Grand Rounds

Results of the DiRECT Trial: Can Weight Loss in a Primary Care Setting Achieve Remission of Type 2 Diabetes?

BACKGROUND AND PURPOSE:

Type 2 diabetes is related to excess weight gain and fat deposition in the liver and pancreas
There is evidence that weight loss can return individuals from type 2 diabetes to normal insulin resistance status and glucose control
Data is lacking as to whether such interventions are practical in a routine primary care setting
Lean et al. (The Lancet, 2017) sought to determine whether intensive weight management within a routine primary care setting can achieve remission of type 2 diabetes

Open-label, randomized trial
DiRECT: Diabetes Remission Clinical Trial
Patients: 20-65 year olds diagnosed with type 2 diabetes within the last 6 years, BMI of 27-45 kg/m², and not receiving insulin
Patients were recruited from 49 primary care practices
Practices were randomly assigned to
- Weight management program (intervention group)
- Best-practice care based on guidelines (control group)
Intervention
- Withdrawal of antidiabetic and antihypertensive drugs
- Total diet replacement (825–853 kcal/day formula diet for 3–5 months)
  - 59% carbohydrate, 13% fat, 26% protein, 2% fiber
- Structured food reintroduction (2–8 weeks)
  - 50% carbohydrate, 35% total fat, and 15% protein
- Structured support for long-term weight loss maintenance
  - Monthly visits
- Regular, not additional, physical activity was encouraged during total diet replacement with activity strategies introduced to help reach and maintain sustainable maximum of up to 15,000 steps/day measured with wearables
Data was stratified for study site and practice size
All outcome data were collected at baseline and at 12 months
Majority of study was not blinded except to study statisticians
Primary outcomes
- Weight loss of ≥ 15 kg or more
- Remission of diabetes, defined as HbA1c < 6.5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications from baseline to month 12

306 individuals were recruited
- 149 participants per group comprised the intention-to-treat population
24% of intervention group lost ≥ 15 kg compared to 0% in the control group (p<0.0001)
Diabetes remission was achieved in 46% participants in the intervention group and six (4%) of the control group
- odds ratio (OR) 19.7, 95% CI 7.8–49.8; p<0.0001
Remission varied with weight loss:
- No remission in 76 participants who gained weight
- 7% of 89 participants who maintained 0–5 kg weight loss
- 34% of 56 participants with 5–10 kg loss
- 57% of 28 participants with 10–15 kg loss
- 86% of 36 participants who lost 15 kg or more
At 12 months, 74% in the intervention group were taking no antidiabetic medications (mean HbA1c 64% [46.8 mmol/mol]) compared with 18% of the control group (mean HbA1c 7.2% [54.6 mmol/mol]; p=0·0032)
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 of −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 in the intervention group, and decreased by 2.9 points in the control group
- Adjusted difference of 6.4 points, 95% CI 2.5–10.3; p=0.0012
Nine serious adverse events were reported: 4% in the intervention group and 1% in the control group
In the same participant, two serious adverse events (biliary colic and abdominal pain) were potentially related to the intervention

Authors acknowledge that bariatric surgery has “dominated discussions of type 2 diabetes remission as the most effective way of producing major weight loss”
- May be associated with risk of long-term problems and may not be practical due to the increasing number of people with type 2 diabetes
Weight loss also led to drops in blood pressure such that intervention group participants were able to stop their blood pressure medications for the 12 months of this study
Remission may not work in individuals who have been diabetic for > 6 years
Almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs, making remission a practical target for primary care
Follow-up will continue to at least 4 years out

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