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Very-low-energy diets and morbidity: a systematic review of longer-term evidence

Published online by Cambridge University Press:  17 July 2012

Y. Mulholland
Affiliation:
Centre for Obesity Research and Epidemiology (CORE), Faculty of Heath and Social Care, Robert Gordon University, AberdeenAB251HG, Scotland, UK
E. Nicokavoura
Affiliation:
Centre for Obesity Research and Epidemiology (CORE), Faculty of Heath and Social Care, Robert Gordon University, AberdeenAB251HG, Scotland, UK
J. Broom
Affiliation:
Centre for Obesity Research and Epidemiology (CORE), Faculty of Heath and Social Care, Robert Gordon University, AberdeenAB251HG, Scotland, UK
C. Rolland*
Affiliation:
Centre for Obesity Research and Epidemiology (CORE), Faculty of Heath and Social Care, Robert Gordon University, AberdeenAB251HG, Scotland, UK
*
*Corresponding author: Dr C. Rolland, email c.rolland@rgu.ac.uk
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Abstract

Evidence from the literature supports the safe use of very-low-energy diets (VLED) for up to 3 months in supervised conditions for patients who fail to meet a target weight loss using a standard low-fat, reduced-energy approach. There is, however, a need for longer-term outcomes on obesity and associated morbidities following a VLED. The present systematic review aims to investigate longer-term outcomes from studies using VLED, with a minimum duration of 12 months, published between January 2000 and December 2010. Studies conducted in both children and adults, with a mean/median BMI of ≥ 28 kg/m2 were included. PubMed, MEDLINE, Web of Science and Science Direct were searched. Reference lists of studies and reviews were manually searched. Weight loss or prevention of weight gain and morbidities were the main outcomes assessed. A total of thirty-two out of 894 articles met the inclusion criteria. The duration of the studies ranged from 12 months to 5 years. Periods of VLED ranged from 25 d to 9 months. Several studies incorporated aspects of behaviour therapy, exercise, low-fat diets, low-carbohydrate diets or medication. Current evidence demonstrates significant weight loss and improvements in blood pressure, waist circumference and lipid profile in the longer term following a VLED. Interpretation of the results, however, was restricted and conclusions with which to guide best practice are limited due to heterogeneity between the studies. The present review clearly identifies the need for more evidence and standardised studies to assess the longer-term benefits from weight loss achieved using VLED.

Type
Systematic Review
Copyright
Copyright © The Authors 2012

The use of very-low-energy diets (VLED) has been severely criticised in the past. Current VLED, however, should not be confused with those from the 1970s which resulted in a number of deaths due to vitamin and mineral deficiencies and poor quality or inadequate amounts of protein(Reference van Itallie1, 2). Modern VLED do not induce such deficiencies.

A VLED is defined as a diet of < 3347 kJ/d ( < 800 kcal/d)(3). A variety of synthetic and food-based formula diets are available, which give energy intakes of 1255–1673 kJ/d (300–400 kcal/d) designed to achieve weight loss while minimising the loss of lean body mass by providing high levels of protein supplemented with vitamins, minerals, electrolytes and fatty acids(Reference Dhindsa, Scott and Donnelly4).

There is sufficient evidence in the literature to ensure the safe use of VLED in the short term(Reference Capstick, Brooks and Burns5, Reference Williams, Mullen and Kelley6). Based on this evidence, institutions such as the National Institute for Health and Clinical Excellence and the National Obesity Forum support the use of this approach for up to 3 months in supervised conditions for patients who fail to meet a target weight loss with a standard low-fat, reduced-energy approach. Despite this, there are still concerns about weight regain following these diets as well as detrimental health effects due to the rapid weight loss they induce. There is a need to review the evidence of longer-term outcomes with the use of VLED on obesity and associated morbidity. We aim to carry out a systematic review of the literature for studies using a VLED, with a minimum follow-up of 12 months, published between January 2000 and December 2010.

Methods

The protocol used for the present systematic review follows the methods recommended by the Cochrane Collaboration(Reference Clarke and Oxman7).

Inclusion criteria

The present review is intended to assess the current literature in this field and update the National Health Service R&D Health Technology Assessment systematic review of diet and lifestyle on weight loss and cardiovascular risk published by Avenell et al. (Reference Avenell, Broom and Brown8). Studies from January 2000 to December 2010 were evaluated. Interventions where the participants had a mean or median BMI of ≥ 28 kg/m2 were included. Interventions evaluated in the present review had to be of at least 12 months duration, including the period of active intervention and follow-up. Studies in children and adults were included. Randomised controlled trials, non-randomised controlled trials and retrospective studies were evaluated. The variation of time on diet using active intervention, follow-up and different follow-up treatments was recorded and accounted for where possible.

Types of intervention

The focus of the present review was to examine the effect of VLED on obesity and associated co-morbidities. The types of dietary interventions evaluated were VLED, also known as VLED defined as a dietary intake of 3347 kJ/d (800 kcal/d) or less. Case studies, however, were omitted.

Outcome measures

Weight loss or prevention of weight gain were the main outcomes assessed from the studies included in the present review. With regard to morbidity, the following outcomes were also included:

  1. (1) Cardiovascular risk (serum lipids, including total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG, systolic and diastolic blood pressure (BP) and glycaemic control)

  2. (2) Liver and kidney function

  3. (3) Fertility

  4. (4) Bone health

  5. (5) Respiratory disorders

  6. (6) Eating disorders

Information about dropouts and adverse events was also gathered.

Outcome measures were considered in relation to the time of active intervention as well as the time and nature of the follow-up period, as these varied widely between studies (i.e. 25 d to 9 months of active intervention and 12 months to 5 years for follow-up).

