of gallstone problems recorded in the American literature almost ceased.

It is clear from all the evidence that any effective weight reduction leads to an increase in cholelithiasis during the weight loss. Subsequently the risk is less. Formulation differences and advice on fluid intake appear to be important. Whether high protein levels encourage cholelithiasis (by reducing gall bladder contractions) is not clear. However higher fat levels do discourage gallstones (by increasing regular gallbladder contractions). As already noted, the recommended fat level in VLCD (to provide essential fatty acids) of about 7g per day is advantageous from the point of view of reducing the incidence of gallstones.

During the past few years it has been suggested that the use of VLCD for weight reduction might lead to calcium deprivation similar to that reputed to occur during the use of a high fibre weight reducing diet (Avenell et al, 1994)

In consequence, several studies have been undertaken to determine the factors causing loss of bone density in post-menopausal women and whether prolonged use of VLCD (up to 15 weeks of continuous use) would lead to a similar loss of bone mass to that reputed to be seen with high fibre diets.

For example Van Loan et al (1998), using dual energy X-ray absorptiometry studied fourteen women during a 15 week diet period, over which period they lost weight at an average of 1 kg per week- They found no loss of bone mineraI caIcium in spite of the marked loss in weight although there was a small loss of bone density. This was equivalent to the findings of Compston et al ( 1992) during an 8 week study with a VLCD.

From other recent studies (Pritchard et al, 1996; Brot et al, 1997, Ensrud et al, 1997, Willing et al, 1997) it is clear that, as could be logically expected, there is a direct relationship between bone density and body weight. It is largely the strains on the bones that determines their density. Whether weight is lost intentionally (by whatever means) or unintentionally, the bone density is reduced roughly in proportion to the loss of weight..

It has also been suggested that VLCD may be abused leading to eating disorders such as anorexia and bulimia. There is not one iota of evidence for this. These disorders are entirely psychological in origin. By the very nature of these disorders, which are concerned with false body image, it would be anticipated that there would be an association with various forms of dieting. However because there is an association, this in no way implies that dieting is causative.

Even if they were not psychological, those patients who are involved try to avoid VLCD because they are too energy dense- They choose less energy dense methods of reducing their weight since the volume of the alternative low energy dense diets reduces the patient’s hunger with less energy intake.

2.6 Data on aspects of use and control in practice

Several recent studies (Apfelbaum, 1993. Van Gaal et al., 1992; Coxon et al., 1992; Kreitzman, Johnson & Ryde, 1992; Rattan et al., 1989) have demonstrated that the initial 15% reduction in resting metabolic rate is a physiological response to reduced food intake within the first few days of dieting and is not related directly to the actual energy intake or to the amount of weight loss. The subsequent long term reduction in the resting metabolic rate depends on the extent of the weight loss irrespective of the method and energy levels by which it is achieved (Figure 2.1) (James et al, 1978; Rattan et al., 1989. Van Gaal et al, 1992; Wadden et al., 1992; Coxon et al., 1992; Wadden et al., 1990; Kreitzman, Coxon et al., 1992; Kreitzman, Johnson & Ryde, 1993).

Figure 2.1. The effect of excess body weight on resting metabolic rate (RMR). Based upon James et al (1978)

It is now clear that the formulae developed by Schofield et aI. (1985) linking the resting metabolic rate to the weight are correct and that the views of the Wadden group, heavily quoted in the 1990 SCF Report that the fall in metabolic rate depended upon the rate at which the weight was lost during dieting were at error

The study by Kreitzman et al. (1993) demonstrated that the total daily energy expenditure is not influenced during dieting, whatever the energy intake. The weight loss showed a high correlation with the total energy expenditure (r = 0.82). In consequence, in those studies where special attention was directed to ensuring compliance, the rate of weight loss per week, which depends on the energy deficit shows good correlation with the energy intake, after the first week of dieting, during which glycogen and the attendant fluid loss complicate the picture (Table 2.8)

These figures represent averages over at least an eight week period. Similar conclusions were drawn by Jensen & Quaade (1996) using somewhat different criteria- It must be noted that, though the correlation is good for groups of dieters, examination of the individual weight loss does not always show such a good correlation even when compliance appears to be good. There are various possible explanations for this (Marks & Howard,1997).

As would be anticipated from what has been said about the resting metabolic rate being dependent on the body mass and not on the rate of its change during dieting, clinical experience and experimental studies show conclusively that there is no greater difficulty maintaining the target rate after rapid than after slow weight loss. The question of weight maintenance is dealt with later.

Weight cycling (yo-yo dieting) does not lead to increased fat stores, reduced metabolic rate, and less effective weight loss with each cycle as was previously suggested. In several excellent studies (Forbes, 1987; Steen et al., 1988, Prentice et al., 1992; van Dale & Saris, 1989; Kamrath et al, 1992; Wadden et al., 1992; Beeson et al., 1989; Bene et al., 1991; Blackburn et al., 1989; Brownell, 1989. Chen & Cunnane, 1993; Goldberg et al., 1990; Jebb et al., 1991; Kamrath et al., 1990; Kaplan et al., 1992, van der Kooy et al 1993) it has been shown that weight cycling does not have an adverse effect on body composition. Hence the metabolic rate and rate of weight loss of the various cycles are equivalent.

Earlier studies in Sweden and the USA (Lissner et al, 1988 a&b; Lissner et al. 1989) suggested that weight cycling increases coronary disease and hypertension risk, but this was not confirmed in more recent studies undertaken by the group who made the original observation (Lissner et al. 1990, 1991; Brownell & Rodin, 1994). It is important to appreciate that Castelli, one of those involved in the Framingham Heart Study, subsequently affirmed that there is no evidence of any undesirable physical sequelae from weight cycling. This has been confirmed by further more recent studies (Willett et al 1995, Wing et al 1995, Itoh et al 1996, Field et al 1999). Nor could Bartlett et al. (1996) find any untoward psychosocial sequelae.

There had also been some papers which suggested that weight cycling produced unstable body weights which in turn lead to a greater mortality risk. More recent studies have confirmed that there is no relationship between weight cycling and risk of premature mortality and that the previous observations resulted from a confounding effect of weight loss due to disease (Williamson 1996, French et al 1999).

But even if such an adverse effect exists, weight cycling is found with all forms of dieting and no causative relationship between VLCD and the reputed increased risk has been established. Hence it has no relevance to the current considerations though it has been regarded in the past as a problem alleged to be related to VLCD.

Some reports state that when a considerable weight loss is necessary, this should be done in a series of three, four or six week periods separated by one week or more when the diet is supplemented by 'normal' food of a higher calorie level.

There is no scientific reason for this procedure, indeed from the point of view of experience it is highly undesirable and de-motivating. The main effect of the higher calorie periods is to increase weight by the accumulation of glycogen and water which serves no useful purpose. Indeed, some studies can be interpreted as demonstrating that intermittent dieting in this fashion may lead to increased protein losses. However this is far from proven. Those who accept the appetite dulling effect of ketosis ( and there are doubts about this effect) stress the discomfort of the intermittent method. As a result of either or both the weight increase and/or the effect on appetite, there is a greater risk of an unsuccessful outcome as a result of people dropping out. Moreover, practical experience of substantial weight losses by continuous VLCD use over many months has shown no undesirable effects.

Very low energy diets per se cannot achieve long-term weight control any more than can any weight loss method. The only way to achieve long-term weight control is by a fundamental change in lifestyle (eg regular exercise, smaller meals, lower fat content).

From the earliest studies of, for example, Stunkard & McLaren-Hume (1959) it has been clear that, in practice, the vast majority of those who lose weight by whatever means (reduced food intake, formula diets, exercise, behaviour modification, drugs etc) are back to about their pre-dieting weight within 1-5 years. In general terms it appears that bariatric surgery, though it has mortality and morbidity in excess of medical management may have better long-term results on weight control. However a recent paper (KIein et aI 2000) stresses that when a successful cohort of surgical and medical weight losers are compared, the differences may not be all that great in psychosocial terms.

The obesity literature now abounds with reports of attempts to effect long-term maintenance of reduced weight and to define the factors that can predict the chances of success in the individual (e.g. de Pue et al 1995, Pasman, Saris & Westerteerp-Plantenga 1999; Karkeila et al, 1999 each looking at different aspects)- There have been some recent studies of the effect of a lipase inhibitor (Orlistat e,g, Rossner et al 2000) which appear promising, but there are so many examples of early enthusiasm and later disappointment in this field, that it appears wise to exclude these observations for the present. Moreover there are some unpleasant side effects associated with the use of Orlistat and this may preclude the long-term use of this preparation.

The current views on the principles which lead to the best long-term results appear to be-

· It is vital to manage excess weight as a progressive chronic disorder The longer and more intense is the support and counselling the better is the result

· Long-term support and counselling by a trained non-professional can be just as or even more effective than professional care (e.g. Wing & Jeffery, 1999). What matters is willingness of the advisor to provide long-term adequate firm support with empathy. Time and patience are essentiaI.

· If the reason for the overeating can be established and alternative strategies established this appears to help

· Reduced fat intake, appetite reduction (including appetite suppressants e.g Apfelbaum et al 1999) are common strategies, but perhaps of greater importance is the encouragement of adequate regular aerobic exercise.

· Self-help groups appear to be of value for some people (Andersen & Grimsmo 1999)

· There is no single technique which works with everybody and tailoring a selection of procedures to the individual is to be encouraged.

