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Type 2 diabetes and the DiRECT Trial
Mike Lean
Glasgow Royal Infrmary
Funded by Diabetes UK to find a practical management solution for T2D, in primary care
MCN meeting Feb 5th 2019
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• 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:
www.directclinicaltrial.org.uk
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Life-expectancy is still reduced by T2DM despite guidelines & drugs to lower glucose/HbA1c, LDL & BP
55 55
European Risk Factor Consortium, NEJM 2011
Year
s o
f lif
e lo
st
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55 55
European Risk Factor Consortium, NEJM 2011
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)
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Weight gain/ obesity is the main driver of T2DM Colditz GA et al. Ann Int Med, 1995
Adjusted RR
(BMI <22 = referent)
0
10
20
30
40
50
60
70
80
90
100
<22 22-
22.9
23-
23.9
24-
24.9
25-
26.9
27-
28.9
29-
30.9
31-
32.9
33-
34.9
>35
BMI (kg/m2)
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2 year RCT Dixon et al (2008) JAMA
-15kg
Guidelines recommend Bariatric surgery But 15% (=15 kg) weight loss achieves most T2DM remissions
13%
73% 83% remissions with >15kg loss
Gastric band vs Usual diet
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0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
Week
Firs
t ph
ase
insu
lin r
espo
nse
(nm
ol/m
in/m
2 )
0 2 4 6 8
3
6
9
12
Week
Pan
crea
s fa
t co
nten
t
(%)
Lim et al, Diabetologia 2011
15kg weight loss on 450kcal/d diet Normalised beta-cell function and pancreas fat
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15kg intentional loss might normalise life expectancy with T2DM
18
16
14
12
10
8
0 2 4 6 8 10 12 14 Weight loss (kg) in first 12 months
Lean et al. Diabetic Medicine, 1990
95% CI
↑ 95% CI
mean Normal life expectancy
15 kg
loss
Life expectancy
(mean age 64
at diagnosis)
T2DM
BMI>25
Lean et al Diabetic Medicine 1990
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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)
15 kg
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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;
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Copenhagen Weight Loss in Knee Osteoarthritis trial: more liberal TDR equally effective
0 – 8 weeks ■ 810kcal/d liquid formula ▲ 415kcal/d liquid formula
♦ (E) Knee exercises group ● (C) Control – no intervention ■ (D) 1500kcal/d [average one formula meal/day]
88.0
90.0
92.0
94.0
96.0
98.0
100.0
102.0
104.0
106.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time (weeks)
Bod
y W
eigh
t (kg
)
n=96 per group n=64 per group
8-16 weeks 1200kcal
Part food/part formula
2 meals /day
)
D = structured food/formula
maintenance programme
(Bliddal et al, secondary care, dietitian managed)
415kcal VLED vs. 810kcal LED No sig. difference in weight loss
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Counterweight-Plus feasibility pilot (n = 91, BMI 47) (820kcal Total Diet Replacement, Food Reintroduction and Maintenance)
-60
-40
-20
0
20
10
-10
-30
0 100 200 300 400 500Days
Wei
gh
t C
han
ge
(kg
)
Lean et al, Br J General Practice (2013)
-16.9kg -12.4kg
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
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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”.
