5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study.

BACKGROUND: In DiRECT, a randomised controlled effectiveness trial, weight management intervention after 2 years resulted in mean weight loss of 7·6 kg, with 36% of participants in remission of type 2 diabetes. Of 36 in the intervention group who maintained over 10 kg weight loss at 2 years, 29 (81%) were in remission. Continued low-intensity dietary support was then offered up to 5 years from baseline to intervention participants, aiming to maintain weight loss and gain clinical benefits. This extension study was designed to provide observed outcomes at 5 years. METHODS: The DiRECT trial took place in primary care practices in the UK. Participants were individuals aged 20-65 years who had less than 6 years' duration of type 2 diabetes, a BMI greater than 27 kg/m2, and were not on insulin. The intervention consisted of withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. After sharing the 2-year results with all participants, UK National Health Service data were collected annually until year 5 from remaining intervention participants who received low-intensity dietary support, intervention withdrawals, and the original randomly allocated groups. The primary outcome was remission of type 2 diabetes; having established in the DiRECT trial that sustained weight loss was the dominant driver of remission, this was assumed for the Extension study. The trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2016, 149 participants were randomly assigned to the intervention group and 149 were assigned to the control group in the original DiRECT study. After 2 years, all intervention participants still in the trial (101 [68%] of 149) were approached to receive low-intensity support for a further 3 years. 95 (94%) of 101 were able to continue and consented and were allocated to the DiRECT extension group. 54 participants were allocated to the non-extension group, where intervention was withdrawn. At 5 years, DiRECT extension participants (n=85) lost an average of 6·1 kg, with 11 (13%) of 85 in remission. Compared with the non-extension group, DiRECT extension participants had more visits with HbA1c <48 mmol/mol (<6·5%; 36% vs 17%, p=0·0004), without glucose-lowering medication (62% vs 30%, p<0·0001), and in remission (34% vs 12%, p<0·0001). Original control participants (n=149) had mean weight loss 4·6 kg (n=82), and 5 (5%) of 93 were in remission. Compared with control participants, original intervention participants had more visits with weight more than 5% below baseline (61% vs 29%, p<0·0001), HbA1c below 48 mmol/mol (29% vs 15%, p=0·0002), without antidiabetic medication (51% vs 16%, p<0·0001), and in remission (27% vs 4%, p<0·0001). Of those in remission at year 2, 26% remained in remission at 5 years. Serious adverse events in the original intervention group (4·8 events per 100 patient-years) were under half those in the control group (10·2 per 100 patient-years, p=0·0080). INTERPRETATION: The extended DiRECT intervention was associated with greater aggregated and absolute weight loss, and suggested improved health status over 5 years. FUNDING: Diabetes UK.

Dietary weight-management for type 2 diabetes remissions in South Asians: the South Asian diabetes remission randomised trial for proof-of-concept and feasibility (STANDby).

Background: We aimed to assess whether a structured weight management programme incorporating a total diet replacement (TDR) (3-5 months ∼850 kcal/day formula diet) weight loss phase is acceptable to people of South Asian ethnicity and can achieve type 2 diabetes (T2D) remissions similarly to other populations. Methods: Adults of South Asian ethnicity, aged 18-65 years, with T2D for ≤4 years, and BMI 25-45 kg/m2 were recruited from primary care and social media, and randomised to commence TDR either immediately (iTDR), or delayed (dTDR) for 3-5 months as a usual care control arm during this period. Intervention effects were tested in randomised comparisons powered to detect significant weight loss, and in an expanded observational analysis to determine remission effect size, including both iTDR and dTDR groups. Acceptability in those recruited was explored by questionnaire and weight change. Trial registration: Current Controlled Trials, ISRCTN10720065. Date of Registration 27/09/2017. Findings: Twenty-five eligible individuals were recruited. Mean baseline (SD) age was 45.8 (11.1) years, weight 88.2 (13.7) kg, BMI 32.1 (3.8) kg/m2, HbA1c 60.4 (11.3) mmol/mol, liver fat by MRI 15.6 (9.4)%. In the RCT, mean(SD) weight change after TDR was -7.7 (7.2)% in the intervention group (n = 13), and -1.2 (1.4)% in the usual-care control group (n = 12) (p = 0.005), with T2D remission achieved by 5/13, compared to 0/12 respectively (p = 0.039). In the observational study, 23/25 started TDR and 19/23 participants completed the TDR phase. Median time spent in TDR was 105 days (IQR 77-134 days). T2D remission was achieved in 10/23 (43%), and weight changes were concordant with the RCT. Overall, 8/23 (35%) lost over 10% bodyweight. Absolute liver fat proportion near halved from 15.3% at the start of TDR to 8.6% (p < 0.001). Interpretation: In UK-based South Asians, TDR-led weight loss and T2D remission rates are comparable to those observed in white cohorts, and the intervention was acceptable in most of those recruited. There is potential to further improve outcomes, but one-third lost >10% body weight, and the mechanism underpinning T2D remission appears similar, driven by weight change with loss of excess ectopic body-fat. Funding: We gratefully acknowledge funding for the MRI scans from the, Miss MJM Smith Trust (registered charity: SC040586). No other external funds were provided for this trial. NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217).