During the 1980s there was quite a large literature, particularly in the USA and among those who favoured behaviour modification, suggesting that the use of VLCD reduced the potential for long-term maintenance and this view was represented strongly in the 1990 SCF Report. However more recent studies show that the results of education towards more exercise and smaller more appropriate food intake can be achieved during and after VLCD use at least as well as with other diets.

Very low caIorie diets have been reported to be a valuable component of long-term weight reduction and control regimes (Dietz & Greenberg, 1985; Palgi et al., 1985; Wadden et aI., 1986; Kirschner et aI., 1988; Sikand et al., 1988; Hovell et al, 1988;

Wadden et al., 1988; Miura et al., 1989. Cox et aI_, 1989. Wadden et al., 1989; Niemi et al., 1990; Anderson & Brinkman, 1990. Atkinson, 1990; Donnelly et al., 1991;

Brownell, 1991; Cox et aI_, 1991; Anderson et al., 1991; Brownell & Wadden, 1991;

Wing et al., 1991; Wadden et al_, 1992; Anderson et al., 1992; Atkinson et aI., 1992; Blair, 1993 inter alia). Indeed several studies over the past five years suggest that the long-term results may be superior when a VLCD is used as one feature of the process which leads to a lifestyle change (Quaade & Jensen 1995, Wadden & Frey 1997, Andersen et al 1999, Apfelbaum et al 1999), though this is far from proven. One interesting feature is that a substantial number of trials in the last few years of the twentieth century used VLCD as their diet component without referring to it as a VLCD. This suggests that VLCD are becoming accepted as equivalent in safety to any formula diet but as more effective. Even more interesting is the fact that some of the behaviour modification groups who wrote most vehemently against VLCD in the 1980s are now using and advising VLCD as the diet component of their overall management.

When the revision of the original 1998 report to the SCOOP Working Group was first started, the aim was to try to determine by an analysis of the literature whether the long-term results using VLCD are at least as good as those with other energy reduced foods. F or the present this has been abandoned because the level of variation in the length and intensity of the support and counselling, the food advice, the form and intensity of the exercise inter alia is so substantial. Added to this there is considerable variation in the drop-out rate and how the drop-out information is handled in the analysis presented in the original papers.

However as a result of a request from the working group we have examined further the question of a comparison of the long-term results with VLCD compared with the results that can be achieved in the long-term using other methods and other diets. This examination confirmed our previous view that it is impossible to find in the literature valid information on which a reasonable appraisal can be based that would withstand even minimal critical analysis.

We would specifically draw attention to the following table showing a selection of the various factors identified in the literature as influencing the long term efficacy viz:

As if this situation were not daunting enough, the individual papers do not attempt to specify even a limited proportion of these confounding features, nor is it possible to find standard answers to even a limited list.

However, while bearing all the concerns about validity in mind, I have taken a random selection of the results and expressed them in the form of graphs. Since it seems that the greatest relevance lies in the percentage change from the original weight that is achieved at each stage, we have expressed the graphs in this form so far as possible. We have accepted the figures as reported in the original paper and not attempted to correct for dropout level (where this is stated) since there are various ways by which dropouts could be corrected.

Specifically we have selected papers (see figures 2.2 to 2.10) which indicate that while the general proposition is true, namely that stopping control of the subjects means a return to their original state, demonstrate that there are a many studies in which this has been avoided, by long-term close control. Moreover even in those groups in which recidivism is the rule, there is a proportion of the population who have sustained a substantial weight reduction. The information which has been presented, shows we believe that the long term results have nothing to do with the precise means of weight reduction or maintenance, but depend on the amount of effort that is put into long-term management. This is scarcely surprising for a psycho-social disorder.

Figure 2.2. A diagram taken from Hensrud et al (1995) showing the effect of a study with an 800kcal food based diet in moderately overweight women. At the end of the dieting period no further action was taken until the subjects returned at the end of 4 years. The result is compared with a control group of normal weight women to show that the normal weight does rise with time. The failure of weight maintenance is typical

Figure 2.3. Diagram from Bjorvell & Rossner (1985). This compares a control group who were given instructions about how to lose weight but then left to look after themselves. The next (dotted) line is that for a food based 600kcal food based diet . In the maintenance phase, the subjects could take part in a regular advisory programme if they wished The lowest (dashed line is that for jaw wiring followed by a regular voluntary advisory service . Note that with the advisory service there was a reasonable weight maintenance, in this study apparently better for VLCD than for jaw wiring

Figure 2.4 This is a diagram based upon the information in the paper by Anderson et al (1992). They used a 500kcal VLCD and achieved a good weight loss. The subjects were encouraged to undertake a weekly advisory programme during the 24 month follow up with self monitored exercise , but only a proportion did.

Figure 2.5 This is a diagram from the Pasman et al (1999) study. This treated the whole group with a 460kcal diet for two months. All subjects took part in an endurance programme for the first four months. Then one group (solid) continued with the exercise for the rest of the period while the others acted as a control group. In this study there was no apparent difference as a result of the exercise regime used.

Figure 2.6 This is a diagram from the study by Torgerson et al (1997). It compares a non VLVD group (hypocaloric food diet throughout) with a group who took VLCD (400-500kcal) for 12 weeks followed by a hypocaloric diet for the rest of the period. The final result for women shows no difference, but that for men a greater weight reduction and then a lower end point. It is interesting that men show better results in most of the papers. This diagram shows that there are specific reasons for different responses, not just the use of VLCD

Figure 2.7 This diagram by Miura (1989) shows the effect of VLCD alone, behaviour modification alone and a combination of the two This particular behaviour modification programme appears to be effective – others do not.

Figure 2.8 This is a diagram from Ohno et al,(1990). Like Figure 8 it shows an effective pattern with VLCD plus behaviour modification but not with VLCD alone.

Figure 2.9 This is the study by Pavlou et al (1989). This study, in contradistinction to others shows a beneficial effect of exercise on the long-term results with both 800 kcal food and formula diets and with a 420kcal VLCD. I am puzzled that the non exercise hypocaloric food diet was so effective in reducing the weight.

Figure 2.10 This diagam comes from Dittchuneit et al (1999) who compared the effect of either a food based diet (1500kcal approximately) or a diet in which two of the meals were replaced by a formula diet for 3 months. For the 24 months maintenance phase all the subjects consumed a maintenance programme diet which substituted one of the three meals by a formula diet. There was a monthly weighing programme but no behaviour modification was attempted..

SECTION III.: RECENT SCIENTIFIC STUDIES WHICH HAVE PRODUCED A BETTER UNDERSTANDING OF THE PROPERTIES OF VERY LOW CALORIE DIETS.

During the 1980s two fundamentally opposing views developed concerning the nature of the body composition changes which occurs when weight is lost and the influence exerted by the composition of the diet on the body compositional changes. This is exemplified by the differences to be seen in the COMA (1987) report and that for example in the SCF (1990) and Codex Alimentarius (1995) reports.

The first view was that propounded by Webster et al (1984), Garrow et al (1985) which supports the older view if James et al (1978). This held that when weight is lost as a result of any energy deficit with a diet which provides adequate macronutrients, be it at 400 or 1200kcal intake per day, protein is naturally and necessarily lost at the same time as fat, the accepted proportion being about 75% fat: 25% protein.

The alternative view, which depended largely on the observations of Forbes (1987) was that the proportion of fat to protein in the weight which was lost varied depending upon the proportion of the fat in the body. Thus it was held that for those who were very obese a substantial proportion of the weight loss consisted of fat while for those of lesser levels of excess weight (and therefore fat) there was a significantly higher proportion of lean fat loss. This would have the effect that not only would there be increased danger of protein deprivation in those of lesser excess weight, but in this group the loss of the additional lean mass would also have a greater lasting effect on future ability to maintain the lower weight due to the reduction in the basal metabolic rate. It was further argued that in the overweight the loss of lean body mass would be replaced by fat during re-feeding.

These alternative views have such a vital effect on our understanding of the body composition effects of dieting that it was felt imperative to examine the extensive recent literature on the subject to determine where the truth lies. To this end the following matters were reviewed.

1. The level of accuracy and reproducibility of the various techniques which have been used for the study of body composition changes.

2. The studies that have been undertaken on body composition changes during weight loss and their interpretation.

There are now a substantial number of papers which deal with the reliability of various analytical methods for determining the composition of weight losses during dieting. A qualitative overview of these is given in the paper by Lukaski (1987) (Table 3.1).

One of the methods not considered in the Lukaski paper is that of nitrogen balance by Kjeldall analysis, a method which was widely used in earlier studies including some of those quoted by Forbes. Because it was so widely used and quoted in the 1980s literature, a study of the reliability was undertaken in Cambridge.(Kreitzman & Beeson 2001). This serves well as an example of one of the difficulties in the whole body composition area:

“Until recently the “Kjeldall method” of nitrogen determination was the only method for direct measurement of protein balance. There are a substantial number of potential errors arising, for example from inappropriate corrections for unmeasured nitrogen intake and loss. However less has been published about the reliability of the method itself and it was therefore felt desirable to check this.

Samples (from 24 hour collections of urine) from eighteen subjects who were undertaking a VLCD weight loss study were submitted for analysis to a widely recognised and extensively used commercial laboratory. The results, shown in (Figure 3.2) as the left hand (unshaded) blocks represented a single analysis for each sample.

Each sample was at the same time pipetted in triplicate into sample bottles and labelled randomly as 54 sequential samples. These were then submitted blind to one of the senior UK academic laboratories whose results have figured extensively in UK nitrogen balance studies over many years. Each sample was analysed in duplicate by the laboratory and the results are presented as an average (shown darker hatched on the charts (Figure 3.1).