Search strategy for the identification of included studies

The present systematic review was restricted to studies where the full study report was available. A wide search strategy was applied to identify as many studies evaluating dietary interventions using VLED as possible and which were relevant to the management of obesity and morbidity. For this purpose, four electronic databases were searched including PubMed, MEDLINE, Web of Science and Science Direct. The search strategy incorporated very-low-calorie/energy diet-related terms and text terms, specific to each database. Reference lists of the included studies and reviews were searched and authors contacted for further details of their trials.

Quality assessment of studies

Full copies of studies were assessed by three researchers for methodological quality. The researchers were not blinded to author, journal or institution. Differences of opinion were resolved by discussion. Trial quality and risk of bias were assessed using items known to be associated with the magnitude of results using the criteria list from Jadad et al. (Reference Jadad, Moore and Carroll9) (procedure of allocation, withdrawals/dropouts, blinding of patients and outcome assessment). The protocol used by Jadad et al. (Reference Jadad, Moore and Carroll9) was slightly modified where in the ‘withdrawals and dropouts’ section, one point was given if numbers of withdrawals were mentioned and an extra point was given if the reasons for withdrawals were also described. Where no dropouts occurred, the study was attributed two points. However, for retrospective or ancillary studies, where essentially a completers analysis was carried out, the studies were attributed no points.

Identified studies

A total of thirty-two out of 894 articles met the inclusion criteria and were included in the systematic review. Reasons for the exclusion of these studies are summarised in Fig. 1.

Fig. 1 Summary of the literature search. VLED, very-low-energy diets.

Results

Study characteristics

There was a large amount of heterogeneity in study design for the papers meeting the inclusion criteria. The studies included ranged from 12 months to 5 years in duration. The periods of VLED ranged from 25 d to 9 months. Several studies incorporated aspects of behaviour therapy, exercise programmes, low-fat diets, low-carbohydrate diets, medication (orlistat and sibutramine) or corset treatment (soft corsets were fitted to cover the torso from the xiphoid to the pubic region; the corset was to be used 12–16 h/d, 7 d/week for 9 months) (Table 1).

Table 1 Summary of the studies included in the review

VLED, very-low-energy diet; HC, high-carbohydrate diet; HP, high-protein diet; Δ, change; LED, low-energy diet; T2DM, type 2 diabetes mellitus; MK-0557, highly selective, orally administered neuropeptide Y Y5 receptor antagonist; BED, binge eating disorder; BP, blood pressure; LCHP, low-carbohydrate, high-protein diet; LL, lighter Life; CAD, coronary artery disease; WR, weight reduction; WM, weight maintenance; ECG, electrocardiogram; IDDM, insulin-dependent diabetes; GI, gastrointestinal; LAGB, laparoscopic gastric band; LF, low fat; LCHO, low carbohydrate; CPAP, continuous airway positive pressure; ODI4, oxygen desaturation index; N/A, not available; AHI, apnoea–hypopnoea index; CBT, cognitive behaviour therapy; SWM, successful weight maintainers; USWM, unsuccessful weight maintainers; BS, bariatric paper.

Mean values were significantly different from baseline: * P < 0·05, ** P < 0·001, *** P < 0·0001.

Mean values were significantly different from VLED end: † P < 0·05.

Mean values were significantly different between groups: ‡ P < 0·05, ‡‡ P < 0·001.

§ No P value provided in original paper.

All of the studies were designed to reduce or prevent weight gain and also examined morbidity. The results for all the studies are summarised in Table 1.

Quality assessment

Table 2 displays the quality assessment of the reported studies, separated by co-morbidity and ranked from highest to lowest. The studies in which drugs were used for weight maintenance generally scored the highest ( ≥ 4)(Reference Mathus-Vliegen17, Reference Erondu, Wadden and Gantz18, Reference Richelsen, Tonstad and Rössner21, Reference Madsen, Rissanen and Bruun29, Reference Madsen, Bruun and Skogstrand30) with the exception of those that were not randomised controlled trials(Reference Laaksonen, Nuutinen and Lahtinen13, Reference Niskanen, Laaksonen and Punnonen28).

Table 2 Quality assessment of the reported studies, separated by co-morbidity and ranked from highest to lowest

Weight change

Of the studies included, thirteen reported significant weight change at VLED end(Reference Dhindsa, Scott and Donnelly4, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Lantz, Peltonen and Agren14, Reference Melin, Karlstrom and Lappalainen15, Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Delbridge, Prendergast and Pritchard22, Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Madsen, Rissanen and Bruun29, Reference Madsen, Bruun and Skogstrand30, Reference Wikstrand, Torgerson and Bostrom32, Reference Hinton, LeCheminant and Smith35, Reference de Zwaan, Mitchell and Crosby39). Of these, twelve studies demonstrated significant reductions in weight at VLED end and one study in the group combining cognitive behaviour therapy (CBT) only(Reference de Zwaan, Mitchell and Crosby39). At study end, of those studies that had varying periods of follow-up from 1 to 5 years, fifteen reported significant changes from baseline in the VLED groups(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Laaksonen, Nuutinen and Lahtinen13Reference Melin, Karlstrom and Lappalainen15, Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Delbridge, Prendergast and Pritchard22, Reference Rolland, Hession and Murray23, Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Niskanen, Laaksonen and Punnonen28, Reference Simonen, Gylling and Howard31, Reference Willi, Martin and Datko33, Reference Hinton, LeCheminant and Smith35, Reference Kajaste, Brander and Telakivi36). There was no clear pattern observed for the period of follow-up or for the means of the weight-maintenance method utilised in that period (exercise therapy, counselling, orlistat, intermittent/on-demand VLED, etc.). However, exercise(Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Fogelholm, Sievanen and Kukkonen-Harjula27), behaviour therapy(Reference Tuomilehto, Seppa and Partinen24, Reference Kajaste, Brander and Telakivi36), medication(Reference Mathus-Vliegen17, Reference Erondu, Wadden and Gantz18, Reference Richelsen, Tonstad and Rössner21) and longer reintroduction phase post-VLED(Reference Gripeteg, Karlsson and Torgerson25) appear to help maintain the weight loss achieved by VLED (Table 2).