A Total Diet Replacement Weight Management Program for Difficult-to-Treat Asthma Associated With Obesity: A Randomized Controlled Feasibility Trial.

BACKGROUND: Obesity is often associated with uncontrolled, difficult-to-treat asthma and increased morbidity and mortality. Previous studies suggest that weight loss may improve asthma outcomes, but with heterogenous asthma populations studied and unclear consensus on the optimal method of weight management. The Counterweight-Plus Programme (CWP) for weight management is an evidence-based, dietitian-led total diet replacement (TDR) program. RESEARCH QUESTION: Can use of the CWP compared with usual care (UC) improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity? STUDY DESIGN AND METHODS: We conducted a 1:1 (CWP to UC) randomized, controlled single-center trial in adults with difficult-to-treat asthma and BMI of ≥ 30 kg/m2. The CWP was a 12-week TDR phase (800 kcal/d low-energy formula) followed by stepwise food reintroduction and weight loss maintenance for up to 1 year. The primary outcome was the change in Asthma Control Questionnaire 6 (ACQ6) score over 16 weeks. The secondary outcome was change in Asthma Quality of Life Questionnaire (AQLQ) score. RESULTS: Thirty-five participants were randomized (36 screened) and 33 attended the 16-week follow-up (n = 17 in the CWP group, n = 16 in the UC group). Overall, mean ACQ6 score at baseline was 2.8 (95% CI, 2.4-3.1). Weight loss was greater in the CWP than UC group (mean difference, -12.1 kg; 95% CI, -16.9 to -7.4; P < .001). ACQ6 score improved more in the CWP than UC group (mean difference, -0.69; 95% CI, -1.37 to -0.01; P = .048). A larger proportion of participants achieved the minimal clinically important difference in ACQ6 score with CWP than with UC (53% vs 19%; P = .041; Number needed to treat, 3 [95% CI, 1.5-26.9]). AQLQ score improvement was greater in the CWP than UC group (mean difference, 0.76; 95% CI, 0.18-1.34; P = .013). INTERPRETATION: Using a structured weight management program results in clinically important improvements in asthma control and quality of life over 16 weeks compared with UC in adults with difficult-to-treat asthma and obesity. This generalizable program is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03858608; URL: www. CLINICALTRIALS: gov.

Physical activity, inactivity and sleep during the Diabetes Remission Clinical Trial (DiRECT).

AIMS: As sustained weight loss is vital for achieving remission of type 2 diabetes, we explored whether randomisation to weight loss plus maintenance in the DiRECT trial was associated with physical activity, inactivity or sleep. METHODS: Participants were randomised to either a dietary weight management programme or best-practice care. The weight management group were encouraged to increase daily physical activity to their sustainable maximum. Objective measurement was achieved using a wrist-worn GENEActiv accelerometer for 7 days at baseline, 12 and 24 months in both groups. RESULTS: Despite average weight loss of 10 kg at 12 months in the intervention (n = 66) group, there were no differences in total physical activity or inactivity compared with the control (n = 104) at any time point. However, in our exploratory analysis, those who lost more than 10% of their baseline body weight performed on average 11 mins/day more light activity than the <10% group at 24 months (p = 0.033) and had significantly lower bouts of Inactivity30min (interaction, p = 0.005) across 12 and 24 months. At 24 months, the ≥10% group had higher daily acceleration (38.5 ± 12.1 vs. 33.2 ± 11.1 mg, p = 0.020), and higher accelerations in the most active 5-hour period (59.4 ± 21.8 vs. 50.6 ± 18.3 mg, p = 0.023). Wakefulness after sleep onset decreased in the intervention group compared with the control group and also in the ≥10% weight loss group at 12 and 24 months. CONCLUSIONS: Randomisation to a successful intensive weight loss intervention, including regular physical activity encouragement, was not associated with increased physical activity although sleep parameters improved. Physical activity was greater, and night-time waking reduced in those who maintained >10% weight loss at 12 and 24 months. TRIAL REGISTRATION ISRCTN03267836.

