Patients with obesity (BMI > 30 kg/m2) aged 18–65 years who had been referred to RIO by their general practitioner were recruited into the study and description of the referral criteria can be found elsewhere . The study obtained a favourable opinion from the South Yorkshire NHS Ethics Committee (ref: 14-YH-0018) and was conducted in accordance with the guidelines laid down in the Declaration of Helsinki. All participants provided written informed consent. The trial was prospectively registered in ISRCTN (ISRCTN31465600).
The present study was a parallel-armed cohort study comparing IER to CER. The weight loss intervention was 6 months, with follow-up at 1 year (i.e. 6 months following cessation of the intervention) for those participants still engaged with the practice. Participants were not randomised, but instead self-selected their dietary intervention group to promote patient autonomy and facilitate long-term successful lifestyle change. Dietary advice was provided by specialist obesity nurses.
Intermittent energy restriction
On 2 days of the week, participants consumed 4 commercially available LighterLife™ very low energy formula-based Food Packs (2638 kJ: 38%, 36% and 26% of total energy as carbohydrate, protein and fat), which met daily requirements for vitamins and minerals. Participants were provided with Food Packs during the 6-month intervention phase only. On the remaining 5 days (“feed days”), participants’ food intake was self-selected, but they were asked to consume a healthy diet compliant with UK-based guidelines issued by the national institute of clinical excellence, NICE (The EatWell Plate: https://webarchive.nationalarchives.gov.uk/20120503053141/http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_126472). These guidelines recommend a diet based on starchy high-fibre foods; ≥ 5 portions of fruit and vegetables; lean protein sources (e.g. meat, poultry, fish and pulses); low-fat dairy (e.g. milk, cheese); and limiting intake of total fat, sugar, salt and alcohol. Advice on portion control (e.g. smaller portions, food swaps) was also provided to attain dietary targets.
Continuous energy restriction diet
Participants assigned to the CER diet were advised to consume a daily hypo-energetic diet of 2092 kJ (500 calories) below their estimated energy requirements, incorporating healthy eating principles (as outlined above). Advice on portion control (e.g. smaller portions, food swaps) was also provided to attain dietary targets. Requirements were calculated using the Harris Benedict equation multiplied by an appropriate physical activity factor in accordance with the standard practice at RIO . All foods were self-selected by participants. The CER intervention served as the “standard treatment” control, compliant with current practice, UK NICE obesity guidelines and the 2013 NHS Commissioning Board policy criteria for Tier 3 services.
As part of the standard RIO service, all participants on both arms of the study had access to a variety of specialist facilities, resources and multidisciplinary specialists including exercise and talking therapists . Participants in both groups were regularly reviewed in the clinic every month, where adherence to dietary advice (including food pack consumption) was discussed.
During the subsequent 6-month period, weight goals (continued weight loss or maintenance) were determined on an individual basis. IER participants were not specifically advised to continue ‘fasting’ (this was patient choice), whilst all participants were advised to continue following healthy eating guidance. Participants in both groups were able to still attend RIO every month for the following 6 months (unless participants in either group dropped out) and IER participants were free to continue the IER diet self-funded (if they chose to). During this time, both groups could access the other elements of RIO standard care, e.g. the gym, cooking skills classes and talking therapies.
Measurements were taken before participants started their diet and then serially over the course of the study by either the specialist nurse or healthcare assistant. These measurements included weight, total body fat, fat-free mass (FFM), waist circumference, systolic and diastolic blood pressure and an overnight fasted blood sample. Body composition was assessed by bioimpedance (TANITA MC-180MA; Tanita Corp, Tokyo, Japan). Waist circumference was measured at the midpoint between the lower margin of the lowest palpable rib and top of the iliac crest at the end of normal expiration. Blood pressure was measured using an automated sphygmanometer following a 5-min rest (7670-16767; Welch Allyn, Skaneateles Falls, NY, USA).
Biochemical analyses (with the exception of insulin) were conducted at two accredited hospital laboratories (Rotherham District General Laboratory; Royal Surrey County Hospital Pathology Partnership, UK) by personnel blinded to group assignment. Fasting insulin was measured in batch upon study completion via radioimmunoassay using a commercially available kit (Merck Millipore, MA, USA; inter/intra assay CVs < 10%) by a study investigator (RA) who was blinded to group assignment at the time of the analyses.
Participants completed validated 7-day diet diaries at 3 time points: baseline (prior to commencing diet), then months 3 and 6 whilst on the diet. Diaries included pictorial guides to aid portion size estimations. All dietary analyses were carried out in diet plan 7 (Forestfield Software, Horsham, UK) using the McCance and Widdowson’s composition of foods integrated dataset. For the purpose of this study, a compliant ‘fast’ day was defined as one where energy intake was ≤ 3347 kJ, which corresponds to the very low energy threshold defined by the NICE Obesity Guidelines .
Data were statistically analysed using SPSS v23 (IBM, Chicago, USA). Data were first checked for normality using the Shapiro–Wilk test, with non-normally distributed data normalised via log transformation if required to permit parametric testing. The primary analysis was a completer-only analysis, owing to the high attrition rates exhibited by both groups. The alternative approach is intention to treat (ITT) analyses which include every subject who is randomized, ignoring noncompliance, protocol deviations and withdrawal which thus maintains prognostic balance generated from the original random treatment allocation. However, in the present study complete outcome data were not available for all randomized participants, i.e. study measurements were not taken for participants who dropped out. Hence, assumptions must be made, e.g. using last observation carried forward (LOCF) or baseline observation carried forward (BOCF) which affect the validity of study outcomes, particularly in the context of the 66% attrition rate. ITT analyses for anthropometric data (for which intermediate outcomes were available) were, therefore, conducted as secondary analyses (presented in the supplementary materials).
To assess between-group differences, a repeated measures analysis of variance was used which included gender and T2DM status as covariates. Other relevant covariates (e.g. age, other comorbidities) were omitted as covariates, as initial exploratory analyses failed to find any significant interaction effects. Paired t tests were used to assess within-group changes between the various study time points. Independent-sample t tests and Chi-square test were used to compare participant characteristics at baseline. Significance was assumed when p < 0.05 (two tailed), and unless otherwise stated, data are expressed as mean ± standard error of the mean (SEM).