Cardiovascular risk

There were twenty-four papers identified that reported the effects of weight loss, at least partially, achieved with a VLED on cardiovascular risk. We reviewed data from each study to determine whether cardiovascular parameters at baseline changed significantly following dietary intervention with VLED (VLED end) or at the final follow-up period (study end).

Blood pressure

Of the identified papers, seventeen(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10Reference Gripeteg, Karlsson and Torgerson25) detailed BP in participants at either VLED end or study end. After the intervention, there were a number of different approaches to follow-up, although most generally included a support or review process.

Overall systolic pressure trends were reported in thirteen of the seventeen studies following the VLED end(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16Reference Rolland, Hession and Murray23). Of the changes at VLED end, six showed significant reductions from baseline(Reference Dhindsa, Scott and Donnelly4, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Jazet, de Craen and van Schie19, Reference Rolland, Hession and Murray23), four of which sustained significant systolic BP reductions at study end(Reference Dhindsa, Scott and Donnelly4, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Jazet, de Craen and van Schie19, Reference Rolland, Hession and Murray23). Also, three more studies reported a significant reduction in systolic BP at study end only(Reference Laaksonen, Nuutinen and Lahtinen13, Reference Melin, Karlstrom and Lappalainen15, Reference Gripeteg, Karlsson and Torgerson25).

Study design varied substantially in all those which showed significant systolic pressure reductions, and thus it is difficult to determine which particular variables have the most significant impact on BP.

Diastolic BP information was also available from these seventeen studies. At VLED end, eleven of the studies showed diastolic reductions which were more pronounced than at study end(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Erondu, Wadden and Gantz18Reference Richelsen, Tonstad and Rössner21, Reference Rolland, Hession and Murray23). Only one study(Reference Jazet, de Craen and van Schie19) showed a significant change from baseline which improved further between the VLED end and the study end. At VLED end, similar trends to those for systolic pressure were observed for diastolic pressure in seven of the seventeen studies(Reference Dhindsa, Scott and Donnelly4, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Melin, Karlstrom and Lappalainen15, Reference Jazet, de Craen and van Schie19, Reference Rolland, Hession and Murray23, Reference Gripeteg, Karlsson and Torgerson25) which demonstrated a significant improvement at study endpoint.

Overall, the time of VLED duration, the time of follow-up and the nature of follow-up (hypoenergetic diet, exercise, medication, counselling, etc.) did not predict BP outcomes in the long term.

Waist circumference

Waist circumference data were reported in eighteen papers(Reference Fogelholm, Kukkonen-Harjula and Nenonen10Reference Lantz, Peltonen and Agren14, Reference Mathus-Vliegen17Reference Gripeteg, Karlsson and Torgerson25, Reference Fogelholm, Sievanen and Kukkonen-Harjula27Reference Madsen, Bruun and Skogstrand30). Of the thirteen papers that reported waist circumference data at VLED end(Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Erondu, Wadden and Gantz18Reference Rolland, Hession and Murray23, Reference Fogelholm, Sievanen and Kukkonen-Harjula27Reference Madsen, Bruun and Skogstrand30), seven studies(Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23, Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Madsen, Rissanen and Bruun29) showed significant reductions at VLED end, five of which maintained significant reductions from baseline at study end(Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23, Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Madsen, Rissanen and Bruun29) (Table 3). In total, nine studies showed a significant reduction in waist circumference at study end(Reference Laaksonen, Nuutinen and Lahtinen13, Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23, Reference Gripeteg, Karlsson and Torgerson25, Reference Fogelholm, Sievanen and Kukkonen-Harjula27Reference Madsen, Bruun and Skogstrand30).

Table 3 Summary of the results for blood pressure and waist circumference

VLED, very-low energy diet; Δ, change; HC, high-carbohydrate diet; HP, high-protein diet; MK-0557, highly selective, orally administered neuropeptide Y Y5 receptor antagonist; LCHP, low-carbohydrate, high-protein diet.

Mean values were significantly different from baseline: * P < 0·05, ** P < 0·001, *** P < 0·0001.

Mean values were significantly different from VLED end: † P < 0·05.

Mean values were significantly different between groups: ‡ P < 0·05, ‡‡ P < 0·001.

§ Statistical significant difference from baseline stated but no P value given.

Similarly to BP, the time of VLED duration, the time of follow-up and the nature of follow-up did not predict waist circumference outcomes in the long term.

Lipid profile

Of the identified studies, twenty-one included cholesterol as primary or secondary outcomes following weight loss and intervention(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16Reference Gripeteg, Karlsson and Torgerson25, Reference Niskanen, Laaksonen and Punnonen28Reference Wikstrand, Torgerson and Bostrom32). The results for the different studies are presented in Table 4.

Table 4 Summary of the blood lipid results

VLED, very-low energy diet; Δ, change; HC, high-carbohydrate diet; HP, high-protein diet; T2DM, type 2 diabetes mellitus; MK-0557, highly selective, orally administered neuropeptide Y Y5 receptor antagonist; IR, interquartile range; LCHP, low-carbohydrate, high-protein diet.

Mean values were significantly different from baseline: * P < 0·05, ** P < 0·001.

Mean values were significantly different between groups: ‡ P < 0·05, ‡‡ P < 0·001.

§ Statistical significant difference from baseline stated but no P value given.

Table 5 Summary of the glycaemia results

HBA1C, glycated Hb; VLED, very-low-energy diet, T2DM, type 2 diabetes mellitus; MK-0557, highly selective orally administered neuropeptide Y Y5 receptor antagonist; Δ, change; LCHP, low-carbohydrate, high-protein diet.

Mean values were significantly different from baseline: * P < 0·05, ** P < 0·001.

Mean values were significantly different between groups: ‡ P < 0·05, ‡‡ P < 0·001.

§ No P value provided for baseline, VLED end, study end or between groups.