Participant experiences in the Diabetes REmission Clinical Trial (DiRECT).

INTRODUCTION: The Diabetes REmission Clinical Trial (DiRECT) has shown that sustained remission of type 2 diabetes in primary care is achievable through weight loss using total diet replacement (TDR) with continued behavioural support. Understanding participants' experiences can help optimise the intervention, support implementation into healthcare, and understand the process of behaviour change. METHODS: Thirty-four DiRECT participants were recruited into this embedded qualitative evaluation study. In-person and telephone interviews were conducted before the TDR; at week 6-8 of the TDR; 2 weeks into food reintroduction (FR); and at 1 year, to learn about participant experiences with the programme. Transcribed narratives were analysed thematically, and we used interpretation to develop overarching themes. RESULTS: Initiation of the TDR and transition to FR were challenging and required increased behavioural support. In general, adhering to TDR proved easier than the participants had anticipated. Some participants chose the optional extension of TDR. Rapid weight loss and changes in diabetes markers provided ongoing motivation. Further weight loss, behavioural support and occasional use of TDR facilitated weight loss maintenance (WLM). A process of behaviour adaptation to change following regime disruption was identified in three stages: (1) expectations of the new, (2) overcoming difficulties with adherence, and (3) acceptance of continuous effort and establishment of routines. CONCLUSIONS: The DiRECT intervention was acceptable and regularity, continuity, and tailoring of behavioural support was instrumental in its implementation in primary care. The adaptation process accounts for some of the individual variability of experiences with the intervention and highlights the need for programme flexibility.

Delivering the Diabetes Remission Clinical Trial (DiRECT) in primary care: Experiences of healthcare professionals.

OBJECTIVE: The Diabetes Remission Clinical Trial (DiRECT) used a formula total diet replacement programme followed by structured weight loss maintenance to induce and sustain weight loss and remission of type 2 diabetes (T2D) in 36% of participants after 2 years. Nurses and dietitians delivering DiRECT in 22 primary care practices in Tyneside and Scotland provided behavioural support to participants. Participant experiences with DiRECT highlighted the key role of support by healthcare professionals (HCPs). We evaluated HCPs' experiences with DiRECT. RESEARCH DESIGN AND METHODS: Healthcare professionals delivering DiRECT were interviewed at 12 months, while general practices (GPs) were sent an implementation questionnaire. The interviews were analysed thematically. The questionnaires were analysed using frequencies and a narrative synthesis. RESULTS: Healthcare professionals representing 11 of 22 intervention practices were interviewed and 10 of 22 GPs completed questionnaires. HCPs' initial concerns over perceived potential negative intervention effects, particularly withdrawing anti-diabetes and anti-hypertensive medications, were barriers to engagement. Trust of HCPs towards the research team and perceived credibility of the study facilitated engagement and adoption. Ongoing support by research dietitians was key to the management of participants. Involvement in DiRECT inspired more focus on behaviour modification in the treatment of other people living with T2D in routine practice. CONCLUSIONS: Diabetes Remission Clinical Trial was considered highly appropriate for the management of T2D in primary care when supported by trained dietitians. Addressing limitations, including varying training needs of HCPs may improve intervention scale-up and tailoring to clinical contexts.

Brief formula low-energy-diet for relapse management during weight loss maintenance in the Diabetes Remission Clinical Trial (DiRECT).

