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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

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Summary

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.

Introduction

Roughly one in 16 adults in the UK and one in ten adults in the USA have type 2 diabetes, 1, 2 with a much higher prevalence (up to one in five) apparent in other parts of the world.3 Diabetes complications are common and expensive to manage, so associated health-care costs are enormous despite the improvements offered through application of clinical guidelines. Type 2 diabetes is particularly devastating for the growing numbers of younger people affected, who tend to be more obese and lose more life years through disabling and painful complications.4

The extreme strength of association between excess weight gain in adult life and type 2 diabetes makes a causal association highly likely. The specific importance of intra-abdominal fat and large waist circumference has been long recognised, and the twin-cycle mechanism, driven by a damaging but reversible accumulation of ectopic fat within the liver and pancreas in susceptible individuals, has been consistently observed.5, 6, 7 Results from several studies have shown that weight loss of at least 10–15 kg frequently leads to normalisation of blood glucose concentrations in people with short-duration type 2 diabetes.8, 9, 10, 11 In the Diabetes Remission Clinical Trial (DiRECT), we reported that almost half (68 [46%] of 149) of a group with type 2 diabetes of up to 6 years' duration achieved remission at 1 year by following a structured weight-management programme;12 among the 36 participants in the intervention group who achieved target weight loss of 15 kg or more, 31 (86%) had achieved remission at 1 year. These results have changed perceptions of a condition previously assumed to be permanent and demanding lifelong drug treatment.

Research in context

Evidence before this study

Before undertaking the Diabetes Remission Clinical Trial (DiRECT) study, we searched PubMed for evidence on remissions of type 2 diabetes with all potential interventions. For the present analysis, we reviewed new literature on remission of type 2 diabetes through weight management, searching PubMed for articles published in English since the publication of the 12-month results of DiRECT (December, 2017) up to Dec 31, 2018, using search terms “clinical trial”, “remission”, “type 2 diabetes”, and “weight loss”. The search identified eight reports, of which only three covered weight-loss interventions; of these, two were reports from DiRECT and one reported results of laparoscopic surgery, which was deemed not relevant.

Added value of this study

The present study extends to 2 years evidence for durable remission of type 2 diabetes following diet-induced weight loss. The results also provide evidence of wider benefits relating to blood pressure, blood lipids, and wellbeing.

Implications of all the available evidence

The findings from DiRECT will provide added impetus to extend the early measures already announced to change existing National Health Service policy and practice for the routine management of type 2 diabetes. These data, and other relevant data on diabetes control, HbA1c, and weight management, all point towards the likelihood that intensive weight management has the potential to reduce or delay complications of type 2 diabetes and improve clinical outcomes.

Sufficient weight loss for remission (>10 kg) can be achieved in various ways, including bariatric surgery, but also through use of a low-calorie formula for total diet replacement, as assessed in DiRECT. The major questions are whether remission can be durable, whether it can be successfully delivered at scale in primary care (where most patients with type 2 diabetes are usually managed), and by how much vascular complications of diabetes can be delayed or avoided. One key issue is how best to support long-term maintenance of weight loss and remission of type 2 diabetes. Maintenance of weight loss is the greatest challenge faced by individuals and is an under-researched area with little robust evidence; notably, in the past, weight loss based on use of formula diets was commonly regarded as effective only in the very short term.13

DiRECT was designed to test an integrated weight-management programme delivered in primary care, with an initial period of effective weight loss (including use of low-calorie formula-based total diet replacement), stepped food reintroduction with emphasis on energy balance, and then structured support for weight loss maintenance with provision for relapse management. Here we report the clinical outcomes in the intervention and control groups at 2 years, in order to assess the durability of the intervention effect identified at the 1-year timepoint.12

Section snippets

Study design and participants

DiRECT was a 2-year, open-label, cluster-randomised controlled trial done at 49 primary care (general practitioner [GP]) practices in Scotland and the Tyneside region of England, UK. The protocol, including details of recruitment methods, study conduct, and planned analyses, has been published elsewhere,14 as have the baseline characteristics15 and the primary study findings at 1 year.12

No specific eligibility criteria for GP practices were defined. Eligible participants were aged 20–65 years,

Results

Between July 25, 2014, and Aug 5, 2016, we recruited 306 individuals from 49 practices (23 intervention and 26 control); the intention-to-treat population consisted of 149 participants in each group (figure 1). As reported previously,12, 15 baseline characteristics were similar between groups (appendix).

116 (78%) of 149 participants in the intervention and 140 (94%) of 149 in the control group attended the 24-month study assessment, thus overall 42 (14%) of 298 randomised participants did not

Discussion

The 2-year results of DiRECT show that continuing remission of type 2 diabetes is possible. Type 2 diabetes was reversible to a non-diabetic state over 24 months for 36% (53/149) of the group that received the primary care-based weight-management intervention, down from the 46% (68/149) who had achieved remission at 12 months.12 Notably, 70% (14/20) of those who maintained a weight loss of more than 15 kg remained in remission at 24 months. These data extend the first-year results of DiRECT by

Data sharing

Deidentified data for the analyses reported in this Article, including individual participant data and a data dictionary defining each field in the set, will be made available to scientists on personal application. The study protocol and statistical analysis plan will also be made available to scientists on personal application. The data will be available from Aug 1, 2019, and provided under an agreed data access agreement. If additional download of data from the Robertson Centre for

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