Obesity and Diabetes -

Future Management

Professor Mike LeanHuman Nutrition University of Glasgow and Otago

Edinburgh 12th September 2016

Disclosures:

• Research/conference support and advisory boards:

(Novo Nordisk, Orexigen, Janssen, Cambridge Weight Plan)

• Medical consultancy for Counterweight Ltd

• I have never tasted Coca Cola, Pepsi or any other cola

• I have never owned a TV

• I have bought shares costing £10 in Eat Balanced Ltd

Proportions of UK overweight (BMI>25) adults

with and without ‘obesity-related’ diseases

Comorbidities: Diabetes, Hypertension, Stroke, Angina, MI.

Vlassopoulos, Combet & Lean 2014, ICO in KL

Data from the SHS (2008-11) n=24,831

Life expectancy with obesity:

BMI 30-35: reduced 2-4 years

BMI 40-50: reduced 8-10 years

Prospective Studies Collaboration (Whitlock et al)

Lancet 2009 (cf, Fontaine et al 2003)

Consequences of metabolic syndrome IGT/DM

- driven by age and body fat

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4 5 6 7 8 9

Blood Glucose (mmol/L)

(Fasting or 2h)

% p

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Current management priorities for

Metabolic Syndrome/T2DM

1. Reduce HbA1c

2. Delay vascular complications

3. Arrest the underlying disease process

– Prevention

– Remission from diabetes

Diabetes Prevention:

weight control is vital

• DPP and DPS: mean 4kg maintained weight loss, and exercise,

prevented most progression from IGT to T2DM (57% prevented)

– Weight loss is the dominant element

– Better than metformin (Torgerson, XENDOS trial)

• Further (minor) T2DM prevention

– Regular physical activity

(increase type-1 muscle fibres)

– Low saturated fat diet

– Fruit and vegetables

– Magnesium

– Cereal fibre

– Low GI Wing et al.,

Diabetes Care 1998

–

Diabetes Prevention:

weight control is vital

• DPP and DPS: mean 4kg maintained weight loss, and exercise,

prevented most progression from IGT to T2DM (57% prevented)

– Better than metformin

– Weight loss is the dominant element (Torgerson, XENDOS trial)

• Further (minor) T2DM prevention

– Regular physical activity

– (increase type-1 muscle fibres)

– Low saturated fat diet

– Fruit and vegetables

– Magnesium

– Cereal fibre

– Low GI Wing et al.,

Diabetes Care 1998

75 drugs currently licensed for reducing HbA1c inT2DM (with multiple trade names)

(plus 25 in the licensing pipeline)

(plus countless more in development)

Alpha-Glucosidase Inhibitors:

acarbose

miglitol

Biguanides

metformin

metformin-alogliptin

metformin-canagliflozin

metformin-glipizide

metformin-glyburide

metformin-linagliptin

metformin-pioglitazone

metformin-repaglinide

metformin-saxagliptin

metformin-sitagliptin

Dopamine Agonist

bromocriptine

DPP-4 Inhibitors

alogliptin

alogliptin and pioglitazone

linagliptin

saxagliptin

sitagliptin

sitagliptin and simvastatin

Glucagon-Like Peptides

albiglutide

dulaglutide

exenatide

liraglutide

Meglitinides

nateglinide

repaglinide

SGLT2 Inhibitors 40 listeddapagliflozin

canagliflozin

empagliflozin

Sulfonylureas

glimepiride

glimepiride and pioglitazone

glimeperide and rosiglitazone

gliclazide

glipizide

glyburide

chlorpropamide

tolazamide

tolbutamide

Thiazolidinediones

rosiglitazone

pioglitazone

SIGN 115 Obesity (2010)

Dietary interventions in adults

• Calculated to produce a 600 kcal/day deficit

• Tailored to the dietary preferences of the individual

• Emphasise achievable and sustainable healthy eating

• Very Low Calorie Diets for rapid weight loss, under medical supervision

Drugs

• Orlistat should be considered as an adjunct to lifestyle interventions

Surgery

• BMI ≥35 kg/mƒƒ2 & severe comorbidities expected to improve ƒƒsignificantly

with weight reduction (eg severe mobility problems, arthritis, T2 diabetes).

• AND completion of a structured weight management programme involving

diet, ƒƒphysical activity, psychological and drug interventions,

without significant and sustained improvement in the comorbidities.

NICE: bariatric surgery and VLCD (2014)

BMI of >40 kg/m2 or 35-40 and other significant disease.

All appropriate non-surgical measures have been tried

without maintained adequate, clinically beneficial weight loss.

NICE Clinical Guideline for Type 2 Diabetes Update June 2015

15Available from: http://www.nice.org.uk/guidance/GID-CGWAVE0612/documents/type-2-diabetes-full-guideline2

90% overweight

or obese

Life-expectancy is still reduced 6-10 years by T2DM,

despite all our drug treatments (Wirral)

Nwaneri et al Postgrad Med J 2012)

Once you have T2 Diabetes…….