BACKGROUND: Weight loss maintenance (WLM) is critical for sustaining type 2 diabetes (T2D) remission, but poorly evidenced. We evaluated brief return to formula low-energy-diet (LED) as relapse treatments (RTs) during the WLM phase of the Diabetes Remission Clinical Trial (DiRECT). METHODS: This post-hoc evaluation included all participants commencing the WLM phase of DiRECT. The protocol offered RT when regain of >2 kg occurred. RESULTS: In total, 123/149 (83%) DiRECT intervention participants commenced the WLM phase after 26 (17%) had withdrawn prior to the WLM phase. Most participants [99/123 (80%)] regained >2 kg during the WLM phase, among whom 60/99 (61%) were recorded as using RT and 39/99 (39%) not using any RT. At baseline, RT users had a higher mean (SD) body mass index [35.8 (4.9) kg m-2 vs. 33.8 (3.9) kg m-2 , p = 0.0231] and had greater social deprivation (P = 0.0003) than non-users, although otherwise the groups were similar. Weight loss ≥ 2k g was achieved in 30/93 (32%) of RT attempts. At 2 years, those regaining >2 kg and using RT (n = 60) had mean (SD) weight losses of 7.4 (6.1) kg, with 25 (42%) remissions and 7 (12%) programme withdrawals. Those regaining >2 kg but not using RT (n = 39) had weight losses of 8.8 (6.0) kg, with 21 (54%) remissions and 4 (10%) programme withdrawals (all not significant). Twelve participants were never recorded as having regained >2 kg or using RTs and, at 2 years, their weight losses were 12.9 (9.2) kg, with 4 (33%) remissions and 8 (67%) programme withdrawals. CONCLUSIONS: Most people with T2D experience weight regain >2 kg during the 2 years after substantial weight loss with a LED. Only one-third of RTs corrected their 2-kg regain, resulting in similar weight losses, remissions and programme withdrawals at 2 years compared to those not using RTs; however, both groups had weight losses below those not recorded as regaining >2 kg during WLM.

Weight loss-induced increase in fasting ghrelin concentration is a predictor of weight regain: Evidence from the Diabetes Remission Clinical Trial (DiRECT).

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomized clinical trial, designed to assess the effect of weight loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (age 53.6 ± 7.5 years, body mass index 34.7 ± 4.4 kg/m2 , 59% men). Intervention participants received a 24-month weight management programme, and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, glucagon-like peptide-1 and peptide YY were measured at baseline, 12 months and 24 months in all participants, and at 5 months in a subset of participants in the intervention (n = 56) and control groups (n = 22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3 ± 6.0% body weight at 5 months but regained weight over time, with weight losses of 10.0 ± 7.5% at 12 months and 7.6 ± 6.3% at 24 months. Weight loss in controls was 1.1 ± 3.7% and 2.1 ± 5.0% at 12 and 24 months, respectively. Body weight increased by 2.3% (95% confidence interval [CI] 0.4, 4.1; P = 0.019) between 12 and 24 months for every 1-ng/mL increase in ghrelin between baseline and 12 months, and weight regain between 12 and 24 months was increased by 1.1% (95% CI 0.2, 2.0; P = 0.023) body weight for every 1-ng/mL increase in ghrelin at 12 months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve weight-loss maintenance.

Weight loss induced increase in fasting ghrelin concentration is a predictor of weight regain: evidence from the Diabetes Remission Clinical Trial.

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomised clinical trial designed to assess the effect of weight-loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (aged 53.6±7.5 years, BMI 34.7±4.4 kg/m2, 59% males). Intervention participants received a 24-month weight-management programme and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, GLP-1, and PYY were measured at baseline, 12 and 24-months in all participants, and at 5-months in a subset of interventions (n=56) and controls (n=22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3±6.0% body-weight at 5-months but regained over time, with weight-losses of 10.0±7.5% at 12-months and 7.6±6.3% at 24-months. Weight-loss in controls was 1.1±3.7% and 2.1±5.0% at 12 and 24-months, respectively. Body-weight increased by 2.3% [95% CI: 0.4,4.1]; p=0.019) between 12 and 24-months for every 1 ng/ml increase in ghrelin between baseline and 12-months, and weight regain between 12 and 24-months was increased by 1.1% (95% CI: 0.2,2.0; p=0.023) body-weight for every 1 ng/ml increase in ghrelin at 12-months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight-loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve WLM. This article is protected by copyright. All rights reserved.

Type 2 diabetes remission: 2 year within-trial and lifetime-horizon cost-effectiveness of the Diabetes Remission Clinical Trial (DiRECT)/Counterweight-Plus weight management programme.

