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

In the early years after diagnosis type 2 diabetes has been shown to be a reversible metabolic condition [1, 2]. Within 10 years of type 2 diabetes diagnosis, about two-thirds of individuals can return to non-diabetic levels of blood glucose control after diet-induced weight loss averaging 15 kg [3]. With stable reduced weight, non-diabetic blood glucose control and changes in the underlying pathophysiological abnormalities persist without glucose-lowering medications for at least 6 months [3]. However, these results have only been observed in a small number of motivated volunteers attending a specialist research unit. The practical implications for routine clinical practice of such diet-induced type 2 diabetes reversal urgently need to be established given widening public interest in this phenomenon.

Bariatric surgery of any kind can reverse metabolic abnormalities in about 70% of people with type 2 diabetes [4], with the likelihood of benefit determined primarily by the extent of weight loss and duration of diabetes [5, 6]. However, with conventional dietary advice mean weight loss is only 3–5% and remission is rare [7]. In the LookAHEAD study, a greater mean weight loss of 8% at 12 months produced remission of type 2 diabetes in 11.5% of participants [8]. The present study was designed to use a more intensive initial ‘total diet replacement’ approach, using a low-energy formula diet with a structured behaviour change programme for long-term weight loss maintenance, delivered in a realistic primary care setting. In a feasibility study, this programme resulted in a mean weight loss of about 17 kg by 12 weeks, with 40% remaining >10 kg and 33% >15 kg below baseline weight at 12 months [9]. Similar figures have been reported for a roll-out of the Counterweight-Plus programme to 288 individuals in routine primary care (L. McCombie, N. Brosnahan, H. Ross, A. Bell-Higgs, L. Govan, M. E. J. Lean, unpublished results). The Diabetes Remission Clinical Trial (www.controlled-trials.com/ISRCTN03267836) was designed to answer a series of linked questions [10]: What proportion of the whole population with type 2 diabetes would agree to undertake substantial weight loss? How many of these could achieve ≥15 kg weight loss and return to non-diabetic blood glucose control off medication (the twin primary endpoints) at 1 year? What happens to the major pathophysiological factors underlying type 2 diabetes during continued follow up? What are the psychological consequences of the programme and can outcomes be predicted by psychometric variables? What proportion of the intervention group remains non-diabetic after 2 years? This paper describes the recruitment process, outcomes of recruitment and baseline characteristics of the study participants.

A cluster-randomised controlled design was employed, with general practices the unit of randomisation. General practices representing populations with wide ranges of social and geographical features across Scotland and in the Tyneside region of northeast England were invited to participate by the Primary Care Research Network (PCRN) in Scotland and North East Commissioning Support (NECS) in England. Practices known to be research-active were approached first as the demands of research work by staff would be too great for many practices.

The research team met with interested practices to discuss participation details. Following these meetings, willing practices were then randomised to intervention or control. Practices randomised to the control group continued to deliver usual diabetes and weight management as per current clinical guidelines. Practices randomised to the intervention group continued to deliver usual guideline-based care in addition to an evidence-based weight management programme (Counterweight-Plus). Randomisation was conducted independently by the Robertson Centre for Biostatistics, University of Glasgow, using a minimisation method to maintain balance across groups between the two study regions (Scotland and Tyneside), including a balance of practice list sizes (n > 5700 or n ≤ 5700).

Within each general practice, all people with type 2 diabetes meeting inclusion and exclusion criteria were identified by a computerised search of general practitioner (GP) records, undertaken by PCRN in Scotland and GP practice staff in Tyneside. Lists generated by the search were reviewed by GPs and any individuals recognised to be unsuitable to approach because of comorbidity or other practical obstacles to participation were removed.

Inclusion criteria were age 20–65 years, type 2 diabetes of duration 0–6 years (diagnosis based on two recorded diagnostic tests using blood glucose and/or HbA_1c [HbA_1c >48 mmol/mol (6.5%) on diet alone or HbA_1c >43 mmol/mol (6.1%) on treatment with oral glucose-lowering agents]), and a BMI of 27–45 kg/m². Potentially eligible individuals were mailed an invitation to participate with an information sheet and asked to respond using prepaid reply envelopes. Full details of methodology have been previously described [10]. A subsequent protocol amendment included the provision of a financial incentive (50 GBP Amazon retail voucher) for those recruited into the control arm. The intervention arm already provided a desirable incentive ‘in kind’ for participation (supply of a formula diet and potential substantial weight loss) but there had been no such incentive for participants in control practices.