When the code was broken, the differences between the academic and commercial laboratories on the same sample were substantial, with each commercial figure representing a substantially higher daily protein loss. However even more surprising was the variation between identical samples tested blind in the same academic laboratory. It is important to stress the importance of the size of the differences within this laboratory. In the worst case, these differed by as much as 5g nitrogen per litre. This would be interpreted as more than 30g protein lost per litre urine

Figure 3.1 The results of the Cambridge study of the reliability of the Kjeldall measurement of nitrogen balance. For details see the text.

In the particular dieting study, the twenty four hour samples that were being analysed generally amounted to 3 litres total volume. Therefore a difference of 5g/litre would have meant differences of about 100g/day of lost protein, purely on the reliability of the method in the laboratory. It is clear that such a difference would render the nitrogen balance meaningless.

It is fully accepted that this just represents the results in one laboratory, albeit one of the reputed best in the UK. The only interpretation which should be applied is that for any laboratory presenting nitrogen balances based on micro-Kjeldall estimations, there should be a blind study at regular intervals of the reliability of the method in their laboratory and preferably a blind audit across a group of laboratories”.

In this respect it is worth pointing out that the problem with a graph of the Forbes/Prentice type which takes results from various laboratories, at different times, is that the cross reliability between laboratories is largely or completely unknown. This concern also applies to the Ballor & Poehlman (1994) widely quoted paper on the influence of exercise on the FFM loss, since this paper utilises information from various laboratories the cross reliability of which is unknown.

It is important to stress that the vast majority of the methods used in papers which purport to determine protein balances during weight loss do not measure nitrogen, but set out to estimate a representation of the protein content of the body from other measurements. The estimate which is most widely presented used to be called “lean body mass (LBM)” but is now better called “fat free mass (FFM)”.

Contrary to popular medical belief FFM does not represent the protein component but consists of at least 6 compartments (intra-cellular water, extra-cellular water, glycogen, bone, minerals, protein). Each of these compartments can change independent of the other to a greater or lesser extent during physiological and pathological conditions (including dieting). For example, the physiological conditions which have a profound effect on indirect body composition estimations include:

Inactivity – not only bed rest but also restriction e.g. plaster cast on a limb.

It is important to stress the importance of the glycogen compartment in this whole discussion. The glycogen store itself is about 400-500g, but each g of glycogen has associated with it between 3 and 5 g of water. Hence with dieting (or re-feeding) there will be a change in the first few days in the glycogen compartment amounting to anything up to 2kg. Thus any current indirect measurement of body compositional change must take account of this substantial component. This particularly applies to the first few weeks of dieting (or re-feeding). This is why it is vital to ignore studies of less than about 4 weeks and also to ignore those in which the post-diet determinations have been made after even a brief period of “maintenance”.

There are several older studies that have investigated the variations from one technique to another (e.g. Yang et al, 1977; Vaswani et al, 1983; Garrow, 1990) However during the past 10 years a substantial literature has been published on technical aspects of neutron activation analysis of various chemicals, a substantial proportion of these papers emanating from the Heymsfield group. This is currently the only method by which chemicals within the living body can be measured directly. Among these chemicals is nitrogen. Neutron activation can determine directly the nitrogen status within the body. Even then it can not measure the protein economy itself since protein is only one of the nitrogen containing body components, albeit the largest one. Unfortunately neutron activation analysis is expensive and there are relatively few units which can currently undertake this determination. In consequence, though neutron activation analysis is the current “gold standard” it is still necessary to rely heavily on indirect estimates of the body composition. Interpretation of the indirect methods must be guarded and the assumptions questioned thoroughly

As a consequence it is important to determine not only the reliability of these various methods in their own right but how far they cross correlate, one with the other, not only under stable conditions but under variable physiological and experimental conditions. There have been many recent papers which have reported such cross comparisons though usually with only a few methods in any one study. These cover studies in normal humans, the aged etc. However one study in the USA (Albu et al, 1992), one in the UK (Kreitzman et al, 1993) and one in Spain (Valtuena et al, 1995) are directly relevant to the present situation and appear to be the best to indicate factors of current importance.

The Albu study (which comes from the Heymsfield group), looked not only at various recent methods, but also how these would be converted to FFM estimates, using different equations and different numbers of compartments. They studied 10 dieters, taking a 600kcal VLCD for 24 weeks and Figure 3.2 shows the dramatically different estimates for fat and FFM that emerge in each individual dieter when different study methods are used. It is important to note from this figure that the variation is not uniform for any individual method (look, for example at the figures for ⁴⁰K water dilution (2C-TBK) compared with those for tritiated water dilution (2C-HD)).

Figure 3.2. Effect of different methods of determination on the estimated fat loss (from Albu et al, 1992)

In the Kreitzman et al (1993) study, not only was the change in body composition of the eleven dieters using a 405 kcal diet for 10 weeks measured by twelve different observations, but for four of the methods, studies were made in entirely independent units, namely:

Thus this study provides information on both the reliability and reproducibility of the individual methods of indirect estimation but also cross laboratory consistancy.

One method of demonstrating the degree of variability within methods and between methods is to calculate the FFM changes for each, the ratio DFFM/DFAT and the mean fat weight i.e. the values used for the Forbes and Prentice diagrams. The ratio which would arise for each subject using each estimate is shown in the graphs in Figure 3.3 (next page)

Once again while the variation in the means is not very great, the individual variations are large and as irregular as those of the Albu study. With such individual variability it is clear that it is

Figure 3.3 The results of the study of the DFFM/DMean Fat Wt ratio in 10 of the 11 subjects who undertook the experimental 10 week VLCD diet. The body composition of each of the 10 subjects was estimated with 8 main methods (many in duplicate/triplicate in different units). The details of the studies are to be found in “The Swansea Trial” Eds Kreitzman SN & Howard AN Smith-Gordon & Co Ltd 1993. Note that the eleventh subject is not included because she was not able to undertake the densitometry measurement.

not possible to reliably recalculate the estimate in any individual patient for one method on the basis of another method.

The third study is that of Valtuena et al (1994), graphs showing the results of which are shown in Figure 3.4. Their results are very similar to those of both Albu et al and Kreitzman et al, though with fewer methods studied.

Figure 3.4 The results of a study by Valtuena (1995) of the DFFM/DMean Fat Wt ratio determined in nine dieters, each studied by three different methods.

It was hoped that it would be possible to determine whether there was any correlation between these studies to indicate whether any characteristic of the subject might show a correlation with deviations in an individual method. Unfortunately it was not possible to do so because of major differences in the methodology. Indeed it was not possible to use the Albu data further because it included a variable maintenance period (24 – 33 weeks). There was an extra problem in further analysis of the Albu study because only 7 of the 10 dieters were studied post diet, but the paper does not indicate which they are.

An overall representation of the variation which derives from the use of different study methods is shown in Figure 3.5

Figure 3.5 Comparison of the body composition results using five different methods in four different studies. Densitometry results are taken as 100 and the results of the other methods expressed as a proportion of these.

In part the different results given by the various methods may be explained on the basis of different degrees of obesity. Thus Gray et al (1989) showed that when the body fat was over 48% of the total weight, impedance overestimates FFM when compared with the results from densitometry. In part it depends on other physiological variables which can change, with time in the same person. For example the observations recorded by de Groot et al (1989) using diets of very similar composition show wide fluctuations in the DFFM/DWt ratio (0.09, 0.37, 0.18, 0.47; see record 24A to 24D in the summary table ***).

Other studies that have examined the variation in the FFM which results from the use of different indirect methods include Murgatroyd & Coward (1989); Heymsfield & Waki (1991); Ballor & Poehlman (1994); Houtkooper et al (2000); Piers et al (2000).

3.1.4 Variation introduced by different formulae for conversion using indirect methods.

From what has been written here it should be clear that each of the indirect methods for estimating FFM require fundamental assumptions to be made in order to calculate FFM (or fat and hence FFM by subtraction). The body compartment which is determined and some of the assumptions that are made for representative indirect methods are shown in Table 3.2.

Table 3.2 The compartment which is determined and some assumptions that are made for some of the common body composition estimation methods.

1) Constant hydration of FFM can not be assumed since total body and compartmental fluid status is variable at different stages of diet and also varies from subject to subject. The test converts TBW into FFM based upon the assumption that FFM is 73% water which is not universally true

2) Stable hydration state within and between subjects is assumed and is not true under different study conditions. Hydration is influenced not only by the intake and excretion of fluids but also by food, hormones, temperature, activity levels, drugs etc both before and during any study.

3) Oedema fluid is different between subjects especially when obese subjects are compared with the non-obese. Loss of this fluid may be sensitive to macronutrient intake.

4) Dietary potassium intake will reflect in ⁴⁰K measurement, e.g in study of formula diet in which the calories are raised with milk to compare with lower calorie water. Milk is potassium rich which is measured in total body potassium pool and would wrongly suggest increased FFM.

5) Many studies show that potassium can change independently of nitrogen. Changes in fluid balance will change potassium without any change in nitrogen.

6) Terrain- The measurement of body potassium assumes a constant source to detector distance and uniform absorption path. Human bodies do not comply, especially when they are changing shape during weight loss. Also varying fat distribution will influence readings.

7) Water confidence. The test involves underwater weighing of the subject in a confined tank and if subjects are obese, external weights are needed to keep subject submerged. Total exhalation is required. The procedure is less problematic in no-obese subjects.