AIMS/HYPOTHESIS: Approximately 10% of total healthcare budgets worldwide are spent on treating diabetes and its complications, and budgets are increasing globally because of ageing populations and more expensive second-line medications. The aims of the study were to estimate the within-trial and lifetime cost-effectiveness of the weight management programme, which achieved 46% remissions of type 2 diabetes at year 1 and 36% at year 2 in the Diabetes Remission Clinical Trial (DiRECT). METHODS: Within-trial analysis assessed costs of the Counterweight-Plus intervention in DiRECT (including training, programme materials, practitioner appointments and low-energy diet), along with glucose-lowering and antihypertensive medications, and all routine healthcare contacts. Lifetime cost per quality-adjusted life-year (QALY) was estimated according to projected durations of remissions, assuming continued relapse rates as seen in year 2 of DiRECT and consequent life expectancy, quality of life and healthcare costs. RESULTS: Mean total 2 year healthcare costs for the intervention and control groups were £3036 and £2420, respectively: an incremental cost of £616 (95% CI -£45, £1269). Intervention costs (£1411; 95% CI £1308, £1511) were partially offset by lower other healthcare costs (£796; 95% CI £150, £1465), including reduced oral glucose-lowering medications by £231 (95% CI £148, £314). Net remission at 2 years was 32.3% (95% CI 23.5%, 40.3%), and cost per remission achieved was £1907 (lower 95% CI: intervention dominates; upper 95% CI: £4212). Over a lifetime horizon, the intervention was modelled to achieve a mean 0.06 (95% CI 0.04, 0.09) QALY gain for the DiRECT population and mean total lifetime cost savings per participant of £1337 (95% CI £674, £2081), with the intervention becoming cost-saving within 6 years. CONCLUSIONS/INTERPRETATION: Incorporating the lifetime healthcare cost savings due to periods of remission from diabetes and its complications, the DiRECT intervention is predicted to be both more effective (QALY gain) and cost-saving in adults with type 2 diabetes compared with standard care. This conclusion appears robust to various less favourable model scenarios, providing strong evidence that resources could be shifted cost-effectively to support achieving remissions with the DiRECT intervention. TRIAL REGISTRATION: ISRCTN03267836 Graphical abstract.

Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial.

BACKGROUND: The DiRECT trial assessed remission of type 2 diabetes during a primary care-led weight-management programme. At 1 year, 68 (46%) of 149 intervention participants were in remission and 36 (24%) had achieved at least 15 kg weight loss. The aim of this 2-year analysis is to assess the durability of the intervention effect. METHODS: DiRECT is an open-label, cluster-randomised, controlled trial done at primary care practices in the UK. Practices were randomly assigned (1:1) via a computer-generated list to provide an integrated structured weight-management programme (intervention) or best-practice care in accordance with guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700 people). Allocation was concealed from the study statisticians; participants, carers, and study research assistants were aware of allocation. We recruited individuals aged 20-65 years, with less than 6 years' duration of type 2 diabetes, BMI 27-45 kg/m2, and not receiving insulin between July 25, 2014, and Aug 5, 2016. The intervention consisted of withdrawal of antidiabetes and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. The coprimary outcomes, analysed hierarchically in the intention-to-treat population at 24 months, were weight loss of at least 15 kg, and remission of diabetes, defined as HbA1c less than 6·5% (48 mmol/mol) after withdrawal of antidiabetes drugs at baseline (remission was determined independently at 12 and 24 months). The trial is registered with the ISRCTN registry, number 03267836, and follow-up is ongoing. FINDINGS: The intention-to-treat population consisted of 149 participants per group. At 24 months, 17 (11%) intervention participants and three (2%) control participants had weight loss of at least 15 kg (adjusted odds ratio [aOR] 7·49, 95% CI 2·05 to 27·32; p=0·0023) and 53 (36%) intervention participants and five (3%) control participants had remission of diabetes (aOR 25·82, 8·25 to 80·84; p<0·0001). The adjusted mean difference between the control and intervention groups in change in bodyweight was -5·4 kg (95% CI -6·9 to -4·0; p<0·0001) and in HbA1c was -4·8 mmol/mol (-8·3 to -1·4 [-0·44% (-0·76 to -0·13)]; p=0·0063), despite only 51 (40%) of 129 patients in the intervention group using anti-diabetes medication compared with 120 (84%) of 143 in the control group. In a post-hoc analysis of the whole study population, of those participants who maintained at least 10 kg weight loss (45 of 272 with data), 29 (64%) achieved remission; 36 (24%) of 149 participants in the intervention group maintained at least 10 kg weight loss. Serious adverse events were similar to those reported at 12 months, but were fewer in the intervention group than in the control group in the second year of the study (nine vs 22). INTERPRETATION: The DiRECT programme sustained remissions at 24 months for more than a third of people with type 2 diabetes. Sustained remission was linked to the extent of sustained weight loss. FUNDING: Diabetes UK.