Statistically significant difference from baseline provided but no P value given.

§§ The conversion factor for fasting insulin is: 1 mU/l = 6·00 pmol/l.

HDL-cholesterol

HDL changes were examined in twenty studies(Reference Fogelholm, Kukkonen-Harjula and Nenonen10Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16Reference Gripeteg, Karlsson and Torgerson25, Reference Niskanen, Laaksonen and Punnonen28Reference Wikstrand, Torgerson and Bostrom32). Of these studies, fourteen reported VLED end data, two of which interestingly reported a significant reduction in HDL(Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Jazet, de Craen and van Schie19). Of these, nine, however, showed significantly increased HDL levels in the VLED arm at study end(Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Laaksonen, Nuutinen and Lahtinen13, Reference Lantz, Peltonen and Agren14, Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Gripeteg, Karlsson and Torgerson25, Reference Niskanen, Laaksonen and Punnonen28, Reference Simonen, Gylling and Howard31, Reference Wikstrand, Torgerson and Bostrom32). Only one study(Reference Madsen, Rissanen and Bruun29) showed an overall significant reduction in HDL. In contrast, although Paisey et al. (Reference Paisey, Frost and Harvey12) showed an increase in HDL, this was only in the group who had to undertake regular exercise and standard dietary intervention and not in the VLED arm.

Insulin and glucose control

Fewer studies examined the effects of VLED on diabetic control and insulin resistance. Only four studies reported a significant improvement in fasting glucose at VLED end(Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23). Fasting plasma glucose data were reported at study end in sixteen studies(Reference Fogelholm, Kukkonen-Harjula and Nenonen10Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Erondu, Wadden and Gantz18, Reference Jazet, de Craen and van Schie19, Reference Richelsen, Tonstad and Rössner21, Reference Rolland, Hession and Murray23Reference Gripeteg, Karlsson and Torgerson25, Reference Niskanen, Laaksonen and Punnonen28, Reference Simonen, Gylling and Howard31, Reference Wikstrand, Torgerson and Bostrom32), four of which showed a significant reduction in fasting glucose at study end(Reference Laaksonen, Nuutinen and Lahtinen13, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23, Reference Gripeteg, Karlsson and Torgerson25).

Of the nine studies(Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Lantz, Peltonen and Agren14Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Erondu, Wadden and Gantz18, Reference Richelsen, Tonstad and Rössner21, Reference Tuomilehto, Seppa and Partinen24, Reference Simonen, Gylling and Howard31) that reported insulin levels at study end, three showed significant improvements(Reference Vasankari, Fogelholm and Kukkonen-Harjula11, Reference Lantz, Peltonen and Agren14, Reference Melin, Karlstrom and Lappalainen15) while five(Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Lantz, Peltonen and Agren14, Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Erondu, Wadden and Gantz18, Reference Richelsen, Tonstad and Rössner21) reported VLED end data which showed no significant change.

HbA1c also represented by fructosamine was reported in seven studies(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Jazet, de Craen and van Schie19, Reference Richelsen, Tonstad and Rössner21, Reference Rolland, Hession and Murray23, Reference Madsen, Rissanen and Bruun29, Reference Willi, Martin and Datko33). Of these, three studies showed significant improvements in the VLED groups at study end(Reference Dhindsa, Scott and Donnelly4, Reference Rolland, Hession and Murray23, Reference Madsen, Rissanen and Bruun29). Interestingly, Jazet et al. (Reference Jazet, de Craen and van Schie19) reported a significant improvement in HbA1c in six patients who regained more than 5 kg weight by the study end(Reference Jazet, de Craen and van Schie19).

We identified four studies where the number of patients taking daily insulin or actual insulin doses were reported(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Jazet, de Craen and van Schie19, Reference Willi, Martin and Datko33). In the three studies that reported insulin doses at study end, reduced daily doses of insulin were noted although statistical significance was not reported(Reference Dhindsa, Scott and Donnelly4, Reference Jazet, de Craen and van Schie19, Reference Willi, Martin and Datko33). Only one study reported an increase in insulin users in the VLED arm at study end(Reference Dhindsa, Scott and Donnelly4). A large reduction in the actual number of insulin users at study end was reported in one other study, although, again, statistical significance was not reported(Reference Jazet, de Craen and van Schie19).

Again, the time of VLED duration, the time of follow-up and the nature of follow-up did not predict glycaemic outcomes in the long term.

Liver and kidney function

Of the thirty-two papers identified, only two commented on liver and kidney function(Reference Melin, Karlstrom and Lappalainen15, Reference Rolland, Hession and Murray23). The paper by Melin et al. (Reference Melin, Karlstrom and Lappalainen15) stated that at 2 years follow-up, there were no significant changes in liver transaminases and plasma urate but data were not provided. Rolland et al. (Reference Rolland, Hession and Murray23), on the other hand, reported significant improvements in alanine aminotransferase (30·0 (sd 17·8) v. 23·2 (sd 8·9) U/l; P < 0·05); alkaline phosphatase (81·6 (sd 19·6) v. 78·0 (sd 22·1) U/l; P < 0·05); γ-glutamyl transferase (33·8 (sd 33·7) v. 24·1 (sd 17·7) U/l; P < 0·05) and estimated glomerular filtration rate (1·29 (sd 11·6) v. 1·33 (sd 0·19) ml/s; P < 0·05) from post-screening to 9 months.

Fertility

In one study, the impact of VLED-induced weight loss on fertility and sexual function was examined(Reference Niskanen, Laaksonen and Punnonen28). Sex hormone-binding globulin rose significantly from 27·6 (sd 11·9) to 48·1 (sd 23·5) nmol/l at VLED end (P < 0·0001) and remained significant despite declining by study end (32·6 (sd 12·9) nmol/l; P < 0·001). Free testosterone levels also increased significantly by VLED end and remained elevated at 212 (sd 84) pmol/l at 1 year (P = 0·002), compared with baseline (185 (sd 66) pmol/l). The number of men presenting with biochemical hypoandrogenism (total testosterone < 11 nmol/l) decreased significantly during the VLED (P < 0·001) and at the 1-year follow-up (P = 0·002).