Treatment aims:

• To reduce HbA1c

• ?To reduce vascular complications

• ??To arrest the underlying disease process

– (Remission from diabetes)

Multiple clinical benefits from major weight loss4 y after laparoscopic adjustable gastric banding

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Hyperte

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Sleep a

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General p

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Self

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Diabete

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Perip

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Join

t pain

Reflux

Improved

Cured

Frigg et al. Obes Surg, 2004

T2DM ‘cured’

in 75%

T2DM ‘resolved’ in 78%

N=4070, mean age 40, BMI 48,

Systematic review and

meta-analysis

Buchwald et al Am J Med, 2009

• “....since my surgery I felt that ‘I wanna die’ feeling..... It was

HORRIBLE...”

• “If I eat too many carbs at one time, I get so tired immediately

after and almost feel drunk and may even slur my words”

• Treating Dumping syndrome: Acarbose, Octreotide.....

Common malabsorptive deficiencies

after gastric bypass surgery

• Iron 20-50%

• Zinc

• Calcium 25-50%

• Vitamins A

B1

B12 12-33%

Folate 45%

D 25-50%

• Protein 10%

• Drugs variable

Sawaya et al, 2013

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”.

The new epidemic: Severe and complicated obesity

SIGN 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”.

The new epidemic: Severe and complicated obesity

SIGN 115: Management of Obesity 2010

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Week

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(%)

Lim et al, Diabetologia 2011

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

15kg intentional loss might

normalise life expectancy

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Weight loss (kg) in first 12 months

Lean et al. Diabetic Medicine, 1990

95% CI

↑ 95% CI

meanNormalise life expectancy

15 kgloss?

Life expectancy(mean age 64

at diagnosis)

Meta-analysis of non-surgical trials with 1-year follow-up:

BEST RESULTS WITH MOST RAPID WEIGHT LOSS

Average weight loss in subjects completing 1-year

80 studies, n = 26,455, completers =18,199 (69%) (Franz et al JADA 2007)

15 kg

To maintain weight loss, behaviours must counteract environment

and physiology: drugs and surgery are most effective (Greenway 2015)

Obesogenic Environment

Physical environment

Food environment

Educational environment

Cultural environment

Social environment

Social Marketing

(normalised behaviours)

Obesogenic medications

Biological & Physiological

Satiety signals - fall with weight loss

(Leptin, PYY, CCK, amylin, insulin, GLP-1)

Orexigenic signals - rise with weight loss

(eg. Ghrelin, GIP)

Metabolic Rate falls with energy

restriction & with weight loss

Leslie et al 2007; Sumithran et al 2011; Maclean 2011; Leibel et al 1995;

Increasing awareness of Behavioural Therapy:

SIGN 2010 Diabetes Guidelines

• 3 pages out of 21 on Diet/Lifestyle, before drug treatment.

– improves self-management, metabolic and psychological outcomes

• Intensive, frequent contact with trained professionals

• Telephone contact, computer-assisted programmes

• Theory-based psychological interventions, motivational interviews

• Structured education curriculum, evidence-based, underpinning

philosophy, specific aims and learning objectives

• Quality-assured, independent audit assessment vs. predefined criteria

Similar emphasis is needed for obesity treatment more generally

Medical weight loss in primary care for overweight &

obese non-diabetic reduces all risk factors at 1-2 years (Naude et al meta-analysis 2014)

Weight loss maintenance programmes after VLCD/TDR:

a meta-analysis of RCTs (Johansson et al 2014)

Thin lines = control

Thick lines = intervention

Copenhagen Weight Loss in Knee Osteoarthritis trial:

more liberal TDR allowed more patients to do well

Little difference in weight loss

415kcal VLED vs. 810kcal LED

0 – 8 weeks

■ 810kcal/d liquid formula

▲ 415kcal/d liquid formula

16 – 68 weeks

■ (D) 1500kcal/d part food/part formula [average one formula meal daily]

♦ (E) Knee exercises group

● (C) Control – no intervention

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Time (weeks)

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Wei

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g)

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 (No anti-obesity drug)

(Bliddal et al, secondary care, dietitian managed)

Counterweight-Plus - Protocol

Nutritionally complete

Total Diet Replacement (TDR)

• Homemade (811calories/day)

• Commercial (832calories/day)

• Cambridge Weight Plan

Plus:

• Structured patient education

– Step down approach optional

• >2.25l fluid per day (4 pints)

• Fibre supplement

Screening

TDR Stage

Food Reintroduction

Weight Loss Maintenance

Lean et al , Br J GP (2013)

Weight Loss Maintenance- Protocol

Stepped Food Reintroduction

• Introduce one 360-400 kcal meal

• Add a meal every two weeks

• Meals based on eatwell plate

• Offer Orlistat

Maintenance

• Low fat diet (30% fat)

• Estimate 500 kcal/d deficit

• 2500 kcal/d upper limit

Relapse Management

- Offer orlistat

- Second attempt LELD stage

Screening

TDR Stage

Food Reintroduction

Weight Loss Maintenance

Lean et al , Br J GP (2013)