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial.

BACKGROUND: Type 2 diabetes is a chronic disorder that requires lifelong treatment. We aimed to assess whether intensive weight management within routine primary care would achieve remission of type 2 diabetes. METHODS: We did this open-label, cluster-randomised trial (DiRECT) at 49 primary care practices in Scotland and the Tyneside region of England. Practices were randomly assigned (1:1), via a computer-generated list, to provide either a weight management programme (intervention) or best-practice care by guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700). Participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician. We recruited individuals aged 20-65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27-45 kg/m2, and were not receiving insulin. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal/day formula diet for 3-5 months), stepped food reintroduction (2-8 weeks), and structured support for long-term weight loss maintenance. Co-primary outcomes were weight loss of 15 kg or more, and remission of diabetes, defined as glycated haemoglobin (HbA1c) of less than 6·5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications, from baseline to 12 months. These outcomes were analysed hierarchically. This trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2017, we recruited 306 individuals from 49 intervention (n=23) and control (n=26) general practices; 149 participants per group comprised the intention-to-treat population. At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p<0·0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19·7, 95% CI 7·8-49·8; p<0·0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0-5 kg weight loss, 19 (34%) of 56 participants with 5-10 kg loss, 16 (57%) of 28 participants with 10-15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10·0 kg (SD 8·0) in the intervention group and 1·0 kg (3·7) in the control group (adjusted difference -8·8 kg, 95% CI -10·3 to -7·3; p<0·0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7·2 points (SD 21·3) in the intervention group, and decreased by 2·9 points (15·5) in the control group (adjusted difference 6·4 points, 95% CI 2·5-10·3; p=0·0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study. INTERPRETATION: Our findings show that, at 12 months, almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs. Remission of type 2 diabetes is a practical target for primary care. FUNDING: Diabetes UK.

Clinical and metabolic features of the randomised controlled Diabetes Remission Clinical Trial (DiRECT) cohort.

AIMS/HYPOTHESIS: Substantial weight loss in type 2 diabetes can achieve a return to non-diabetic biochemical status, without the need for medication. The Diabetes Remission Clinical Trial (DiRECT), a cluster-randomised controlled trial, is testing a structured intervention designed to achieve and sustain this over 2 years in a primary care setting to determine practicability for routine clinical practice. This paper reports the characteristics of the baseline cohort. METHODS: People with type 2 diabetes for <6 years with a BMI of 27-45 kg/m2 were recruited in 49 UK primary care practices, randomised to either best-practice diabetes care alone or with an additional evidence-based weight management programme (Counterweight-Plus). The co-primary outcomes, at 12 months, are weight loss ≥15 kg and diabetes remission (HbA1c <48 mmol/mol [6.5%]) without glucose-lowering therapy for at least 2 months. Outcome assessors are blinded to group assignment. RESULTS: Of 1510 people invited, 423 (28%) accepted; of whom, 306 (72%) were eligible at screening and gave informed consent. Seven participants were later found to have been randomised in error and one withdrew consent, leaving 298 (176 men, 122 women) who will form the intention to treat (ITT) population for analysis. Mean (SD) age was 54.4 (7.6) years, duration of diabetes 3.0 (1.7) years, BMI 34.6 (4.4) kg/m2 for all participants (34.2 (4.2) kg/m2 in men and 35.3 (4.6) kg/m2 in women) and baseline HbA1c (on treatment) 59.3 (12.7) mmol/mol (7.6% [1.2%]). The recruitment rate in the intervention and control groups, and comparisons between the subgroups recruited in Scotland and England, showed few differences. CONCLUSIONS/INTERPRETATION: DiRECT has recruited a cohort of people with type 2 diabetes with characteristics similar to those seen in routine practice, indicating potential widespread applicability. Over 25% of the eligible population wished to participate in the study, including a high proportion of men, in line with the prevalence distribution of type 2 diabetes. TRIAL REGISTRATION: www.controlled-trials.com/ISRCTN03267836 ; date of registration 20 December 2013.