Bone health

In three papers, changes in bone mass following a VLED intervention were examined(Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Dixon, Strauss and Laurie34, Reference Hinton, LeCheminant and Smith35). The study design is described in Table 1.

Hinton et al. (Reference Hinton, LeCheminant and Smith35) examined the effects of both weight loss and weight maintenance on serum bone turnover by measuring osteocalcin and C-terminal telopeptide of type I collagen (CTX) as markers of bone formation and resorption, respectively.

Both osteocalcin and CTX showed a significant increase at VLED end, but these were not significantly correlated, suggesting an imbalance in bone resorption and formation during weight loss. At study end, osteocalcin and CTX became significantly correlated, suggesting that bone formation and resorption were balanced during weight maintenance. Changes in body weight were significantly and negatively correlated with changes in CTX only at VLED end and study end.

Fogelholm et al. (Reference Fogelholm, Sievanen and Kukkonen-Harjula27) similarly examined changes in bone mineral density (BMD) or bone mineral content (BMC) in three groups of postmenopausal women (Table 1). At VLED end, total BMC remained unchanged; however, there was a significant reduction noted in lumbar trochanteric and radial BMD (P < 0·05). A reduction in total body BMC and significantly lower lumbar and femoral neck BMD were reported at study end, with the recovery of distal radius BMD. Group exercise allocation had no statistically different effect on BMD at the various sites.

In the study by Dixon et al. (Reference Dixon, Strauss and Laurie34), total body BMC had decreased significantly in the laparoscopic gastric band ( − 0·087 (sd 0·12); P = 0·002) as well as the intensive dietary weight-loss group ( − 0·061 (sd 0·9); P = 0·002) at 24 months. The changes were not significant between the two groups.

Respiratory disorders

Sleep apnoea

In two studies, the effect of VLED on the alleviation of symptoms associated with the obstructive sleep apnoea syndrome was investigated(Reference Tuomilehto, Seppa and Partinen24, Reference Kajaste, Brander and Telakivi36) and in one study the effects of weight reduction in obese patients with asthma were examined(Reference Stenius-Aarniala, Poussa and Kvarnström37).

Kajaste et al. (Reference Kajaste, Brander and Telakivi36) did not provide VLED end data, although other time periods of 6, 12, 24 months and study end were reported. No significant differences were observed for weight loss at any point of the study. Changes in sleep apnoea were assessed by measuring the oxygen desaturation index, the average number of oxygen desaturation events per h of sleep exceeding 4 % from baseline. Improvements in oxygen desaturation index from baseline were significant at 24 months. Significant correlations were observed between oxygen desaturation index improvements and weight change at 6 and 24 months (P < 0·001). At the 3-year follow-up, five patients reported no obstructive sleep apnoea syndrome symptoms.

Tuomilehto et al. (Reference Tuomilehto, Seppa and Partinen24) assessed changes in sleep apnoea by measuring the apnoea–hypopnoea index (AHI). At VLED end, the mean total AHI was statistically improved in the VLED v. control group (P = 0·036). Based on the AHI values, twenty-two of the thirty-six patients (61 %) in the intervention group, and in twelve of the thirty-eight patients (32 %) in the control group, were objectively cured (P = 0·019) at VLED end. This change was maintained at the 1-year follow-up, where the mean total AHI in the intervention group was 6·0 events/h and that in the control group was 9·6 events/h (P = 0·043). Changes in AHI during the 12-month follow-up were strongly associated with changes in weight and waist circumference which was independent of baseline BMI. Moreover, significant improvements in mean arterial oxygen saturation were observed in the intervention group when compared with the control group after 1 year.

Asthma

Stenius-Aarniala et al. (Reference Stenius-Aarniala, Poussa and Kvarnström37) was the only study which investigated the effects of VLED on obese patients with asthma. The details of the study design are given in Table 1.

Data for flow vital capacity and forced expiratory volume in 1 s were collected. Forced expiratory volume in 1 s (percentage of predicted) improved significantly more in the treatment group at VLED end, and was maintained even after 1 year (P = 0·02). There was also a significantly greater median reduction of dyspnoea in the treatment group when compared with the control group (13 v. 1 mm on the visual analogue scale; P < 0·05). The daily use of rescue sympathomimetics decreased significantly more in the treatment group (1·2 v. 0·1 doses; P < 0·05).

Eating disorders

Binge eating disorder

In two studies, the effect of VLED on binge eating disorder (BED) was reported(Reference Raymond, de Zwaan and Mitchell38, Reference de Zwaan, Mitchell and Crosby39).

In de Zwaan et al. (Reference de Zwaan, Mitchell and Crosby39), patients with BED participated in a 6-month intervention. The change in binge eating was not different between the BED-only group when compared with the BED+CBT group at any time point. However, during the fasting period of VLED, an improvement in the absence of binge eating was observed in both groups (80·6 % were binge free in the BED+CBT group v. 80·4 % in the BED − CBT group; P = 0·98). At study end, forty-seven participants were binge free and 56·3 % did not meet the criteria for BED, again with no significant difference between the groups.

A study by Raymond et al. (Reference Raymond, de Zwaan and Mitchell38) investigated the influence of several factors on the diagnostic criteria of obese individuals with and without BED, 1 year after following a VLED programme. The details of the study are given in Table 1. At baseline, sixty-three participants were diagnosed with BED, thirty-six with sub-threshold BED and twenty-nine with no binge eating symptoms (no BED). Of the sixty-three individuals with BED, thirty-six (57 %) no longer met the criteria at 12 months. Conversely, at 12 months, sixteen (13 %) of the BED patients moved to a more severe category. At 12-month follow-up, nine of the patients (25 %) with sub-threshold BED and three (10 %) with no BED at baseline also met the full BED criteria. A significant association was found between BED diagnosis and weight gained at 12-month follow-up (P = 0·0087).

