DiRECT (Diabetes Remission Clinical Trial) First time randomized trial shows remission of T2DM with dietary and lifestyle intervention Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet 2017

DiRECT: Background & objective T2DM management is focused on pharmacological treatment Caloric restriction is beneficial for T2DM patients, but not tested in routine primary care. Study objective The DiRECT study was designed to assess whether intensive weight management can produce sustained remission of T2DM in the primary care setting. Background Current guidelines for the management of type 2 diabetes (T2DM) focus on pharmacological treatment to reduce blood glucose and the associated elevated CV risk. Life expectancy is, however, still markedly reduced in T2DM patients. There are data showing that T2DM can be returned to normal glucose control by caloric restriction, but this intervention has not been tested in routine primary care. Lean MEJ, et al. Lancet 2017

Study design (1) Main inclusion criteria Endpoint at 12 months T2DM diagnosis within the previous 6 years(*) age 20–65 years BMI: 27 - 45 kg/m2 Endpoint at 12 months Weight loss ≥15 kg DM remission defined as HbA1c <6.5% (<48 mmol/mol) after 2 months without antidiabetic medications Main exclusion criteria current insulin use HbA1c >12% weight loss of >5 kg within the past 6 months recent eGFR <30 mL/min/1.73m2 severe or unstable HF (*) most recent HbA1c value > 6.0%, if HbA1c <6.5% antidiabetic medication was continued Lean MEJ, et al. Lancet 2017

Study design (2) Control Group (N=149) ITT population (N=298) best-practice care by guidelines for up to 52 weeks Intervention Group (N=149) stop anti-diabetic and anti-hypertensive medications Total Diet Replacement 12-20 weeks Food Reintroduction 2-8 weeks The DiRECT study was an open-label, cluster-randomized trial at 49 primary care practices. Participants in the intervention group were asked to follow the Counterweight-Plus weight management program [9] and aim for achieving and maintaining at least 15 kg weight loss. A total diet replacement phase with a low energy formula diet (825-853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) for 3 months was used, followed by structured food reintroduction of 2-8 weeks (about 50% carbohydrate, 25% total fat, 15% protein) and an ongoing structured program with monthly visits for long-term weight loss maintenance. All oral antidiabetic drugs were discontinued on day 1 of the program, with standard protocols for reintroduction according to national guidelines. Antihypertensive drugs were withdrawn in light of the rapid BP reductions seen upon commencement of a low energy diet. At the start of food reintroduction, physical activity strategies were introduced to help participants in the intervention group to reach and maintain their individual sustainable maximum. Weight Loss Maintenance up to 52 weeks ITT: Intention-to-treat; Total Diet Replacement: 825-853 kcal/day formula; Lean MEJ, et al. Lancet 2017

Main results (1/2) Lean MEJ, et al. Lancet 2017 Percentages of patients in each group - At 12 months, weight loss ≥15 kg was seen in 26 (24%) of participants in the intervention group and in no control participants (Fisher’s exact p<0·0001). - Diabetes remission was seen in 68 (46%) of intervention participants and in six (4%) of control participants (OR: 19.7, 95%CI: 7.8-49.8, P<0.0001). - At 12 months, 74% in the intervention group were taking no antidiabetic medication, compared with 18% of controls, and in the latter group 5% commenced antidiabetic medication. IG: Intervention group; CG: Control group; DM: Diabetes Mellitus; (*) Additionally, 5% in the CG started antidiabetic medications Lean MEJ, et al. Lancet 2017

Main results (2/2) Mean change in weight (kg) Mean change in HbA1c (%) - The intervention group showed on average 10.0 kg weight loss and the control group 1.0 kg (adj difference: -8.8, 95%CI: -10.3 to -7.3, P<0.0001). - Mean HbA1c reduced by -0.9% (SD: 1.4) in the intervention group, and increased with 0.1% (SD: 1.1) in the control group (adj difference: -0.85%, 95%CI: -1.10 to -0.59, P<0.0001). P<0.0001 P<0.0001 IG: Intervention group; CG: Control group; Lean MEJ, et al. Lancet 2017

Conclusions T2DM of up to 6 years’ duration can be reversed by weight loss with help of an evidence-based structured weight management program delivered in a community setting, by routine primary care staff. Almost a quarter of participants who followed the intervention achieved at least 15 kg of weight loss at 12 months. Almost half of patients in the intervention group showed remission of diabetes, and were off antidiabetic medication. Lean MEJ, et al. Lancet 2017