Diabetes Remission Clinical Trial (DiRECT) using diet in diabetes

Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) is still significantly associated with development of vascular complications and premature death:

• biochemical remission of T2DM has been shown with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments
  
  
• 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 (1)

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.

Methodology:

• an 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
  • 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
    • this is provided by soups and shakes as produced by the Cambridge Weight Plan. The intervention replaces usual foods with the shakes and soups. There is an ample fluid intake during this intervention phase (2.25 L, for 12 weeks)
    • this 12 week period is followed by stepped food reintroduction (FR) (2-8 weeks), and structured support for long-term weight loss maintenance
      • FR phase includes a stepped transition to a food-based diet based on the "Eatwell" guidelines while reducing Total Diet Replacement (TDR)
        • to allow flexibility for participants whose confidence varies, the FR phase can be varied between protocol-defined limits of 2-8 weeks before switching to full food-based weight loss maintenance
        • participants monitor weight on a weekly basis and compare this with caloric intake and activity levels. Participants will return for review at 2 weekly intervals throughout the FR phase
          
          
    • weight loss maintenance phase (weeks 19-104)
      • participants were advised to follow a food based diet and will be provided with an individually tailored energy prescription, to support weight stabilisation and prevent weight regain.
      • those who are physically capable were advised to increase daily physical activity. Step-counters will be provided with the recommendation to aim to reach and maintain their individual sustainable maximum, up to 15,000 steps/day
        
        
    • relapse management for weight regain or re-emergence of diabetes
      • if weight regain occurs, or if diabetes is found to have returned (HbA1c >=48 mmol/mol) at any time during the 18-month weight loss maintenance stage, 'rescue plans' to reverse weight gain will be offered
        • weight regain of >2 kg: offer the use of TDR to replace one or two main-meal per day for 4 weeks, offer orlistat 120 mg tid, with each meal
        • weight gain of >4 kg, or to <15 kg below starting weight or if diabetes recurs: offer 4 weeks TDR with fortnightly practice nurse/dietitian review and then a 2-4 week FR. Individualised dietary advice, based on the Eatwell guidelines, and physical activity targets will be reinforced for weight loss maintenance. Orlistat treatment, as above, will be offered for the remainder of the weight loss maintenance period, with repeat advice to restrict dietary fat
          
          
  • 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

Results:

• between July 25, 2014, and Aug 5, 2017, 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, 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
    
    
  • 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 in the intervention group and 1.0 kg in the control group
    
    
  • 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.

Authors' interpretation:

• 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

Commentary:

• "The results of the long awaited trial Direct of weight loss through supported adherence to a liquid low calorie diet are exciting and the concept of inducing remission for overweight type 2 diabetic patients appealing; but while this trial was conducted in UK general practices the substantial dietary and motivational support provided is clearly not presently available to GPs struggling already with the demands of prevention and treatment of diabetes patients. Further research on the sustainability and cost effectiveness and whether it works in the Sout Asian and other ethnic diabetes communities is urgently needed..." Dr Paul O'Hare, Warwick Medical School, University of Warwick, Coventry, UK (May 10th 2018)

DiRECT study at five years (3)

• extension study, where continued dietary support was offered up to 5 years from baseline (n=85), found participants in the intervention group lost an average of 6.1 kg, with 11 (13%) in remission of type 2 diabetes, with wider benefits seen for HbA1c, blood pressure, and lipids

Reference:

• Lim EL, Kg H, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetol. 2011;54:2506-14
• Lean ME et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial.Lancet. 2018 Feb 10;391(10120):541-551
• Lean MEJ et al. 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. Lancet Diabetes and Endocrinology February 26th 2024.