Mental health

The effects of VLED on mental health were investigated in two studies. In one study, depression was examined(Reference Legenbauer, Petrak and de Zwaan40) and in another study the effect of mental disorders on the maintenance of weight loss was investigated(Reference Legenbauer, de Zwaan and Mühlhans41).

Legenbauer et al. (Reference Legenbauer, Petrak and de Zwaan40) investigated the effect of eating and depressive disorders on weight loss after VLED treatments and after surgical weight reduction treatment. A greater number of participants in the VLED group met the criteria for diagnosis of depressive disorder at baseline, when compared with bariatric surgery patients. Although a lifetime history of depression did not differ between the groups, history of depressive disorder (both current and lifetime) had a significant negative predictive value on longer-term weight loss in the bariatric surgery group but not in the VLED group at 4 years. Conversely, in the bariatric surgery group, a positive association was demonstrated in patients who had a history of eating disorder, with greater weight losses achieved at study end. The authors suggested that this observation may be due to a number of limitations in their study, including the lack of randomisation, high attrition rate and the lack of evaluation of recurrence or severity of depression on long-term outcomes.

Legenbauer et al. (Reference Legenbauer, de Zwaan and Mühlhans41) assessed the effect of mental disorders on the maintenance of weight loss among the patients who had previously successfully participated in a VLED programme. Of the 166 participants, 28·3 % maintained a weight loss of at least 5 % of their initial weight for 3 years. In 71·7 % of the participants who maintained a loss of less than 5% of their pretreatment weight, lower levels of cognitive control, higher levels of disinhibition and higher levels of perceived hunger were reported at the 3-year follow-up compared with those with >5 % loss.

Dropouts and adverse events

Of the thirty-two studies included in the present review, dropout information was available for twenty-eight studies(Reference Dhindsa, Scott and Donnelly4, Reference Fogelholm, Kukkonen-Harjula and Nenonen10, Reference Paisey, Frost and Harvey12Reference Gripeteg, Karlsson and Torgerson25, Reference Fogelholm, Sievanen and Kukkonen-Harjula27, Reference Madsen, Rissanen and Bruun29Reference Wikstrand, Torgerson and Bostrom32, Reference Dixon, Strauss and Laurie34, Reference Kajaste, Brander and Telakivi36Reference Legenbauer, de Zwaan and Mühlhans41). In five of these studies, no dropouts were reported(Reference Laaksonen, Nuutinen and Lahtinen13, Reference Jazet, de Craen and van Schie19, Reference Madsen, Rissanen and Bruun29, Reference Simonen, Gylling and Howard31, Reference Stenius-Aarniala, Poussa and Kvarnström37). Dropouts were more notable during the follow-up as opposed to the VLED period. In only three of the remaining studies did they specify higher dropout rates during the VLED phase when compared with the follow-up period(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Tuomilehto, Seppa and Partinen24). For the studies that reported dropouts during the VLED phase, this appears to be in the first few weeks(Reference Tuomilehto, Seppa and Partinen24, Reference Wikstrand, Torgerson and Bostrom32). The main reasons for discontinuing the VLED appeared to be withdrawal from the study before starting the diet, distaste of products, poor compliance and work schedules(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Tuomilehto, Seppa and Partinen24, Reference Gripeteg, Karlsson and Torgerson25, Reference Wikstrand, Torgerson and Bostrom32, Reference Kajaste, Brander and Telakivi36). There was one death recorded in the first 5 weeks of a VLED but this was not linked to the VLED diet by the authors(Reference Tuomilehto, Seppa and Partinen24). In one study where 23·7 % of the patients dropped out in the VLED phase, only 0·1 %, however, were due to adverse effects(Reference Erondu, Wadden and Gantz18).

Few reasons were given for dropout during the follow-up phase; however, it was observed that younger patients and patients with higher baseline BMI were significantly more likely to drop out(Reference Wikstrand, Torgerson and Bostrom32, Reference Legenbauer, Petrak and de Zwaan40) while those receiving behaviour therapy were more likely to be retained(Reference de Zwaan, Mitchell and Crosby39).

Of the thirty-two studies, fourteen monitored for adverse events(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Melin, Karlstrom and Lappalainen15, Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Erondu, Wadden and Gantz18, Reference Jazet, de Craen and van Schie19, Reference Tuomilehto, Seppa and Partinen24, Reference Gripeteg, Karlsson and Torgerson25, Reference Simonen, Gylling and Howard31Reference Willi, Martin and Datko33, Reference Kajaste, Brander and Telakivi36, Reference Legenbauer, Petrak and de Zwaan40, Reference Legenbauer, de Zwaan and Mühlhans41). Of these studies, two stated that no adverse effects were reported(Reference Simonen, Gylling and Howard31, Reference Willi, Martin and Datko33). Of the remaining studies, five reported minor transient adverse events including nausea, vomiting, diarrhoea, biliary colic, elevation of liver function enzymes, dry skin, hair loss and dizziness(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Erondu, Wadden and Gantz18, Reference Tuomilehto, Seppa and Partinen24, Reference Wikstrand, Torgerson and Bostrom32).