8) Oedema fluid contributes to weight and loss of this fluid will change body weight by a greater proportion than that shown by skinfold measurements, not least because the areas where skinfold measurements are made are not those where oedema fluid would be expected to be marked. This will therefore suggest higher FFM loss per weight loss but not related to a loss of protein

But even this is not the limit of variation because many of the estimates include “correction factors”. These are not the same from one study to another, even when the same method is used (as an example see Table 3.3.)

Table 3.3. The effect of different prediction equations on the conversion of hydrostatic measurements to body fat estimates (from ***)

But even without variation introduced by the use of different formulae, there is evidence that the calculations can not be applied across different levels of obesity. Thus Lohman (1977) showed that for subjects with over 30% fat, the Siri equation for the calculation from densitometry measurements yields higher values for FFM that does that of Brozek.

To summarise the situation, the accuracy of each method of body composition estimation depends upon:

· Biological variations influencing the interpretation of indirect methods when these actually measure independently variable body components

· Different formulae for converting the observations into a measurement of reputed fat mass, fat free mass etc.

It must be appreciated that for weight loss studies these problems are further complicated by the fact that the tests are undertaken both before and after the diet. Each has its own level of inaccuracy and each is influenced by physiological variables, including those that arise from endocrine changes resulting from the diet and the stage of the diet itself (e.g. first week of re-feeding).

Even then there are further complications, for it has been demonstrated clearly by Saris that exercise during dieting can influence the preservation of lean body mass.

3.1.6 Significance of these variations in relation to the Forbes/Prentice graphs.

If every single point in the Forbes/Prentice graph was based upon a determination of the same body component using the same technique and converted to FFM using the same formula, there would still be the problem that results from individual variation. However the situation is far less clear than this. Of the studies quoted by Forbes (1987) and Prentice et al (1991) as the source of their data for the graphs which we have examined carefully, the data is probably derived from the following techniques

We have used the words “probably derived” because some of the studies have used more than one technique and it is not clear which result has been taken for the Forbes/Prentice graph. It has been assumed that when there was a densitometry estimate available this was the one that was used, but there is no direct evidence that this was the case.

On the basis of what has been presented above, it is submitted to the Working Party that, as presented, doubt must be cast on the accuracy of the overall graph as shown in Figure 11b of the Prentice et al (1991) (see Figure 3.6 of this discussion paper). That graph was based on different indirect methods of estimation, undertaken in different laboratories and applying different formulae to derive the body composition.

Figure 3.6 Figure 1 from the Prentice et al (1991) paper which the Working Party asked to be re-examined.

3.2 Re-examination of the old data and examination of new data relating to body composition changes

Despite all the problems that have been identified, it appeared to be desirable to examine each of the papers cited by Forbes(1987) and Prentice et al (1991) to determine the method used and other relevant information.

In addition a search has been undertaken for other relevant papers over the period from about 1960 to 2000. Over 100 papers which were available for detailed analysis could be identified.

From these we have attempted to identify those studies which must be eliminated because they were invalid and to indicate why (Appendix 4). Ideally only those studies should be included which are based on formula diets, the exact composition of which could be verified. Unfortunately this removed almost all the studies of 800-1200kcal diets since the vast majority of these are food based. We therefore modified the criteria maintaining a category based on the following criteria

There were a certain number of these studies which were quite clearly inappropriate (hydrolysed collagen diet, starvation, use for only a few days etc) and these have been totally rejected. For the remainder, including those that have been rejected for other reasons (e.g. method of estimation of the composition) we have shown all the actual raw data, the basis of the calculations and the DFFM/DWt ratio and mean fat weight in Appendix 4. From this table it was possible for any member of the Working Group to check the data. They can then determine whether they feel that the plots of DFFM/DFAT and mean fat weight which have been made are valid. The ratios and mean fat weight of those studies that have been regarded as “acceptable” and “provisional” as bold in this table to make it easier to distinguish them.

It is disappointing to find how few valid observations are available from some 40 years of studies worldwide. Of more than 60 papers examined only about 20 contain valid data. This is clearly the only data on which we can try to determine whether

From this “valid” data we have shown on separate Figures (Figures 3.7 and 3.8 – next page) the ratios plotted against MFW for the use of formula based VLCD 400 to 800Kcals (Figure 3.7) and formula and food based diets between 800 and 1200 kcals (Figure 3.8). We have also plotted the information for the individual dieters in those studies (Deurenberg 1989: Kreitzman & Howard 1993; Valtuena et al 1995,) in which there are enough observations at various body fat levels (Figures 3.9, 3.10 and 3.11 – two pages on).

On the basis of the information given in Appendix III and plotted in Figs 3.7 to 3.11 it is submitted that there is no current evidence for either of the above widely publicised views, namely that the composition of the weight which is lost depends on the body fat level or that VLCD produce a higher proportion of FFM loss that do higher energy providing diets.

Hence there is no evidence that VLCD are more dangerous than other diets when used in the overweight as opposed to the obese. We have sought to determine whether these views can be supported by statistical analysis but the data is too limited. In any case the use of statistical methods must be suspect when the data is liable to such a high level of error.

The figures which follow have not been re-labelled from those presented to the Working Group.

In the above diagrams relatively little of the information has been expressed in terms of the original or finishing BMI level, but information expressed in this way was requested by the Working Group.

Unfortunately, the body composition data (by any method) expressed in terms of BMI, are not available for all the studies. Forbes expressed his results in terms of mean fat weight and most subsequent authors followed this pattern. However, if it is accepted that a MFW of 30kg is broadly equivalent to a BMI of 30 then it is clear from Appendix 4 that there are a substantial number of individuals in the range <30 MFW for diets of <400kcal, 400-600kcal 600-800kcal and above 800kcal.

For some of the studies it is possible to examine the DFFM/DWt ratio for individual subjects above and below MFW 30. Therefore although it is not possible to compare with other studies (due to different methods), it is possible to assess the situation within the same study. We would specifically draw attention to the fact that not only do these cover patients whose pre-treatment BMI (or MFW) is below 30 but it is clear from the data presented that some at least of the subjects were reduced to BMI levels between 20 and 25

3.2.3 The body composition studies expressed in terms of the energy value of the diets.

Energy content	Number of studies
<400	1
400-600	4
600-800	1
>800	11
Various	2

There is no indication that the energy value of the diet used influenced the body composition changes with weight loss

This study, which is always quoted concerning the effect of “semi-starvation” clearly influenced the Forbes analysis of changes in body composition with changes in body weight during dieting.

It was undertaken on a group of 32 young male volunteers. At the start of the study the mean BMI was 21.9. As a result of 24 weeks dieting this was reduced to a mean of 16.9. Body composition studies were undertaken at time 0, 12 weeks and 24 weeks by hydrodensitometry. The exact technique differs somewhat from modern methods and the results can not be compared directly with those quoted in Appendix 4.

The ratio of DFFM/DWt loss for the first 12 weeks (BMI change from 21.9 to 18.7) is 0.63. The ratio for the second twelve weeks (BMI change from 18.7 to 16.9) is 0.57. Thus the lower the BMI the less was the protein lossas opposed to the opposite determined by Forbes.

However it is our opinion that the Keys’ study should be discounted as of no relevance to considerations of VLCD dieting for the following reasons:

· The average BMI at the start of the Minnesota dieting period was 21.7 (i.e. low area of normal) and not a level at which dieting should be contemplated.

· The dieting took the BMI down to average 16.9 (the pictures within the book show how emaciated they were), the residual fat averaged only 3.4kg according to their calculations and this is substantially below any target weight for therapeutic dieting.

· Three different food diets with substantially different proportions of fat, carbohydrate and protein were used on different days.

· The average energy intake per day over the 24 weeks and 32 subjects was no less than 1569 kcal, but this hides a range of means for individual subjects between 1213 and 1833 kcal. The range between individuals by weeks stretched from 608 to 2095 kcal. The diet was adjusted individually each week to achieve a theoretical weight loss curve. The energy value and composition of the diet was changed depending on the previous week’s weight loss. The adjustment was mainly by additional carbohydrate and hence the glycogen stores would have changed erratically.

· A high enough energy expenditure to achieve the required weight loss with the high energy intake was achieved by daily exercise mainly outside in the bitter cold (Minnesota in the winter!)

· “The weight loss was complicated by clinical oedema and relative increase in interstitial fluid volume” Keys attempted to adjust the composition to allow for this fluid accumulation. The adjustment which he applied changes the ratio for the second 12 weeks to 0.34. This is even further against the Forbes effect

Interestingly one of the volunteers in the Kreitzman study had a starting and finishing BMI almost equal to the mean in the Minnesota study but with a ratio of 0.36, well within the ordinary densitometry range in that study

On the next page we have reproduced the Forbes and Prentice graphs as they were shown in their original papers. (shown as Graphs 3.12 a & b)

However it is clear that the two points to the far left of each of these diagrams can not represent figures determined from a regular dieting programme since they represent subjects whose mean body fat wt is under 10kg (i.e. a sub-normal mean BMI).

If then we accept all the other points on these graphs as being valid (and it will be recalled that in the discussion above (page * et seq) we drew attention to problems in accepting them) we can derive two revised graphs (shown as Graphs 3.13 a & b)

There is then no indication from visual inspection that there is any increase in the proportion of fat free mass loss at lower mean body fat levels.