The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial.

BACKGROUND: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33% of all enrolled patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion. The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological predictors of response. METHODS/DESIGN: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance. Main inclusion criteria: men and women aged 20-65 years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m(2). Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and HbA1c <48 mmol/mol at one year. Further follow-up at 2 years. DISCUSSION: This study will establish whether a structured weight management programme, delivered in Primary Care by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards, will inform future service strategy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03267836 . Date of Registration 20/12/2013.

Feasibility and indicative results from a 12-month low-energy liquid diet treatment and maintenance programme for severe obesity.

BACKGROUND: There is no established primary care solution for the rapidly increasing numbers of severely obese people with body mass index (BMI) > 40 kg/m(2). AIM: This programme aimed to generate weight losses of ≥15 kg at 12 months, within routine primary care. DESIGN AND SETTING: Feasibility study in primary care. METHOD: Patients with a BMI ≥40 kg/m(2) commenced a micronutrient-replete 810-833 kcal/day low-energy liquid diet (LELD), delivered in primary care, for a planned 12 weeks or 20 kg weight loss (whichever was the sooner), with structured food reintroduction and then weight-loss maintenance, with optional orlistat to 12 months. RESULT: Of 91 patients (74 females) entering the programme (baseline: weight 131 kg, BMI 48 kg/m(2), age 46 years), 58/91(64%) completed the LELD stage, with a mean duration of 14.4 weeks (standard deviation [SD] = 6.0 weeks), and a mean weight loss of 16.9 kg (SD = 6.0 kg). Four patients commenced weight-loss maintenance omitting the food-reintroduction stage. Of the remaining 54, 37(68%) started and completed food reintroduction over a mean duration of 9.3 weeks (SD = 5.7 weeks), with a further mean weight loss of 2.1 kg (SD = 3.7 kg), before starting a long-term low-fat-diet weight-loss maintenance plan. A total of 44/91 (48%) received orlistat at some stage. At 12 months, weight was recorded for 68/91 (75%) patients, with a mean loss of 12.4 kg (SD = 11.4 kg). Of these, 30 (33% of all 91 patients starting the programme) had a documented maintained weight loss of ≥15 kg at 12 months, six (7%) had a 10-15 kg loss, and 11 (12%) had a 5-10 kg loss. The indicative cost of providing this entire programme for wider implementation would be £861 per patient entered, or £2611 per documented 15 kg loss achieved. CONCLUSION: A care package within routine primary care for severe obesity, including LELD, food reintroduction, and weight-loss maintenance, was well accepted and achieved a 12-month-maintained weight loss of ≥15 kg for one-third of all patients entering the programme.

A community pharmacy weight management programme: an evaluation of effectiveness.

BACKGROUND: Community pharmacies may offer an accessible way of delivering weight-management programmes but there have been few trials that use clinically significant weight loss outcomes, objective measures of weight and follow-up to 12 months. We aimed to evaluate weight change among patients who used the Counterweight weight management programme delivered by community pharmacies. METHODS: The Counterweight Programme was introduced into community pharmacies in Fife, Scotland in 2009 for patients with a BMI ≥ 30 kg/m(2) or a BMI ≥ 2830 kg/m(2) with a co-morbidity in localities in which Counterweight was not available at GP practices. The aim was to achieve an energy deficit of 500-600 kcal per day. Counterweight specialist dietitians delivered training, support and patient information materials to community pharmacies. Patient weight was measured by pharmacy staff at each weight management session. Weight data recorded at each weight management session were used to estimate weight change and attendance at 3, 6 and 12 months. RESULTS: Between March 2009 and July 2012, 458 patients were enrolled by the community pharmacies. Three-quarters of patients were women, mean age was 54 (SD 7.4) years and mean BMI 36.1 (SD 5.9) kg/m(2). Of 314 patients enrolled for at least 12 months, 32 (10.2% on an intention to treat basis) had achieved the target weight loss of ≥5%; this was 41.6% of those who attended at 12 months representing a mean weight loss of 4.1 kg. Using Last Observation Carried Forward, 15.9% achieved the target weight loss within 12 months of enrolling. There was no significant effect of sex, baseline BMI or age on weight loss. CONCLUSIONS: The Counterweight pharmacy programme has a similar effectiveness to other primary care based weight management programmes and should be considered as part of a range of services available to a community to manage overweight and obesity.