1. Type 2 diabetes and the DiRECT Trial
Funded by Diabetes UK
to find a practical management solution for T2D, in primary care .
Type 2 diabetes and the DiRECT Trial
Mike Lean
Glasgow Royal Infrmary
MCN meeting Feb 5th 2019

2. Disclosures: Departmental research funds, support for conference attendance and fees for Advisory Boards and lecturing from Novo Nordisk, Lilly, and Cambridge Weight Plan. Medical consultancy fees from Counterweight Ltd. Shares costing £10 in Eat Balanced.
Photograph if you must!
All slides are posted on:

3. Life-expectancy is still reduced by T2DM despite guidelines & drugs to lower glucose/HbA1c, LDL & BP
Years of life lost 55 55
European Risk Factor Consortium, NEJM 2011

4. (McCombie et al BMJ 2017: data from Medtrak, April 2017)
488 drugs (70 generic compounds) are licenced for T2DM excluding insulins, plus >25 seeking licences, and more in development
(McCombie et al BMJ 2017: data from Medtrak, April 2017) 55 55
European Risk Factor Consortium, NEJM 2011

5. Weight gain/ obesity is the main driver of T2DM Colditz GA et al
Weight gain/ obesity is the main driver of T2DM Colditz GA et al. Ann Int Med, 1995
Adjusted RR
(BMI <22 = referent)
100 90 80 70 60 50 40 30 20 10
<22
22-
23-
24-
25-
27-
29-
31-
33-
>35
22.9
23.9
24.9
26.9
28.9
30.9
32.9
34.9
BMI (kg/m2)

6. 83% remissions with >15kg loss
Guidelines recommend Bariatric surgery But 15% (=15 kg) weight loss achieves most T2DM remissions
Gastric band vs Usual diet
13%
-15kg
83% remissions with >15kg loss
73%
2 year RCT Dixon et al (2008) JAMA 6

7. 15kg weight loss on 450kcal/d diet Normalised beta-cell function and pancreas fat
Lim et al, Diabetologia 2011

8. 15kg intentional loss might normalise life expectancy with T2DM
(mean age 64 at diagnosis) 18
95% CI 16
Normal life expectancy
mean 14 ↑ 12
95% CI 10
T2DM
BMI>25 8
15 kg
loss 2 4 6 8 10 12 14
Weight loss (kg) in first 12 months
Lean et al Diabetic Medicine 1990
Lean et al. Diabetic Medicine, 1990 8

9. BEST LONG TERM RESULTS ARE WITH MOST RAPID WEIGHT LOSS VLCD reliably achieves 15kg weight loss
Subjects completing 1-year in 80 studies: n = 26,455, completers = 18,199 (69%) (Franz et al JADA 2007) 9

10. To maintain weight loss, behaviours must counteract both environment and physiology
Obesogenic Environment
Physical environment
Food environment
Educational environment
Cultural environment
Social environment
Social Marketing (normalised behaviours)
Obesogenic medications
Biological & Physiological Adaptation Satiety signals - fall with weight loss (Leptin, PYY, CCK, amylin, insulin, GLP-1) Orexigenic signals - rise with weight loss (eg. Ghrelin) Metabolic Rate falls with energy restriction & with weight loss
Leslie et al 2007; Sumithran et al 2011; Maclean 2011; Leibel et al 1995;

11. D = structured food/formula maintenance programme
Copenhagen Weight Loss in Knee Osteoarthritis trial: more liberal TDR equally effective )
D = structured food/formula maintenance programme
8-16 weeks 1200kcal
Part food/part formula
2 meals /day
810 kcal/d
0 – 8 weeks
■ 810kcal/d liquid formula
▲ 415kcal/d liquid formula
415 kcal/d
♦ (E) Knee exercises group
● (C) Control – no intervention
■ (D) 1500kcal/d [average one formula meal/day]
415kcal VLED vs. 810kcal LED
No sig. difference in weight loss
(Bliddal et al, secondary care, dietitian managed)
n=96 per group
n=64 per group

12. Counterweight-Plus feasibility pilot (n = 91, BMI 47) (820kcal Total Diet Replacement, Food Reintroduction and Maintenance)
Maintaining weight loss ≥15kg at 12 months:
33% of all 91 patients
44% of patients with a known 12-month weight
57% of those who lost >15kg on LELD
Highly cost-effective:
4 times more lose >15kg as with bariatric surgery
Weight Change (kg)
-12.4kg
-16.9kg
Days
Lean et al, Br J General Practice (2013) 12