Low levels of protein and perhaps carbohydrate in the diet there may be serious changes in composition of the body weight loss

Figures 3.13 a & b. The Forbes and Prentice graphs with the two left hand points, which can not represent regular weight reduction results removed

3.5 Further data relating to body composition changes during weight loss with VLCD.

There are two extensive individual studies (Hoie, Bruusgaard and Thom, 1993; Donnelly, Jacobsen and Whatley,1994) which provide excellent information relating to the question of whether the loss of fat free mass is greater at a lower BMI level.

In that undertaken by Hoie et al, (1993) body composition analysis was undertaken by near-infra-red interactance (Futrex 5000). It was conducted on 82 women and 45 men and a 430kcal diet containing 61.5 g high quality protein and 30.5g carbohydrate was consumed daily for eight consecutive weeks. Dr Hoie has very kindly provided me with the summary of the original data on which his paper was based, (unfortunately the data on each individual dieter has been lost in the intervening 10 years). Nevertheless the information in his original paper and that in the summary tables is adequate to reach substantial conclusions.

Thus, the proportion of the total group in the various BMI categories at the start of dieting and after 8 weeks as calculated from his data is shown in Table 3.4. From this it is clear that as a result of an average loss of some 3.9 BMI units for women and 4.8 units for men some 20% of the group came into the normal weight category (BMI 20-25) at the conclusion of the 8 weeks diet with a further 30% now having a BMI between 25 and 30.

Table 3.4 Number (%) of dieters in each BMI range at start and end of an 8 week diet (Hoie et al (1993)

The ratio of FFM/Wt loss overall was 0.25 with no significant difference between men and women. Without the records for the individual dieters it has not been possible to construct a scatter diagram of this ratio compared with the initial BMI but Hoie et al (1993) found that the ratio did not differ significantly over the whole range from 51 down to 25 (r = -0.03; P = 0.75). >>>

The study by Donnelly et al (1994) on the other hand was conducted only in women (116) using a diet providing 520kcals (protein 50g, carbohydrate 79g) for 12 weeks and with body composition determined by hydrodensitometry (Brozek et al equation).

For the Donnelly et al study, Table 3.5 indicates the number and percentage of subjects who fell into different BMI categories before and after the diet. Before dieting the lowest BMI was 27, the highest 64 (mean 37.6) and with a mean fall of 20.2kgs over the 12 weeks, the mean BMI level at the end of dieting was 30.2 with no less than 16 (14%) achieving a normal weight (BMI<25) (range 21.9 – 52.1)

Table 3.5 Number (%) of dieters in each BMI range at start and end of 12 week diet. (Donnelly et al, 1994)

Figure 3.13 shows the relationship between the ratio of the FFM/Wt loss and the BMI level. The mean FFM/Wt loss ratio was 0.19 (r = -0.9 x 10^-7) confirming that there is no difference in the FFM proportional loss at different BMI levels. It is worthy of note that the level of compliance to the diet was excellent with only 4 dieters showing a weight loss per week of less than 1kg. Each of these four with poor compliance recorded a FFM/Wt loss ratio that was substantially out of line including both those at the extremes.

Figure 3.13 A scatter diagram of the ratio of FFM to weight loss compared with the initial BMI in 116 women dieting for 12 weeks on a 520Kcal VLVD (Based on data from Donnelly et al, 1994)

Although the Hoie et al (1993) study used near infra-red interactance to measure the body composition, while Donnelly et al (1994) used densitometry, the proportion of fat lost to weight lost was of the same order in both studies. Moreover the study by Hoie et al was based on a relatively high daily protein ketogenic diet while that of Donnelly et al involved a non-ketogenic diet with more modest protein content.

From the information derived from the 20 studies involving a relatively limited number of dieters (using VLCD and LCD) coupled with that from the two extensive studies which examined ketogenic/non-ketogenic VLCD and the two genders, it can be concluded that there is no difference in the proportion of fat which is lost during dieting:

3.7 Submission related to the matter of positive and negative nitrogen balances

In an earlier portion of this submission we have examined the accuracy, reliability and reproducibility of Kjeldall determinations in general (Section 3.1.2). Investigation of the current literature in those areas where there are economic considerations (e.g. studies of protein in animal carcasses for commercial exploitation) indicate that the Kjeldall method has been largely abandoned. This is not to say that with appropriate control and care it is not possible to determine the nitrogen balance by the use of Kjeldall determinations. However it does stress the need for such careful controls and means that balance studies which use this technique must be examined carefully to determine what controls have been applied.

This is particularly relevant in the light of some of the discussion papers which have been presented to the Working Group concerning the nitrogen balance during weight loss as a result of dieting. Many of these are quoted as showing either a positive nitrogen balance or alternatively a negative nitrogen balance in the early stages which subsequently becomes positive after a period of some three to four weeks. There is a fundamental problem here.

While weight is being lost with any weight reducing programme, there is no possibility that there can be a zero, let alone positive nitrogen balance. This was established and accepted by the authorities as long ago as 1987 (see Appendix F of The COMA Report (1987) on the Use of Very Low Calorie Diets in Obesity). This appendix was prepared by John Garrow in response to the Cambridge Nutrition calculation of protein losses (see page 38).

It stems from the fact that when adipose tissue is lost or gained, a significant proportion consists of fat free mass (FFM). This FFM contains protein. In the calculation given by Garrow (which uses the proportion 25%FFM/75%fat for adipose tissue) this “allowable” protein loss (as Garrow calls it) amounts to 4.75% of the total weight lost. Although there are some differences of opinion about the exact proportion of the weight lost which consists of FFM the acceptance of this principle implies that there must be nitrogen loss when weight is being lost. This has been discussed in detail in an earlier sections of this present paper (3.1 to 3.6). Since this nitrogen loss is always present in weight loss, we would prefer to refer to it as “obligatory” rather than “allowable”

Hence what we must look at during weight reduction is not the nitrogen balance as calculated, but whether nitrogen losses are greater than the “obligatory nitrogen losses”.

We have accordingly examined as much of the nitrogen balance literature as we can find to determine whether at a level of 50g of quality protein intake per day in the form of a VLCD, the nitrogen losses are greater than the obligatory nitrogen losses.

4. We have excluded several of the papers because at 50g protein intake per day, they report a positive nitrogen balance per day even when the matter of the obligatory nitrogen loss is ignored. These include those of Apfelbaum et al, 1967; Winterer et al, 1980; Blackburn et al, 1975; Bistrian et al, 1977a; Bistrian et al, 1976; Marliss et al, 1978 ; Bistrian et al, 1977b; Hoffer et al, 1974; Genuth, 1979; Phinney et al, 1988; Vasquez et al, 1985. In these papers the positive nitrogen balance occurred at various levels of carbohydrate intake above about 30g available carbohydrate per day.

5. There is a further group which should be rejected from analysis because the length of the study was substantially less that 4 weeks or there was no nitrogen balance or there were obvious fallacies in the design. (Hoffer et al 1984 – No nitrogen balance provided; Genuth et al, 1974 - No absolute values for nitrogen; Yang & van Itallie, 1976 10 day experiments only; Baird et al 1974 - Short periods only with various diets; Aoki et al, 1975 - 7 day experiments only; Howard et al, 1978 100g CHO – 5 day balance only; Hendler et al 1988- 21 day only on CHO; Greenberg et al 1976 – not dieting; post operative; Bistrian 1977 – unable to find paper).

6. We have equally excluded from the analysis those with a carbohydrate level below 30g/day (since the 1970s it has been known that these levels are inappropriate) and where the protein level is less than 30g (for a similar reason). (Yang & van Itallie, 1984 – mixes groups with no CHO and high CHO; Bistrian et al, 1977. CHO below 30g/day; Marliss et al, 1978 CHO less than 30g; Koppeschaar et al, 1983 25g protein and 25g CHO; Wynn et al 1985 Various CHO values mixed; Fisler et al, 1982 – CHO below 30g/day; Vasquez et al, 1992 – only 10g CHO/day)

This leaves a total of 15 published papers which can be used for further analysis, namely:

Balance b = as re-calculated for any additional losses not included in the paper (i.e. nitrogen loss in faeces = 0.7g nitrogen/d = 5g protein /day; miscellaneous losses = 0.4g nitrogen/day = 3g protein/day)

Obligatory protein loss 0.475% (weight loss – 2.5kg). This is the Garrow Formula (see COMA Report (1987) (cumulative g protein)

Balance c. The theoretical balance for an intake of 50g/day protein rather than that used in the paper (cumulative g protein)

* Note: with studies less than 4 weeks it is far from clear whether the Garrow obligatory protein loss formula applies. We have accordingly excluded all the studies lasting substantially below 4 weeks, but included those at 3 weeks with this caveat.

It will be seen that for many of these studies the total protein loss (Balance b) is not much greater than the obligatory loss even at the lower protein intakes. There are 2 studies of 4 weeks or more and a protein intake of 50g or more and in both these balance b does not show a greater loss that the obligatory loss. When a theoretical calculation is made to adjust to an intake of 50g/day the loss is nearly always no greater than the obligatory loss.

We fully accept that this is not an ideal presentation. In previous sections we have already suggested that nitrogen determinations by the Kjeldall method are suspect. Moreover the re-calculation to an intake of 50g has no scientific support. Nevertheless there are no current observations of nitrogen balances determined by neutron activation. Hence, we submit that if Kjeldall determined nitrogen balances are to be considered (and they are discussed in other papers submitted to the working group and included in the draft SCOOP Report), then adjustments of the type given in Table 3.6 are the only possible way of presenting the picture.