A total of seven studies commented on major adverse events throughout the study period(Reference Paisey, Frost and Harvey12, Reference Jazet, de Craen and van Schie19, Reference Tuomilehto, Seppa and Partinen24, Reference Gripeteg, Karlsson and Torgerson25, Reference Kajaste, Brander and Telakivi36, Reference Legenbauer, Petrak and de Zwaan40, Reference Legenbauer, de Zwaan and Mühlhans41). In three studies, significant cardiac events were noted, none of which was reported as being directly related to the VLED intervention. In summary, one death was attributable to myocardial infarctions(Reference Kajaste, Brander and Telakivi36) and one from heart failure at 35 weeks post-VLED(Reference Gripeteg, Karlsson and Torgerson25). Paisey et al. reported one non-fatal myocardial infarction in the VLED group but also a non-fatal myocardial infarction in the conventional diet group. In this study, however, one patient was able to have a coronary bypass as a result of weight loss achieved through the VLED. Finally, one case of acute coronary syndrome(Reference Jazet, de Craen and van Schie19) was also reported in the VLED arm. In another three studies, seven other deaths were reported(Reference Tuomilehto, Seppa and Partinen24, Reference Legenbauer, Petrak and de Zwaan40, Reference Legenbauer, de Zwaan and Mühlhans41), although the cause of death was not reported. In two of the studies which included type 2 diabetic patients, one other death occurred from primary biliary cirrhosis(Reference Paisey, Frost and Harvey12) and a case of prostate cancer was also diagnosed(Reference Jazet, de Craen and van Schie19). In another study, five patients were lost to follow-up due to illness but the type of illness was not specified(Reference Legenbauer, Petrak and de Zwaan40). Overall, none of the major adverse effects noted in any of these studies was reported to be related to the VLED itself.

Discussion

The present review suggests that long-term weight loss and improvements in co-morbidities ranging from cardiovascular risk to respiratory disorders can be advised in the longer term using VLED. These improvements, however, are more likely to be associated with the weight loss induced, rather than the way in which the weight loss is achieved.

Previous studies have argued that despite greater initial reductions in weight loss with VLED, weight regain is similar to a conventional diet(Reference Willi, Martin and Datko33). In accordance with the meta-analysis by Anderson et al. (Reference Anderson, Kendall and Jenkins42), the present review suggests that significant weight loss appears to be sustained in the longerterm following a VLED for obese and overweight individuals with co-morbidities. The present systematic review also demonstrates that in the longer term, and in agreement with previously reported evidence, significant weight-loss maintenance following a VLED was demonstrated mainly in the groups who used a conventional diet with exercise or adjuncts such as orlistat(Reference Paisey, Frost and Harvey12, Reference Richelsen, Tonstad and Rössner21).

Cardiovascular risk

Jazet et al. (Reference Jazet, de Craen and van Schie19) suggested that cardiovascular risk factors may be reduced, irrespective of weight loss or regain, in the long term following a VLED(Reference Jazet, de Craen and van Schie19). In the present review, however, significant reductions in systolic and diastolic BP were generally associated with significant weight loss(Reference Dhindsa, Scott and Donnelly4, Reference Paisey, Frost and Harvey12, Reference Melin, Karlstrom and Lappalainen15, Reference Jazet, de Craen and van Schie19, Reference Rolland, Hession and Murray23, Reference Gripeteg, Karlsson and Torgerson25, Reference Laaksonen, Kainulainen and Rissanen26) as were improvements in waist circumference(Reference Jazet, de Craen and van Schie19, Reference Linna, Borg and Kukkonen-Harjula20, Reference Rolland, Hession and Murray23, Reference Gripeteg, Karlsson and Torgerson25, Reference Laaksonen, Kainulainen and Rissanen26, Reference Niskanen, Laaksonen and Punnonen28).

Lipid data appear to conflict and study design is significantly varied. Rolland et al. (Reference Rolland and Broom43) recently reported the effects of VLED on HDL where an improvement is often seen during weight maintenance, although not necessarily at VLED end(Reference Cushman and Evans44). This is in keeping with our findings on the review of long-term evidence.

Although changes in plasma glucose were associated with significant weight reduction, insulin levels also improved regardless of significant weight losses, but, again, may be influenced by additional factors in the study design. Few studies reported insulin requirements, but the results suggested reduced doses at study end.

Fertility

The limited long-term evidence that we currently have for the use of VLED for improving fertility does not allow us to make any concrete conclusions. An interesting case study of an obese type 2 diabetic and hypertensive patient(Reference Katsuki, Sumida and Ito45) who followed a VLED to improve her likelihood of conceiving demonstrated the usefulness of VLED for pregnant control of glucose metabolism and BP. In addition, short-term evidence does suggest that weight loss improves fertility in obese women with polycystic ovary syndrome(Reference Franks, Kiddy and Hamilton-Fairley46, Reference Kiddy, Hamilton-Fairley and Bush47). This warrants the need for further investigation into the use of VLED for improving fertility in the longer term.

Bone health

There has been concern expressed about the effect of weight loss on bone health(Reference Ramsdale and Bassey48Reference Villareal, Banks and Sinacore54). Very little is currently known of the long-term effects of weight loss on bone turnover. The limited evidence for VLED suggests an imbalanced turnover during the VLED phase, which resumes balance during weight maintenance. The imbalance observed during the VLED phase may simply be due to the reduced energy intake(Reference Ihle and Loucks55), or may reflect a delay in osteoblast formation relative to osteoclastic resorption(Reference Hinton, LeCheminant and Smith35). The evidence also suggests that, in long-term weight loss, the total body BMC is significantly decreased regardless of whether exercise is included in the weight-maintenance phase(Reference Fogelholm, Sievanen and Kukkonen-Harjula27) or if the weight loss is achieved through surgical or dietary means(Reference Dixon, Strauss and Laurie34). Nevertheless, more evidence is required to fully understand the effects of VLED on bone health, perhaps by looking at BMD directly as well as serum markers of bone formation and breakdown.

Respiratory disorders

The long-term use of VLED in the treatment of sleep apnoea demonstrates an improvement in the disease where greater weight loss is associated with greater improvements. These benefits may be further improved through the administration of behaviour therapy. More research is required to determine the optimal duration of VLED or the extent of weight loss which is required for the resolution of apnoeic events in obese individuals.