13. National NHS Guideline Scottish Intercollegiate Guidelines Network 115: Management of Obesity (2010)
Weight loss interventions should be targeted to improving these comorbidities; in many individuals a greater than 15-20kg weight loss (will always be over 10%) will be required to obtain a sustained improvement in comorbidity”.
SIGN 115 recommends weight loss target of greater than 15-20% (15-20kg) for patients with BMI >35kg/m2 with associated disease, in order to manage conditions relating to excess weight, e.g. diabetes, heart disease, osteoarthritis, sleep apnoea SIGN 2010
The Counterweight Programme data, 5 demonstrates that of those entering 5.8% achieve >15kg weight loss at 12months. Personal Communication Counterweight 2012. 13

14. DiRECT trial design: Weight Management within routine Primary Care
Design: Open-label, cluster-randomised by GP practices
Typical T2D patients: Duration <6 years, age <65, HbA1c <10%
Co-primary outcomes:
Numbers maintaining ≥15kg weight loss at 12 months
Numbers with remission of diabetes at 12 months
(HbA1c <6.5%, off anti-diabetes drugs for >2 months)
Powered to detect/exclude >22% remissions at 12m (n==280)

15. DiRECT Intervention: Counterweight-Plus Protocol
1. Total Diet Replacement
Nutritionally complete (vitamins & minerals)
830 kcal: 61%E carb, 13% fat, 26% protein
2. Stepped Food Reintroduction
Add a ~400kcal meal every 2-3 weeks
Step-counters: gradually increase PA
3. Weight Loss Maintenance
Food-based diet +/- meal replacements
50%E carbohydrate, 35% fat, 15% protein
Offer Relapse Management (regain >2kg)
Visits 2-4 weekly at own primary care centres
Programme delivered by usual primary care staff
Maintain PA ~30mins/ day
STOP all diabetes meds
STOP all BP meds
Protocol for prescription
based on Guideline
Lean et al, Br J General Practice (2013),
Leslie et al, BMC Family Practice (2016) 15

16. Results: participant retention
Drop-outs:
12 month outcome data collected within a 100 day window from routine GP clinic records

17. Baseline data: analysed participants
Total number 298
Men / women 59% / 41%
Age (years) 54 (SD 7)
Weight (kg) men 106 (SD 16)
women 91 (SD 13)
BMI (kg/m2) 35 (SD 4)
Duration of T2DM (<6y) 3.1 (SD 1.7) HbA1c (mmol/mol) 59 (SD14)(7.5%) Diet alone 24% I drug 48% 2+ drugs 28% Blood Pressure 135/85 Smoking (current) 12% Former 38% Never 50%
Intervention and Control groups
well balanced for all criteria
40% from practices with highest deprivation

18. Baseline medical backgrounds
Diabetic Retinopathy (12%)
Hypertension (BP>130/80) (57%)
1 antihypertensive drug (23%)
2+ antihypertensive drugs (32%)
Antidepressant drugs (23%)
Total prescribed drugs none (2%)
(16%)
(39%)
(30%)
(13%)

19. Results: weight changes over 12 months
-14.5 kg
+1.0 kg
+1.9 kg

20. ITT 12-month Primary Outcome Results
1st Co-Primary Outcome: ≥15 kg weight loss
Intervention 36/149 (24%) p <0.0001
Control /149
2nd Co-Primary Outcome: Remission of diabetes*
Intervention 68/149 (46%) p <0.0001
Control / (4%)
* HbA1c <48 mmol/mol (<6.5%)
off all anti-diabetes medication for at least 2 months

21. ≥10 kg loss: 73% are in remission
Remissions by 12m weight loss: entire study population
86.1%
57.1%
33.9%
≥10 kg loss: 73% are in remission
6.7% 0%
None
0-5 kg
5-10 kg
10-15 kg
≥15 kg
Weight loss at 12 months

22. ITT secondary outcomes: mean changes at 12m
Intervention Control P
Weight (kg) <0.0001
HbA1c (mmol/mol) <0.0001
% on anti-diabetes meds % %
Systolic BP (mm Hg) ns
% on antihypertensive meds % 61% <0.0001
Serum Triglycerides (mmol/l) <0.0001
Quality of Life (EQ5)

23. Liver and pancreas in Responders (Remissions), Non-responders and Controls
Taylor R, Lean M et al. unpublished (IDF 2017)

24. DiRECT: Conclusions and Actions
T2DM results from excess body fat + age. But not necessarily permanent
Almost half can achieve remission (73% with >10kg loss)
Main predictors of remission:
More weight loss, Greater age, Lower HbA1c, More anti-HTs
Warnings? More anti-diabetes meds, possibly antidepressants
Remission should be a primary aim of diabetes care
Record, recode and reward (patients and clinics) for remissions
Ethics: Offer optimal non-surgical weight management first, before prescribing (or trialling) additional treatments for T2D

25. McCombie et al BMJ 2017

26. Priorities of people currently living with T2DM The Lancet: Finer (Diabetes UK/ James Lind Alliance Priority-Setting Partnership)
Can type 2 diabetes be cured or reversed?