To ascertain whether the individuals volunteering and included were representative of the wider population with type 2 diabetes, defined by the inclusion and exclusion criteria, anonymised data on sex, height and weight, duration of diabetes and index of multiple deprivation were collated for all who were invited to participate.

Ethics approval for the Diabetes Remission Clinical Trial (DiRECT) was secured on 24 January 2014. NHS research and development approvals for participating Health Board areas in Scotland and Clinical Commissioning Groups in Tyneside were then secured. All subsequent protocol amendments have been similarly approved. Written informed consent was secured from all participants.

DiRECT has a realistic or ‘pragmatic’ design to provide information about the management of type 2 diabetes in a routine primary care setting in a largely unselected population in order to maximise transferability of results. Certain inclusion criteria were applied for recruitment into DiRECT for various practical reasons. An upper BMI limit of 45 kg/m² was set because the protocol required a subsample to undergo abdominal magnetic resonance imaging. An upper age limit of 65 years was fixed to avoid the greater mortality rates associated with older people in a study planned to continue for 2 years and to optimise attendance at study visits given the greater mobility problems often faced by older people with type 2 diabetes. Furthermore, individuals were excluded if they had suffered myocardial infarction or stroke within the 6 months prior to recruitment because of engagement in other programmes.

Volunteers for clinical research are usually relatively more health conscious and there can be a risk of attracting unrepresentative ‘concerned but healthy’ individuals. The DiRECT cohort included, at baseline, 12% with existing retinopathy, 12% with one or more known manifestations of heart disease and 13% with microalbuminuria indicating nephropathy. Impaired renal function (eGFR <60) was present in 3%. In addition to their diabetes, as may be expected, a high proportion (57%) had known hypertension and 31% were prescribed two or more antihypertensive medications. Polypharmacy was common, with 43% being prescribed six or more different drugs daily and 13% prescribed ten or more drugs. Almost a quarter of the entire cohort was prescribed antidepressant medications, some of which are associated with weight gain [11]. Thus, the DiRECT cohort does not appear to include an excess of ‘worried well’ or unusually healthy people with type 2 diabetes.

Recruitment of participants to any study is challenging. Poor recruitment can result in inadequate study numbers and underpowered trials [18]. DiRECT was based in primary care in order to provide realistic results transferable to routine practice. Of the invited practices, 14% accepted, reflecting the relatively small proportion of general practices in the UK that are research-active. Many of those are at capacity for taking on new research projects, being busy NHS general practices with limited availability of doctor and nurse time for research. There was great interest in DiRECT, but many of the research-active practices had already committed to research studies on other topics. Moreover, practice participation required practices to be able to provide six to ten individuals who would meet the inclusion criteria; this excluded some smaller practices. Recruitment to DiRECT was monitored closely and recruitment methods were refined to include strategies known to maximise recruitment (e.g. reminder letter, telephone contact and incentive) [18]. It is remarkable that 28% of all invited to participate expressed interest in doing so, and most of those who initially volunteered participated (72%). This far exceeds many other trials that recruited using similar methods [19] and those that recruited by other means [20, 21]. The study recruited more than the numbers required to satisfy the a priori power calculation (140 per group) within the 2 years allocated for recruitment, and recruitment proved difficult to halt resulting in modest over-recruitment. The ready acceptance of a low-energy liquid diet has been observed in all of our previous studies [1, 3, 9].

Triacylglycerol, insulin, fasting glucose and eGFR were less good in Scottish participants, in keeping with the slightly greater age and higher waist circumferences. None of these differences could be considered clinically important. Average alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) levels were higher than the normal reference range. There were a small number with ALT and GGT raised more so than aspartate aminotransferase (AST). This will be partly the result of fatty liver, which is common in this participant group, but more substantial elevations in GGT without comparable ALT elevations suggest that some participants may have had undisclosed alcohol excess. Of the 12 participants with GGT >150 at baseline, only one reported very high alcohol consumption (72 units per week). In most instances transaminases were also elevated but there were no other features in the baseline data which might account for abnormal liver function tests. There were minor excesses of high albumin/creatinine ratio (ACR) in Tyneside, the reasons for which were not clear although the numbers are small and do not allow determination of whether such minor albuminuria was sustained or transient.

A remarkably high proportion of eligible people with type 2 diabetes volunteered to enter DiRECT, including more men than is usual for weight management trials. The participants recruited were broadly representative of the unselected general population of people with up to 6 years’ duration of type 2 diabetes, and the subset in Tyneside were similar to the Scottish subset. The recruitment rates into the intervention and control arms were almost identical. The results of the weight management intervention in DiRECT are thus likely to be widely applicable to people with type 2 diabetes.