Type 2 diabetes and the DiRECT Trial · 2020. 4. 8. · Can type 2 diabetes be cured or reversed? Draft Business Model 200 referrals (1-to-1) 80 remissions 120 improved Cost = £170k

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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

• 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

Life-expectancy is still reduced by T2DM despite guidelines & drugs to lower glucose/HbA1c, LDL & BP

55 55

European Risk Factor Consortium, NEJM 2011

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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)

Weight gain/ obesity is the main driver of T2DM Colditz GA et al. Ann Int Med, 1995

Adjusted RR

(BMI <22 = referent)

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BMI (kg/m2)

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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Lim et al, Diabetologia 2011

15kg weight loss on 450kcal/d diet Normalised beta-cell function and pancreas fat

15kg intentional loss might normalise life expectancy with T2DM

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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

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

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;

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]

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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

Counterweight-Plus feasibility pilot (n = 91, BMI 47) (820kcal Total Diet Replacement, Food Reintroduction and Maintenance)

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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

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)

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)

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

Results: participant retention

Drop-outs: 12 month outcome data collected within a 100 day window from routine GP clinic records

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

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%)

Results: weight changes over 12 months

-14.5 kg +1.0 kg +1.9 kg

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

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

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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Liver and pancreas in Responders (Remissions), Non-responders and Controls

Taylor R, Lean M et al. unpublished (IDF 2017)

• 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

McCombie et al BMJ 2017

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?

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

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…….

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

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

Health by stealth: the Eat Balanced Pizza

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

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

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)

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/

http://www.directclinicaltrial.org.uk/

http://www.directclinicaltrial.org.uk/

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.

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).