3.8 Studies which provide information on the desirable carbohydrate level.

It is vital to appreciate that the safety of 40g+ carbohydrate is confirmed by the fact that some 90% (45,000) of the patients studied in the published trials were at daily carbohydrate levels between 30 and 45g. Hence the clinical effects are well known and the safety well established. with VLCD with carbohydrate levels substantially below 50g/day (but over 30g/day).

The substantial majority (almost 90%) of the published papers which demonstrate the safety of modern VLCD (see Table 2.1) were concerned with diets containing less than 45g/day carbohydrate. Such diets produce a mild ketosis in the majority of the dieters. The mean plasma ß-hydroxybutyrate with 40 to 45g available carbohydrate per day is 1mmol/L with a maximum in a group of 491 dieters tested after over two weeks continuous dieting 5mmol/L (Tiessen & Weinkove, personal communication). From the early studies (Baird & Howard, 1974) it has been apparent that when the available carbohydrate is less than 30g per day the level is inadequate to prevent mineral losses and increased uric acid levels. However all the clinical biochemical investigations at levels above 30g/day have failed to show abnormalities. Moreover, in the United Kingdom and several other countries, the carbohydrate level for some years was under 35g/day and the practical clinical results were good at this level. On the other hand there is virtually no published experience with carbohydrate levels in excess of 50d/day (Table 2.1)

There are two arguments in favour of a mildly ketogenic diet, namely appetite suppression and a greater sparing of lean body mass. Search of the literature shows that there is an almost even split between those who favour a mildly ketogenic one and those who favour a higher carbohydrate level which renders the substantial proportion of dieters non-ketotic.

We would submit that unless it can be shown that there is clear evidence presented that the non-ketotic solution has substantial benefits for the maintenance of the protein economy, it would be better to leave it open that VLCD with available carbohydrate levels above 40g/day are safe. If a higher value is given, it is important to determine precisely how powerful is the evidence for the necessity, or even benefits of non-ketotic diets. I note incidentally that the minutes specifically ask that any evidence showing that above 50g carbohydrate/day is safer than 50g/day should be circulated, but no such evidence was circulated.

The biochemical argument for the merit of ketone bodies is that other than glucose, they are the only compounds that can be metabolised by the brain and indeed are preferentially used by that organ. Hence when glycogen stores are depleted, under any circumstances, the production of ketone bodies means that protein breakdown is less necessary to provide glucose. Thus the phenomenon of protein sparing has been described not only in starvation, (e.g. Cahill, 1976; Sapir and Walser, 1977) but also under surgical stress (Williamson et al, 1977; Rich and Wright, 1979; Crowe et al, 1989). We would draw attention to the protein balance data shown in Table 3.6. This indicates that even at levels of protein intake below 35g/day many of the papers show that protein losses are no greater that the obligatory losses during weight reduction by any means. Unfortunately this evidence is not as powerful as it might be, because there are virtually no observations with non-ketogenic carbohydrate levels.

As further support for this view, we would draw attention to the paper by Fery et al (1996). They conclude (page E829) “The present study, based on the prolonged suppression of FFA and KB or of FFA alone, suggests that both compounds participate in the conservation of the protein mass during fasting and indicates that this process is operative after only a few days of food deprivation” and then “During fasting the elevated levels of both FFA and KB exert a suppressive action on gluconeogenesis, they maintain glucose concentration at low levels and they protect the protein stores”. A similar conclusion is reached in the review of the subject by Tessari et al (1996), which provides a substantial number of further references. What many of these papers, referenced in this review by Tessan et al point out is that there is not just one factor which is responsible for the pattern. It depends on a balance of the level of the substrates and the balance of the influence of the many hormones which, as shown in various discussion papers for the Working Group are substantially changed during the administration of VLCD as the sole source of nutrition.

It has been argued that the paper by Halliday et al (1993) speaks about “this apparent sparing of protein is solely due to the increased rate of protein synthesis”. This is exactly what one would expect to see (Williamson et al, 1977; Nair et al, 1988; Crowe et al, 1989; Halliday et al, 1993). In this respect we would draw attention to the paper by Nair et al (1988) which appears to be particularly pertinent.

There is a constant flux of amino acids from tissue proteins, a flux that is increased during weight loss. When glucose levels are low, but there are adequate levels of ketone bodies and FFA available to provide for both brain and muscle metabolic needs, gluconeogenesis decreases and free amino acids in the circulation encourage protein synthesis producing exactly the effect that have been described by several groups and to which attention has been directed

The main evidence advanced by those who favour the non-ketogenic solution are the Vazquez papers. The Vazquez et al (1995) paper is quoted as demonstrating that the cumulative nitrogen losses are lower in the high carbohydrate groups. Unfortunately the Kjeldall nitrogen observations must be treated with reservation (see section 3.1.2 for discussion on this aspect). Specifically, in the Vazquez et al (1995) study, by day 28 the subjects receiving 70g/day were in positive nitrogen balance which is impossible during weight loss (see sections 3.2-3.6).

The Vazquez & Adibi (1992) study has no relevance to the discussion. The ketogenic diet which they used contains only 10g available carbohydrate per day. Since the pioneer studies of the 1970s (e.g. McLean Baird & Howard, 1974) it has been known that at carbohydrate levels below 30g/day, there is substantially greater protein breakdown than above 30g. At the other extreme, they used 86g/day for their non-ketogenic diet. Since they did not study any intermediate carbohydrate intakes (e.g. between say 30g and 45g/day) it can not be concluded that this would not be just as beneficial as the 86g/day.

The Vazquez also relies heavily on leucine data. Leucine data has been criticised at various times as not being fully representative of the protein economy. For example in the study by Bowtell et al (1998) on the modulation of total body protein metabolism by variation in dietary protein it appeared that leucine oxidation is very dependent on leucine availability rather than on other factors.

This is supported by the further study by the Bowtell group (2000) which demonstrated that the sparing effect of glucose on leucine oxidation appeared to be dependent on a previous high protein intake. In that particular study their low protein intake at 0.7g/kg/day (as opposed to the high intake of 1.8g/kg/day for the high protein group) and this low protein intake would be broadly that used in the VLCD studies. Another observation that raises doubt about relying too heavily on leucine tracer studies is that of Pannemans et al (1997). They used both 15N-glycine and –[1-13C]-leucine in the same protein balance study and found that in fasting elderly women who were consuming a 20% rather than a 10% protein diet, protein turnover (both anabolic and catabolic) was higher as measured by glycine but equal in both diets as measured by leucine. Furthermore, in the Halliday et al (1993) paper which has already been quoted, further differences are high-lighted between glycine and leucine measurements, though not in the same study.

We would therefore submit that there is no uncontroversial evidence that there is a protein sparing effect with the higher carbohydrate level which will ensure an absence of ketosis. With the very substantial amount of evidence that at levels below 45g/day available carbohydrate, there is no justification

3.9 Observations made after the circulation of the first draft of the report to the working group.

"1. I am very concerned about having section 6.3 (on nitrogen balance), in the present form and section 7.3 on the ratio between the fat mass/fat free mass ratio being constant in the same document. If you accept section 7.3, the protein mass is reduced by about 25% for any weight loss. This means that there can not be a positive nitrogen balance during any weight loss period of more than the few initial days (glycogen and water loss). Yet section 6.3 is based on the concept of achieving positive nitrogen balance. These two concepts are scientifically mutually exclusive. To put both concepts in the same report without drawing attention to the scientific contradiction would in my opinion, lead to considerable doubts about the validity of what is in most other respects an excellent report

2. There is clearly still a dispute in the Working Group about the question of whether ketogenic or non-ketogenic diets are preferable. You will note that the vast majority of the experimental and general use experience relating to safety is at levels which would be mildly ketogenic. The Group has already accepted that in practice VLCD at carbohydrate levels per day over 40g (perhaps even over 30g) are safe. The other considerations leading to a higher suggested carbohydrate level are theoretical and largely depend upon analytical techniques which are known to be suspect. Nevertheless, I do not believe that it is necessary to argue this further. If the working group concludes that carbohydrate below 40g/day is undesirable, but above, say 45g/day is, in practice, reasonable and safe this will mean that those who favour a mildly ketogenic diet can continue to use it while those who favour a non-ketogenic one can add more carbohydrate.

3. Section 8.4 deals with the matter of dietary fiber. It does not reach a conclusion on content, but in the conclusion this becomes translated into “Fiber: 10 g to max. 30g as an ingredient” I agree that it is now desirable to define a fiber content, but believe that the what is meant by “fiber” for VLCD use should be clear. I equally submit that only the ‘minimum’ amount per day about 10g should be given for the following reasons:

4. Insoluble fibres, particularly those that can chelate and those with a high phytate content can block at least mineral absorption. The reduction in the availability of Ca and Mg and other minerals may be dangerous. Very little work has been done on this in relation to high fiber use with VLCD. I would prefer the term “insoluble or soluble fibre” which would avoid this mineral availability problem.

5. A high content of soluble fibre (e.g. 30g/day) without other food is very likely to produce severe diarrhoea either by the osmotic effect or by the substantial alteration in the intestinal flora. Other recent work with which I have been involved suggests that this is very likely to be a problem.

6. Examination of the fiber content of current VLCD in Table 4.2 indicates that there is virtually no information on the effects above about 10g/day soluble fiber. The prime role of the SCOOP report is to provide data. I believe that this recommendation of 10 – 30 g/day goes well beyond this.