National NHS Guideline Scottish Intercollegiate Guidelines Network
115: Management of Obesity (2010)
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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)
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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
DiRECT Intervention: Counterweight-Plus Protocol
Lean et al, Br J General Practice (2013),
Leslie et al, BMC Family Practice (2016)
Maintain PA ~30mins/ day
STOP all diabetes meds
STOP all BP meds
Protocol for prescription
based on Guideline
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Results: participant retention
Drop-outs: 12 month outcome data collected within a 100 day window from routine GP clinic records
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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
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Baseline medical backgrounds
• Diabetic Retinopathy 35 (12%)
• Hypertension (BP>130/80) 169 (57%)
1 antihypertensive drug 69 (23%)
2+ antihypertensive drugs 94 (32%)
• Antidepressant drugs 68 (23%)
• Total prescribed drugs none 6 (2%) 1-2 47 (16%) 3-5 116 (39%) 6-9 89 (30%) 10+ 40 (13%)
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Results: weight changes over 12 months
-14.5 kg +1.0 kg +1.9 kg
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ITT 12-month Primary Outcome Results 1st Co-Primary Outcome: ≥15 kg weight loss
Intervention 36/149 (24%) p <0.0001 Control 0/149 2nd Co-Primary Outcome: Remission of diabetes*
Intervention 68/149 (46%) p <0.0001 Control 6/149 (4%) * HbA1c <48 mmol/mol (<6.5%)
off all anti-diabetes medication for at least 2 months
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Remissions by 12m weight loss: entire study population
None 0-5 kg 5-10 kg 10-15 kg ≥15 kg
Weight loss at 12 months
86.1%
57.1%
33.9%
6.7% 0%
≥10 kg loss: 73% are in remission
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ITT secondary outcomes: mean changes at 12m
Intervention Control P
Weight (kg) -10 -1 <0.0001
HbA1c (mmol/mol) -10 +1 <0.0001 % on anti-diabetes meds 22% 82% 0.0032
Systolic BP (mm Hg) -1.3 -1.7 ns % on antihypertensive meds 32% 61% <0.0001
Serum Triglycerides (mmol/l) -0.3 +0.1 <0.0001
Quality of Life (EQ5) +7.2 -2.9 0.0012
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0 4 8 1 2
0
5
1 0
1 5
2 0
M o n th s
Liv
er
fat
(%)
R e s p o n d e rs
N o n -R e s p o n d e rs
C o n tro ls
Liver and pancreas in Responders (Remissions), Non-responders and Controls
Taylor R, Lean M et al. unpublished (IDF 2017)
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• 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
DiRECT: Conclusions and Actions
• 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
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McCombie et al BMJ 2017
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Priorities of people currently living with T2DM The Lancet: Finer 2017 (Diabetes UK/ James Lind Alliance Priority-Setting Partnership)
1. Can type 2 diabetes be cured or reversed?
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Draft Business Model 200 referrals (1-to-1) 80 remissions 120 improved
Cost = £170k pa
Diabetes Remission
Service 'Hub‘ = dietitian
Practice 1
Remission Clinic
Practice 2
Remission Clinic
Practice 3
Remission Clinic
Practice 4
Remission Clinic
Practice 5
Remission Clinic
Referring practices Cost within DiRECT
£1100 per patient entered £2500 per remission
Current cost to NHS of a T2D patient = £2500 p.a. Xin et al, Lancet DE, 2018
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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…….
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The ‘No Doubts Diet’! 830 kcal/day the cheap, culturally resonant, way
https://www.directclinicaltrial.org.uk/Documents/The%20Lean%20Team%20No%20Doubt%20Diet%20plan.pdf
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Preserving metabolic health: Improving weight-loss maintenance and diabetes remissions
• Physical activity
• Meal replacements
• Intermittent ‘fasting’
• Lower carbohydrate diet?
• Higher carbohydrate diet?
• Low carbon emission diet
• Personal trainer
• Community support
• Plate Model (Armstrong & Lean 1992)
145o
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Health by stealth: the Eat Balanced Pizza
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Low-Carb vs High-Carb diets for T2DM? Meta-analyses for Body Weight (A) and HbA1c (B)
No significant effects for LDLc, HDLc, TC, BP, or attrition rate. TG fell 0.13mm0l.l more on LCD DOM, 2019
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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
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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)
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Thank you • GP practices and patients
• Academic & clinical colleagues
• Ethical and R&D committees
• Cambridge Weight Plan
• Counterweight Ltd
• Diabetes UK, and funding donors
http://www.directclinicaltrial.org.uk/
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http://www.directclinicaltrial.org.uk/
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http://www.directclinicaltrial.org.uk/
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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 60-65 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.
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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).