Behavioural Strategies –

Weight Loss Maintenance

All Appointments for 12-24 months:

Review of outcome goals

Weight Tracker

- Provide feedback on performance

Rewards

- For effort or progress towards behaviour

Preventing Relapse

- Self talk- cognitive restructuring

Maintaining Change

-Provide normative information about the

-behaviours of others

Counterweight-Plus feasibility study

in severe obesity (n = 91, mean BMI 47) (820kcal Total Diet Replacement, Food Reintroduction and Maintenance)

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Lean et al , Br J General Practice (2013)

Popular Belief: Patients regain all the weight, or more

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Lean et al , Br J General Practice (2013)

25%

25%

50%

In Fact:

• 25% fail to engage at all

– Lose <5kg (yet claim to be adhering to programme)

• 50% follow some or most of the programme

– Achieve and maintain 5-20kg weight loss

)

• 25% adhere fully

– Lose and maintain >20kg weight loss

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

Efficiency of Obesity treatmentCost-effectiveness: Per £1 million NHS spend:

Lap Band surgery, complications and follow up @ £7,500

• 133 patients can be treated: 80% achieve >15kg 12m weight loss

• >15kg loss for 106 patients

Counterweight-Plus TDR & Maintenance programme @ £811

• 1161 patients can be treated: 30% achieve >15kg 12m weight loss

• >15kg loss for 383 patients

plus >10kg loss for 459 patients

Lean et al , Br J General Practice (2013)

2013-2018funded by DiABETES UK

to Mike Lean and Roy Taylor

• Cluster-Randomised Trial: Counterweight-Plus* 810kcal/d LELD

and weight maintenance programme vs usual care

– Both arms follow current clinical guidelines

– 280 patients, BMI >27, diagnosed T2DM <6 years, not on insulin

• Co-primary endpoints: weight loss >15kg and non-diabetic HbA1c

– at 12 & 24 months off all drugs (plus life-long clinical monitoring)

• Mechanistic and Magnetic Resonance studies

• Qualitative and process evaluation

• Planned economic analyses

* Supported by Cambridge Weight Plan

Obesity Crisis Solutions:Ethics of treatments for obesity and type 2 diabetes

• No drug should be prescribed without providing trained

professional support, for an optimal diet and lifestyle

change programme

• No clinical trial should be permitted unless an optimal

diet and lifestyle change programme is provided, to both

intervention and placebo arms

Epidemic!*

Medical Responsibility

Optimal medical care

within available resources

• Diet & lifestyle

• Drugs

• Surgery

• Palliative

Political Responsibility

Government interventions to remove

primary causes

• Catering outlets increasing

• Meals/snacks outside home increasing

• Portion sizes increasing

• Physical inactivity……

* WHO: ‘Critical Threshold for Intervention’

Health by Stealth: Eat Balanced pizzas now

reach 32,000 Scottish children every week

PIZZA POWER KIDS by Eat Balanced

now in Primary Schools in:

• East Renfrewshire

• Moray

• Argyle and Bute

• Aberdeen City

• South Ayrshire

Trials in another 10 councils:

• Fife

• East Ayrshire

• North Ayrshire

• Clackmannanshire

• Edinburgh City

• Glasgow City

• Highland

• Tayside (includes Dundee, Perth &

Kinross, Angus)

9-month weight changes in 20,975 young adults randomised to an on-line public health intervention

Nikolaou, Hankey & Lean, Obesity 2015

Control Group

n = 2,134

‘Rational Model’

(NTICV)

n = 1,810

‘Stealth Model’

(GD)

n = 2,057

Future: Address body fat or adipose

tissue mass (not BMI)

Best R2 vs MRI

(total body fat)

R2 (m/f)

Algindan et al MRI

validation study (total

adipose tissue)

BMI 0.66-0.95 0.66/0.82

Waist 0.77-0.94 0.77/0.78

Body fat equation

(Algindan et al 2015)

0.76-0.84 0.82/0.89

DEXA 0.8-0.95 -

BIA massive

variability

-

Algindan, Hankey, Govan , Gallagher, Heymsfield, Lean

Br J Nutrition 2015

Prospective associations of

beverage consumption with

incident type 2 diabetes:

random effects meta-

analysis.

*Unadjusted for adiposity.

†Adjusted for adiposity.

‡Adjusted for adiposity and

within person variation.

(Imamura et al. BMJ 2015)

©2015 by British Medical Journal Publishing Group

Romaguera-Bosch et al. Diabetologia 56:1520, 2013

SSBs and BMI-adjusted risk of diabetes in

EPIC-Interact (Europe)

Future management: Conclusions

• Measure and deal with excess body fat, not BMI

• Direct major resources for research and routine management of

obesity, not its complications

• Target an amount of weight loss relevant to obese people and their

medical needs, not statistics

• Tackle the real problem faced by patients ie weight-loss maintenance,

not weight loss

• Provide optimal non-surgical weight-management routinely, and

accept that not all will succeed (they may not do well with surgery either)

• End manipulation of consumers, with damage to health, for profit