Chris SainsburyBHF Glasgow Cardiovascular Research Centre

Rethinking Obesity

a. lifestyle change

b. antihypertensives

a. lifestyle change

b. antihypertensives

c. both

a. lifestyle change

b. antihypertensives

c. both

(but which do you think is more likely to reduce CV risk?)

?

?

what is the evidence in obesity management?

Accepted wisdom

Obesity is an environmental / behavioural problem

Behavioural therapy is the best way to treat obesity

Challenges

Obesity is an environmental / behavioural problem

Behavioural therapy is the best way to treat obesity

genetic in!uences often ignored

diet / exercise yields poor results

adapted from Stunkard et al NEJM 1986;314:193-8

in an obeseogenic environment,

genetic factors determine who becomes obese

in an obeseogenic environment,

genetic factors determine who becomes obese

and who becomes very obese

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1995<25 25-30 30-40 40+

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2003<25 25-30 30-40 40+

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2015<25 25-30 30-40 40+

diet / exercise yields poor results

(why might this be?)

adapted from Leibel et al NEJM 1995;332:621-628

atkins weight watchers ornish

adapted from Dansinger et al JAMA 2005;293:43-53

NEJM 2002;346:393-403

Why do we continue to advocate behavioural therapy?

1 shifting responsibility for failure

2 not historically had e!ective drug therapy

Gender Increased Substantially increased

Men

Women

≥94 cm (~37 in)

≥80 cm (~32 in)

≥102 cm (~40 in)

≥88 cm (~35 in)

Risk of obesity-associated metabolic complications

Waist circumference

Mortality ↓ 20–25% total mortality↓ 30–40% diabetes-related deaths↓ 40–50% obesity-related cancer deaths

BP

Diabetes ↓ >50% in diabetes risk↓ 30–50% in fasting glucose↓ 15% in HbA1c

Lipids ↓ 10% total cholesterol↓ 15% LDL-cholesterol↓ 30% triglycerides↑ 8% HDL-cholesterol

Adapted from Jung R. British Medical Bulletin 1997; 53: 307-321

↓ 10mmHg systolic pressure↓ 20mmHg diastolic pressure

Moderate (~10%) weight loss is bene"cial (i.e. 10 kg weight loss from 100 kg bodyweight)

•Xenical (orlistat)1:•non-centrally acting•gastric and pancreatic lipase inhibitor• reduces dietary fat absorption

•Sibutramine2:•centrally acting serotonin noradrenaline reuptake

inhibitor• increases satiety

•Rimonabant3:•peripheral and centrally acting•selective cannabinoid receptor (CB1) antagonist

1. Xenical Summary of Product Characteristics. May 2006.2. Reductil Summary of Product Characteristics. November 2005.3. Acomplia Summary of Product Characteristics. June 2006.

Licensed products in UK for obesity

P9791884/August 29th, 2007

Week

–6.1%

–10.2%*Mea

n w

eigh

t los

s (%

)

Adapted from Sjöström et al. Lancet 1998; 352: 167–72

52–4 0 362412

0

–12

–8

–2

–4

–6

–10

Xenical (orlistat) produces greater weight loss than placebo and diet

*p<0.001 vs placebo

Placebo + diet (n=340)

Orlistat + diet (n=343)

Active treatment begins

P9791884/August 29th, 2007

Xenical (orlistat) significantly reduces waist circumference compared to placebo

98

100

102

104

106

108

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Week

Wai

st c

ircum

fere

nce

(cm

)

Placebo + diet (n=266)

Xenical + diet (n=265)

–6.0 cm

–2.6 cm

*p<0.0001 vs placebo

Adapted from Broom I et al. Int J Clin Prac 2002; 56: 494-499.

*

P9791884/August 29th, 2007

Effect of weight loss with Xenical (orlistat) on lipid levels in patients with multiple co-morbidities at one year

–8

–6

–4

–2

0

2

4

6Total-cholesterol LDL-cholesterol

Cha

nge

(%)

Adapted from Broom et al. Int J Clin Pract 2002; 56: 494–9

–7.1%

–0.6%

p<0.0001

–1.3%

+3.8%

p<0.0001

Placebo + diet (n=266)

Xenical + diet (n=265)

P9791884/August 29th, 2007

–10

–8

–6

–4

–2

0

–5.6

–7.7

Diastolic BP†

–4.6

–9.4

Systolic BP*

Mea

n ch

ange

(m

mH

g)

Adapted from Sharma AM & Golay A. J Hypertens 2002; 20: 1873–8

Effect of weight loss with Xenical (orlistat) on blood pressure in hypertensive patients after 1 year

p=0.022

p=0.017* Baseline SBP ≥140 mmHg† Baseline DBP ≥90 mmHg

Placebo + diet (n=289)

Xenical + diet (n=339)

P9791884/August 29th, 2007

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Anti-hypertensives Lipid-lowering drugs

Perc

enta

ge o

f pa

tient

s

Stopped medicationReduced dose

Weight loss with Xenical (orlistat) can lead to reductions in the need for concomitant medication

Adapted from Wirth A. Diab Obes & Metab 2005; 7: 21-27

Patients with diabetes

Patients with dyslipidaemia

Patients with hypertension

Wadden et al NEJM 2005 353:2111-2120

sibutramine

sibutramine + lifestyle

lifestyle

sibutramine + brief lifestyle

follow up duration and long term success

0 1 2 3

control intervention

weigh

t loss

/ ex

ercis

e /

diet /

smok

ing ce

ssat

ion

0 1 2 3

control intervention

weigh

t loss

/ ex

ercis

e /

diet /

smok

ing ce

ssat

ion

0 1 2 3

control intervention

weigh

t loss

/ ex

ercis

e /

diet /

smok

ing ce

ssat

ion

NEJM 2002;346:393-403

JAMA. 1999;281:235-242.

2 monotherapies

3 combination therapy

4 pre emptive therapy

1 behavioural therapy

2 monotherapies

3 combination therapy

4 pre emptive therapy

BP

1 behavioural therapy

2 monotherapies

3 combination therapy

4 pre emptive therapy

Cholesterol

1 behavioural therapy

2 monotherapies

3 combination therapy

4 pre emptive therapy

obesity1 behavioural therapy

1 behavioural therapy

2 monotherapies

3 combination therapy

4 pre emptive therapy BP / chol / obesity / ?

Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.

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1975 1980 1985 1990 1995 2000 2005 2010 20151975 1985 1995 2005 2015

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obesity trends - men%

pop

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1975 1980 1985 1990 1995 2000 2005 2010 2015

Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.

1975 1985 1995 2005 2015

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obesity trends - women%

pop

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