7. If the minimum is defined as “10 g soluble fiber” it would not stop those who want to use more from doing so.

8. If we accept the concept that there should be a “soluble fiber content of 10g/day” this provides broadly about 5 g ‘available carbohydrate’ (perhaps more under certain specific conditions). If therefore we reach a conclusion that the content should be “a minimum of 50 g/day available carbohydrate” this equals the CODEX content but based on 45g normal carbohydrate and 10g soluble fiber. The use of the word ‘minimum’ would mean that those who prefer more could use more."

SECTION IV:. MEDICAL AND SCIENTIFIC JUSTIFICATION FOR THE USE OF MODERN NUTRIENT COMPLETE FORMULA DIETS WITH ENERGY VALUE LESS THAN 800 KCALS PER DAY

The evidence presented in this report demonstrates that the safety of formula diets does not depend upon the energy content but on the macronutrient and micronutrient levels. There is, therefore, no valid reason for imposing an entirely arbitrary lower limit on products that are available to assist those who need to lose weight. It would be scientifically irrational to expect that energy intake per se, as opposed to the composition of the diet would affect safety. In all humans, the daily nutrient and energy needs are made up from both stored deposits and dietary sources. So far as energy is concerned, even a thin 60kg ‘reference woman’ has some 115,000 kcals available from her body fat alone. This equates to enough energy to provide for her total requirement for some 80 days.

This discussion paper establishes beyond reasonable doubt that the overall safety of VLCD is of the same order as that of LCD in the 800-1200 kcal range. It is difficult to be more precise than this about the relative safety of the different energy levels of the formula diets because, whereas the VLCD have been subjected to very extensive study over several years the number of formal studies of the safety of LCD in the range 800 - 1200kcal) is by comparison small.

The literature examining the use by health clinics, and the use by consumers who obtained VLCD on free sale confirms that they can be regarded as a valuable means of weight reduction and as an adjuvant for the maintenance of a lower weight. But no only are VLCD as good and safe as LCD and food based diets but they have advantages in some subjects, viz:

· It is widely accepted that food-based diets (even those devised by dietitians) are far fRom ideal, both in energy content (Stordy, 1992) and micronutrients (Fisher & Lachance, 1983). Formula diets on the other hand provide the energy, macronutrients and micronutrients that are required, bearing in mind that the adipose tissue contains a very substantial energy store. Formula diets have been shown to be more effective than normal food based diets as judged by compliance during weight reduction- Accordingly, it should be no surprise to see that a high proportion of recent papers, even those that advise behaviour modification and exercise, advise food replacement with a formula food. Of these current evidence suggests that VLCD are among the most effective diets for weight reduction and weight maintenance..

· There is no perfect single weight reducing method and a variety of diets to suit differing desires and prejudices is desirable, providing such diets do not carry additional health hazards. This is particularly valid for diets, like VLCD, which have been extensively studied over at least 25 years and which can be shown to exert positive health benefits (see below).

· There is recent evidence that the rapidity of weight loss confers additional positive health benefits independent of the actual amount of weight which is lost, when compared with food-based diets or higher energy level formula diets. This applies to

a. the management of some cardiovascular disorders (particularly hypertension where anti-hypertensive drugs could be withdrawn, Kreitzman & Beeson, 1996)

b. but particularly with non-insulin dependent diabetes mellitus (see, for example Lean et al., 1990; Henry & Gumbiner, 1991; Wing & Greeno, 1994; Wing et al, 1994; Hernandez-Bayo et al, 1985) in which metabolic control and lipid profile is markedly improved by the rapid fall in weight using VLCD.

· Moreover, meal replacements of various types, not specifically aimed at slimmers and therefore not restricted under current legislation, are widely available at energy values under 150kcal. Most of these have an inadequate nutrient content both for essential amino acids and micronutrients. These "snacks" which are readily and freely available can be, and are, used extensively as meal replacements for weight reducing purposes even though they can not be advised for this use. It is therefore highly desirable to make nutritionally complete and safer alternatives like VLCD equally readily available

· Additionally, in some cases, unscrupulous claims are made for protein-rich foods supplemented with various levels of vitamin and minerals. There is currently no means by which their use can be controlled and the risk of inadequate nutrition is clear.

· There is a view that a proportion of the obese are dependent on food - probably specifically fat. With any dependence it is vital to wean the subject off their substance of dependence as the first stage in effecting a change in behaviour This clear benefit of formula VLCD over traditional food-based diets has proved to be a valuable adjunct to weight maintenance in some people.

It is therefore submitted that modern nutrient-complete formula VLCD have an important place in weight reduction and their availability under the same regulations as other formula diets (of 800kcals and above} is fully justified

SECTION V:. HEALTH PRECAUTIONS DURING WEIGHT CONTROL

There is no dispute that like many weight loss programmes VLCD should only be used as the sole source of nutrition by those in otherwise good health, unless the dieter is under the advice or supervision of a medical practitioner.

A list of contraindications has been published in most examples of the current legislation. For some physiological and pathological conditions, we submit that the contraindication should be absolute, that is, VLCD should only be used by those with considerable expertise in the field. For the remainder, in our opinion the ultimate responsibility for deciding on the balance of benefit/risk lies with the medical practitioner, who will be best able to judge the overall needs of the individual patient. In those circumstances we submit that VLCD should only be used with the explicit agreement of the practitioner.

We would draw attention to the fact that some specialist out-patient clinics have used VLCD in a number of obese patients suffering from disorders in the list of medical contraindications. They have encountered no problems and a high success record (Weinkove et al., 1987. Shapiro et al., 1989 Paisey et al, 1998; Miles, Cavan & Kerr , 2000). However, it is important to stress that considerable experience of the use of VLCD is essential for such use.

In particular the changing attitude towards the use of VLCD in NIDDM should be noted. This condition was originally placed by many authorities in the list of contraindications. Recent studies (Fukuda et al 1989. Wing et al 1991; Kelley et al 1993; Wing et al 1994; Brown et al 1996; Gumbiner et al 1996; inter alia) have shown that VLCD (probably intermittent use, and obviously under medical supervision) has considerable value in the management of NIDDM. The extent of these successful studies raises questions about the validity of the report from Koffler and Kisch (1996) in just one unit that VLCD can lead to diabetes.

Advice that any form of dieting should be used only under the supervision of a medical practitioner also applies to those who are receiving an established list of prescribed medications and this list is widely quoted in current legislation. There is little dispute about the medications in this list. Since many patients are unaware of the nature of the medication which they are being prescribed, we believe that the sensible advice is that any patient receiving prescribed medication should only undertake any form of dieting under the direction of or after receiving clearance from their medical practitioner.

		*No studies*	%	*No subjects*	%

Total		461		52,783

Date of publ
	Up to 1975	9		340
	1976-1980	25		1,525
	1981-1985	72		2,591
	1986-1990	121		8,096
	1991-1995	139		23,887
	After 1995	85		15,694

Energy cont	Per day
	Up to 450 kcal	280	66	31,949	66
	Over 450 kcal	146	34	16,566	34

Protein	Per day
	Up to 50g	180	44	19,212	38
	Over 45g	233	56	31,303	62

Carbohyd	Per day
	Up to 45g	292	73	40,608	90
	45 to 50g	25	6	763	2
	Over 50g	82	21	3,627	8
Use length
	Under 4 wks	81	18	17,006	33
	4 wks or more	371	82	34,705	67

Energy/day	<400kcal	111	27.4	4,182	9.1
	400-599kcal	261	64.4	40,674	88.6
	600-799kcal	33	8.1	1,053	2.3
Carboh/day	30-40g	149	44.2	34,194	80.4
	41-45g	81	24.0	3922	9.2
	46-50g	25	7.3	763	1.8
	>50g	82	24.3	3,627	8.5

Disorder	Morbidity	Mortality
Diabetes	110-500 %	520-790 %
Cerebrovascular accident	11-440 %	150-220 %
Coronary heart disease	130-240 %	200-210 %
Cancer		130-160 %
Post-operative wound infection	700%

Total $ 39.3 billion

Non-insulin-dependent diabetes mellitus	57 %
Gallbladder	30 %
Hypertension	20 %
Cardiovascular	19 %
Cancer	2.5 %

		*No studies*	%	*No subjects*	%

Total		461		52,783

Date of publ
	Up to 1975	9		340
	1976-1980	25		1,525
	1981-1985	72		2,591
	1986-1990	121		8,096
	1991-1995	139		23,887
	After 1995	85		15,694

Energy cont	Per day
	Up to 450 kcal	280	66	31,949	66
	Over 450 kcal	146	34	16,566	34

Protein	Per day
	Up to 50g	180	44	19,212	38
	Over 45g	233	56	31,303	62

Carbohyd	Per day
	Up to 45g	292	73	40,608	90
	45 to 50g	25	6	763	2
	Over 50g	82	21	3,627	8
Use length
	Under 4 wks	81	18	17,006	33
	4 wks or more	371	82	34,705	67

Reports on tasks

for scientific cooperation (SCOOP)

Task 7.3 – Collection of data on products intended

Preamble

Introduction

Summary

Overall conclusions

Section II The experimental studies and clinical experience reviewed here demonstrate that products with an adequate and specified macronutrient and micronutrient composition but an energy content below 800kcals per day (VLCD) are at least as safe as those of higher energy content (LCD)

Energy/day

Carboh/day

Compositional standards.

Protein

Fat

Micronutrients

Fibre

Energy

There is a range of minima between 400-450kcal. The energy value per se has no direct relevance and the minimum should be established based upon the energy provided by the defined minimum for the macronutrient recommendations.