Eating disorders

VLED have been criticised in the past for increasing the occurrence of BED. The long-term evidence remains unclear, as one study demonstrated improvements in BED, while the other study reported varied outcomes with some patients improving and others worsening. The role of CBT in the treatment of BED in conjunction with VLED also remains unclear. A study by Svendsen et al. (Reference Svendsen, Rissanen and Richelsen56) was not included in the present review as long-term weight loss was not described in the paper. Nevertheless, they showed that 36 months after having followed a VLED for 8 weeks, decreased binge eating was a predictor of sustained weight maintenance while weight loss was associated with decreases in binge eating. More research and evidence are required to elucidate the effects of VLED on BED.

Dropouts and adverse events

Recent reviews have concluded that, in the long term, VLED have no worse outcomes or adverse effects than standard diets(Reference Mustajoki and Pekkarinen57). Previous studies have argued that VLED are associated with high cost and high attrition rates(Reference Tsai and Wadden58). Our findings suggest that dropouts are higher during the follow-up phase and are rarely due to the VLED itself. Few studies suggested reasons for this and future studies may provide more information on reasons for high attrition in the follow-up period.

In the present review, we found that few papers reported significant adverse events. The minor adverse events outlined were as expected when following a ketotic diet(Reference Delbridge and Proietto59). Few deaths and major adverse events such as myocardial infarctions were reported. There appears, however, to be a lack of rigour in the reporting of adverse events. Standardisation of adverse events reporting would be beneficial in providing further evidence of short- and long-term safety outcomes.

Strengths and limitations

The present review represents a detailed systematic review of an important area of controversy. Despite the complexity of the present review, due to the high variation in the study design of the reviewed papers, we have attempted to separate the effects attributable to VLED and other interventions. The heterogeneity in study design, particularly in terms of the VLED period, length of follow-up and additional interventions, however, makes the interpretation of the results difficult and conclusions with which to guide best practice limited. A meta-analysis was planned but not able to be completed because of the inconsistent protocols. In addition, study quality was variable where 62·5 % of the studies had a score of 2 or less. However, this may simply reflect the way in which the quality was assessed, as studies were scored for double blinding, which is not possible to achieve in behavioural studies. Perhaps a different method of assessment investigating sample size, conduct of study, details of follow-up analysis and interpretation would have been more suitable for the assessment of these papers.

There remains limited evidence on the effects of VLED on specific disease groups, which is partially due to the strict safety protocols which accompany this dietary approach. Although evidence is mounting for use in some groups at higher cardiovascular risk, such as type 2 diabetics, there is little evidence of outcomes in other obesity-related secondary diseases, such as non-alcoholic fatty liver disease. Future areas of research may provide more information on the outcomes of VLED dependent on age, sex, ethnicity and specific disease. There is need, however, for clarification of nutritional completeness of different VLED used in research. With the exception of energy intake, current VLED should either be nutritionally complete or include supplements to avoid any deficiencies. Of the thirty-two studies investigated, only four commented on nutritional completeness(Reference Richelsen, Tonstad and Rössner21, Reference Dixon, Strauss and Laurie34, Reference Hinton, LeCheminant and Smith35, Reference Stenius-Aarniala, Poussa and Kvarnström37) and two commented on the use of a supplement(Reference Kukkonen-Harjula, Borg and Nenonen16, Reference Simonen, Gylling and Howard31). When we looked for the manufacturer's information about the different VLED used, these were all stated to be nutritionally complete. Only one paper made no comment of the VLED that was used or its nutritional completeness(Reference Laaksonen, Nuutinen and Lahtinen13).

The data presented in the present review are often conflicting. There is a great need for consistency in the design of studies to allow accurate data extrapolation, and long-term studies to show sustained outcomes. Long-term information on the use of intermittent or on-demand VLED is an area which has not been explored in many studies. The ‘yo-yo’ effect of rapid weight loss and regain associated with VLED has previously been criticised(Reference Prentice, Jebb and Goldberg60). However, several studies have demonstrated that intermittent VLED use does not have any detrimental effect on metabolic parameters such as RMR, fasting insulin, insulin resistance, leptin, inflammatory markers, lipids or BP(Reference Prentice, Jebb and Goldberg60Reference Harvie, Pegington and Mattson63).

The role of VLED combined with varying intensity of exercise, and also behaviour modification through counselling, needs to be explored in more depth. This is consistent with the findings of a recent systematic review which stated that VLED were more efficacious if combined with behaviour modification and active follow-up(Reference Ayyad and Andersen64). In the long term, weight regain may occur, but the VLED may instigate behaviours which facilitate longer-term changes for the prevention of weight regain and overall health and well-being. The use of behaviour therapy may be particularly useful for those individuals with a history of eating and mental health disorders who appear to have more difficulty in maintaining long-term weight loss.

Conclusion

Overall, the present review suggests that long-term weight loss and improvements in cardiovascular risk, fertility and respiratory disorders are achievable with the use of VLED, particularly in conjunction with behaviour therapy and exercise. There is currently little evidence to suggest any detriment to bone health, liver or kidney function, but data assessing these factors remain limited. We clearly identify that there is a need for further standardised research of VLED use in healthy and at-risk groups, the results of which could better inform best practice.

Acknowledgements

This research was funded by LighterLife Limited, UK. Professor Broom is the medical director for LighterLife Limited. Y. M., C. R. and E. N. carried out the literature search and data extraction, and were involved in the interpretation of the results and the writing of the manuscript. J. B. provided scientific expertise and was involved in the review and the writing of the final manuscript.

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Figure 0

Fig. 1 Summary of the literature search. VLED, very-low-energy diets.

Figure 1

Table 1 Summary of the studies included in the review

Figure 2

Table 2 Quality assessment of the reported studies, separated by co-morbidity and ranked from highest to lowest

Figure 3

Table 3 Summary of the results for blood pressure and waist circumference

Figure 4

Table 4 Summary of the blood lipid results

Figure 5

Table 5 Summary of the glycaemia results

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Very-low-energy diets and morbidity: a systematic review of longer-term evidence
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