27. Remission Service 'Hub‘ = dietitian
Draft Business Model 200 referrals (1-to-1) 80 remissions 120 improved Cost = £170k pa
Cost within DiRECT
£1100 per patient entered
£2500 per remission
Diabetes
Remission Service 'Hub‘ = dietitian
Practice 1
Remission Clinic
Practice 2
Practice 3
Practice 4
Practice 5
Referring practices
Current cost to NHS of a T2D patient = £2500 p.a.
Xin et al, Lancet DE, 2018

28. Changing how we manage diabetes since Dec 2017: As of September 2018…
England
First CCG (N. Tyneside) has commissioned a DiRECT/ Diabetes Remission Service for 270 patients
Scotland
5 -13 Health Board already using Counterweight Plus
New £42m allocated for sustainable intensive weight management for T2DM
ADA/EASD Joint statement has promoted Remission of T2DM as a management target, and described the DiRECT intervention
New T2DM Remission trials planned in US, India, Nepal, Oman, New Zealand, Europe
Interest in trial in Lebanon, Abu Dhabi, Saudi…….

29. The ‘No Doubts Diet’! 830 kcal/day the cheap, culturally resonant, way

30. Preserving metabolic health: Improving weight-loss maintenance and diabetes remissions
Plate Model (Armstrong & Lean 1992)
Physical activity
Meal replacements
Intermittent ‘fasting’
Lower carbohydrate diet?
Higher carbohydrate diet?
Low carbon emission diet
Personal trainer
Community support
145o

31. Health by stealth: the Eat Balanced Pizza

32. Low-Carb vs High-Carb diets for T2DM
Low-Carb vs High-Carb diets for T2DM? Meta-analyses for Body Weight (A) and HbA1c (B)
DOM, 2019
No significant effects for LDLc, HDLc, TC, BP, or attrition rate. TG fell 0.13mm0l.l more on LCD

33. Low Glycaemic Load Diets:
Either reduce total carbohydrate
Or choose slow-release low GI carbohydrates
Or combine with other foods and nutrients
eg.
Fats
Amylose-rich non-digestible carbohydrate
Legumes

34. Association between SSB and T2DM attenuated by adiposity: reduced ORs (black bars) and increased p values (grey bars) (Han TS, 坚持-专注 (Jim) & Lean MEJ: European J Nutr 2018)

35. Thank you http://www.directclinicaltrial.org.uk/
GP practices and patients
Academic & clinical colleagues
Ethical and R&D committees
Cambridge Weight Plan
Counterweight Ltd
Diabetes UK, and funding donors

38. Predictors of Weight loss and Remission
Sex! More men achieved ≥15kg weight loss than women (33% vs 14%, p=0.008), but remissions were similar (p=0.33).
Age was not associated with achieving ≥15kg weight loss (p=0.36), however older patients had more remissions (17% aged <50 y; 61% aged y)
Baseline HbA1c was not associated with weight loss (p=0.49), but remission more likely with lower HbA1c (OR 28% lower per % point HbA1c, p=0.038).
Longer diabetes duration more likely to achieve ≥15kg weight loss (OR 31% greater per year (p=0.032), but duration was not associated with remission.
Neither outcome was associated with socioeconomic deprivation, smoking or alcohol intake.

39. Predictors of Weight loss and T2D Remission
Loss of ≥15kg was more likely with greater baseline weight (<90kg: 8%; ≥110kg: 40%;
trend p=0.024) or BMI (<30kg/m2: 9%; ≥40kg/m2: 31%; p=0.027).
But neither weight (p=0.93) nor BMI (p=0.26) associated with T2D remission.
Prior anti-diabetic and anti-hypertensive drugs not associated with weight loss.
Remission less likely with more anti-diabetic drugs (OR 0.43 per drug, p<0.001)
Remission more likely with more antihypertensives (OR 1.37 per drug, p=0.045)
Blood pressure was not associated with weight loss,
Remission more likely with higher systolic (p=0.017) & diastolic BP (p=0.013)..
Antidepressant use may impair ≥15kg weight loss (p=0.085) and remission (p=0.064).