Section V The precautions for VLCD use should be those which apply to any method for losing weight

1.1 The prevalence of excess weight

1.2 Excess weight and morbidity

1.3 Weight increase and mortality

1.4Weight increase and mortality

1.5The economic cost of obesity

SECTION II: THE SAFETY OF VERY LOW CALORIE DIETS IN EXPERIMENTAL AND CLINICAL USE.

2.5 Data on side effects

2.6 Data on aspects of use and control in practice

SECTION III.: RECENT SCIENTIFIC STUDIES WHICH HAVE PRODUCED A BETTER UNDERSTANDING OF THE PROPERTIES OF VERY LOW CALORIE DIETS.

3.8 Studies which provide information on the desirable carbohydrate level.

SECTION V:. HEALTH PRECAUTIONS DURING WEIGHT CONTROL

Physiological situations

Children and adolescents Pregnancy and lactation

The elderly

Physiological situations

Illnesses and disorders

Prescription drugs

Medical supervision of individuals apparently clinically healthy apart from excess weight

Ref	Total subjects	Starting data (BMI)			VLCD dieting			VLCD weeks BMI < 30
		Mean	S.D.	Lowest	Av wks	Total weeks	Av BMI lost	Total	Proportion
Kirschner et al ’88 – men	603	34.9	0.95		13.2	7,960	9.23	3,327	41.8%
- women	2,348	37.5	0.80		14.1	33,107	6.8	745	2.25%
Kanders et al ’89 - men	143	38			16	2,288	7.6	?	<5%
Women	718	35			16	11,488	6.65	2,849	24.8%
Bode 1999 - men	2,142	40.3	23.2	23.2	14	29,988	10.1	2,527	8.4%
- women	10,754	38.9	6.6	23.9	14	150,556	6.7	18,481	12.3%

Kilocalorie content	Number of Studies		Number of subjects
<400	111	27.4%	4,182	9.1%
400-600	261	64.4%	40,674	88.6%
600-799	33	8.2%	1,053	2.3%

Carbohydrate content	Number of studies		Number of subjects
30-40g	149	44.2%	34,194	80.4%
41-45g	81	24.0%	3,922	9.2%
46-50g	25	7.4%	763	1.8%
>50g	82	24.3%	3,627	8.5%

Reference	Number	Duration

Fisler et al 1982	10	40-55 days
Amatruda et al 1983	6	40 days
Phinney et al 1983	10	28 days
Ms Lean Baird 1985	13	4 weeks
Drenick et al 1985	16	40 days
Lockwood et al 1985	11	40 days
Amatruda et al 1988	6	40 days
Kirscher et al 1988	4026	Various details of monitoring unclear
Weigle et al 1989	11	95 days average
Moyer et al 1989	24	6 weeks
Anderson 1990	104	8 weeks
Doherry et al 1991	12	16 weeks

Weight loss procedure	Average loss/week women	Reference
Exercise alone	0.1 kg/week	Garrow & Summerbell, 1995
1200kcal diet daily	0.3-0.5 kg/week	Heshka et al, 1996; Wadden, 1993; Topubro & Astrup, 1997

800kcal diet daily	0.5-0.7 kg/week	Garrow, 1993
300-500kcal diet daily	1.0-1.5 kg/week	Pekkarinen et al, 1996 Tyttig & Rossner, 1995 Hoie & Bruesgaard, 1995, Rude et al, 1993; Wadden, 1993; Toubro & Astrup, 1997

As to:	Variation
Pre-treatment data	Expressed in different units: kg, kg excess, BMI, %excess, Mean of group (?SE), median, range, Exact definition of normal weight is not given Educational and work status. Probable reason for excess weight
Treatment	How deal with dropouts – sometimes not even mentioned How long; ? goal set; ?what form of diet: ?food, formula, ? calories, ?macronutrient levels (sometimes data not given) ? behaviour modification –if so what and how frequent. ?eating cues,? Rate of eating,? Record keeping, ?rewards given – if so what and when ? counselling – if so by whom, frequency, nature length etc ? psychiatric appraisal and how followed ? diet education – if so how much, what etc ? medication – if so what. Frequently not stated at all ? how good is compliance actual loss/week cf expected ? exercise – if so what type, how often, ? compliance ?any time in hospital/clinic – if so conditions applied
Weight loss – how expressed	? as % excess weight change; ? as BMI; ?as median of group, ?as mean of group (?+SE); ? as kg change Some times the weight loss is expressed in different units from the pre-treatment situation making it impossible to translate one to the other.
Change to maintenance	? sudden; ?gradual change if so details of rate of change;? Specific foods/food types allowed or restricted;
Maintenance	? goal setting ? target – if so what and how expressed ? behaviour modification maintained – if so what and how ? counselling – if so how often, for how long, by whom etc ? seen at all . ? contacted by telephone – by whom, how, frequency etc ? exercise – if so ? advised or undertaken with group, what type, how frequently, how controlled etc ? dietary advise – if so in form of avoidance, ? strict diet. ? calorie counting, ?”sensible eating pattern” etc Formula intake allowed as component – if so under what conditions, ? redieting allowed as necessary during follow up ? regular weighing – if so what frequency, under control or at home, ? what to do in event of change ? medicine – if so what type and how controlled Spouse/family/lay friends etc involvement ? group care Educational and work status. Has probable reason for excess weight been dealt with adequately

Method	Measures	Assumptions & conditions that create false estimates
Tritiated water	Exchangeable body water	Constant hydration of FFM (1) Stable hydration state (2) Oedema fluid (3)
40K	Body potassium pool	Dietary intake of K uniform (e.g. milk, fruit etc) (4) Constant ratio of K/N (5) Uniform body terrain (6)
Hydrodensitometry	Average body density	Very sensitive to hydration (1) Water confident (7) Dietary status 2) Sensitive to bladder and gut contents Variable equations which do not always agree
Impedance	Total body water space	Constant hydration of FFM (1) Stable hydration state (2) Oedema fluid (3)
Skinforlds	Local fat deposition	Uniform fat distribution – subject variability Does not measure visceral fat Constant hydration (1) (2) (8) Operator consistency

BMI Range	Number (%) time 0	Number(%) time 8 wks
20-24.9	0	25 (20%)
25-27.9	7 (6%)	19 (15%)
28-299.9	19 (15%)	19 (15%)
>30	101 (79%)	64 (50%)

BMI range	Number of dieters (time 0)	Number of dieters (12 wks)
20-24.9	0 (0%)	16 (14%)
25-29.9	9 (8%)	48 (41%)
30-34.9	37 (32%)	37 (32%)
35-39.9	39 (34%)	8 (7%)
40-44.9	20 (17%)	4 (3%)
>44.9	11 (9%)	3 (3%)

Reference no.	Weeks	Wt loss /week	Prot intake g/day	CHO g/day	Balance a	Balance b	Obligatory loss	Balance c
1	6	2.7kg	31	40	-437	-437	-643	+361
2	4	2.4kg	31	40	-602	-602	-355	-70
3	4	2.5kg	33	40	-152	-264	-333	-333
4	4	2.4kg	34.5	40	-264	-264	-342	+147
5	4	2.9kg	33	40	-552	-552	-432	-76
6	4	2.7kg	33	40	-433	-433	-403	43
7	8	2.0kg	33	40	-490	-490	-641	462
8	4	2.9kg	50	45	110	-86	-437	-86
9	4	2.7kg	33	45	-323	-519	-404	-43
10	3*	2.1kg*	46	40	-433	-433	-180	-349
11	4	2.1kg	52	76	-117	-201	-275	-257
12	3*	2.7kg	50	50	-569	-569	-261	-569
13	11	1.5kg	42	44	-761	-761	-651	-145
14	5	2.2kg	30	40	-706	-706	-408	-6
15	5	3.2kg	30	40	-1415	-1415	-650	-595

Reports on tasks

for scientific cooperation (SCOOP)

Task 7.3 – Collection of data on products intended

Preamble

Introduction

Summary

Overall conclusions

Section II The experimental studies and clinical experience reviewed here demonstrate that products with an adequate and specified macronutrient and micronutrient composition but an energy content below 800kcals per day (VLCD) are at least as safe as those of higher energy content (LCD)

Energy/day

Carboh/day

Compositional standards.

Protein

Fat

Micronutrients

Fibre

Energy

There is a range of minima between 400-450kcal. The energy value per se has no direct relevance and the minimum should be established based upon the energy provided by the defined minimum for the macronutrient recommendations.

Section V The precautions for VLCD use should be those which apply to any method for losing weight

1.1 The prevalence of excess weight

1.2 Excess weight and morbidity

1.3 Weight increase and mortality

1.4Weight increase and mortality

1.5The economic cost of obesity

SECTION II: THE SAFETY OF VERY LOW CALORIE DIETS IN EXPERIMENTAL AND CLINICAL USE.

2.5 Data on side effects

2.6 Data on aspects of use and control in practice

SECTION III.: RECENT SCIENTIFIC STUDIES WHICH HAVE PRODUCED A BETTER UNDERSTANDING OF THE PROPERTIES OF VERY LOW CALORIE DIETS.

3.8 Studies which provide information on the desirable carbohydrate level.

SECTION V:. HEALTH PRECAUTIONS DURING WEIGHT CONTROL

Physiological situations Children and adolescents Pregnancy and lactation The elderly

Physiological situations

Illnesses and disorders

Prescription drugs

Medical supervision of individuals apparently clinically healthy apart from excess weight

Physiological situations

Children and adolescents Pregnancy and lactation

The elderly