roche presentation on rethinking obesity. treating obesity in the same manner as established cardiovascular risk factors

2. Rethinking Obesity
Chris Sainsbury
BHF Glasgow Cardiovascular Research Centre

6. a. lifestyle change
b. antihypertensives

7. a. lifestyle change
b. antihypertensives
c. both

8. a. lifestyle change
b. antihypertensives
c. both
(but which do you think is more likely to reduce CV risk?)

10. ?

12. ?

15. what is the evidence in obesity
management?

16. Accepted wisdom
Obesity is an environmental / behavioural problem
Behavioural therapy is the best way to treat obesity

17. Challenges
Obesity is an environmental / behavioural problem
genetic in uences often ignored
Behavioural therapy is the best way to treat obesity
diet / exercise yields poor results

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

19. in an obeseogenic environment,
genetic factors determine who becomes obese

20. in an obeseogenic environment,
genetic factors determine who becomes obese
and who becomes very obese

21. 50
40
30
20
10
0
1995
<25 25-30 30-40 40+

22. 50
40
30
20
10
0
2003
<25 25-30 30-40 40+

23. 50
40
30
20
10
0
2015
<25 25-30 30-40 40+

24. diet / exercise yields poor results
(why might this be?)

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

26. atkins weight watchers ornish
adapted from Dansinger et al JAMA 2005;293:43-53

27. NEJM 2002;346:393-403

28. Why do we continue to advocate behavioural therapy?
1 shifting responsibility for failure
2 not historically had e ective drug therapy

29. Waist circumference
Risk of obesity-associated metabolic complications
Gender Increased Substantially increased
≥94 cm (~37 in) ≥102 cm (~40 in)
Men
≥80 cm (~32 in) ≥88 cm (~35 in)
Women

30. Moderate (~10%) weight loss is bene cial (i.e. 10 kg weight loss from 100 kg bodyweight)
↓ 20–25% total mortality
Mortality
↓ 30–40% diabetes-related deaths
↓ 40–50% obesity-related cancer deaths
↓ 10mmHg systolic pressure
BP
↓ 20mmHg diastolic pressure
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

31. Licensed products in UK for obesity
• 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.

32. Xenical (orlistat) produces greater weight loss
than placebo and diet
Active treatment begins
Week
0 12 24 36 52
–4
0
–2 Placebo + diet (n=340)
Mean weight loss (%)
Orlistat + diet (n=343)
–4
–6 –6.1%
–8
–10 –10.2%*
*p<0.001 vs placebo
–12
P9791884/August 29th, from
Adapted 2007 Sjöström et al. Lancet 1998; 352: 167–72

33. Xenical (orlistat) significantly reduces waist
circumference compared to placebo
Placebo + diet (n=266)
108
Xenical + diet (n=265)
Waist circumference (cm)
106
104 –2.6 cm
102
*
100 –6.0 cm
*p<0.0001 vs placebo
98
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Adapted from Broom I et al. Int J Clin Prac 2002; 56: 494-499.
Week
P9791884/August 29th, 2007

34. Effect of weight loss with Xenical (orlistat) on lipid levels
in patients with multiple co-morbidities at one year
Total-cholesterol LDL-cholesterol
6
Xenical + diet (n=265)
+3.8%
4 Placebo + diet (n=266)
2 p<0.0001
Change (%)
0
–0.6%
–2 –1.3%
–4 p<0.0001
–6
–8 –7.1%
Adapted from Broom et al. Int J Clin Pract 2002; 56: 494–9
P9791884/August 29th, 2007

35. Effect of weight loss with Xenical (orlistat) on blood
pressure in hypertensive patients after 1 year
Systolic BP* Diastolic BP†
0
Mean change (mmHg)
–2
–4
Placebo + diet (n=289)
–4.6
–6
–5.6 Xenical + diet (n=339)
–8
–7.7
–10 * Baseline SBP ≥140 mmHg
–9.4 † Baseline DBP ≥90 mmHg
p=0.017
p=0.022
Adapted from Sharma AM & Golay A. J Hypertens 2002; 20: 1873–8
P9791884/August 29th, 2007

36. Weight loss with Xenical (orlistat) can lead to
reductions in the need for concomitant medication
Patients Stopped medication
40
with dyslipidaemia Reduced dose
Percentage of patients
30
Patients
Patients
with diabetes
with hypertension
20
10
0
Anti-hypertensives Lipid-lowering drugs
Adapted from Wirth A. Diab Obes & Metab 2005; 7: 21-27
P9791884/August 29th, 2007

37. sibutramine
sibutramine + lifestyle
lifestyle
sibutramine + brief lifestyle
Wadden et al NEJM 2005 353:2111-2120

38. follow up duration and long term success

39. weight loss / exercise / diet / smoking cessation
0
control
1
2
intervention
3

40. weight loss / exercise / diet / smoking cessation
0
control
1
2
intervention
3

41. weight loss / exercise / diet / smoking cessation
0
control
1
2
intervention
3

42. NEJM 2002;346:393-403

43. JAMA. 1999;281:235-242.

44. 1 behavioural therapy
2 monotherapies
3 combination therapy
4 pre emptive therapy

45. 1 behavioural therapy
2 monotherapies
3 combination therapy
BP
4 pre emptive therapy

46. 1 behavioural therapy
2 monotherapies
Cholesterol
3 combination therapy
4 pre emptive therapy

47. 1 behavioural therapy
obesity
2 monotherapies
3 combination therapy
4 pre emptive therapy

48. 1 behavioural therapy
2 monotherapies
3 combination therapy
4 pre emptive therapy BP / chol / obesity / ?

50. obesity trends - men
5050
45
4040
35
% population
3030
25
2020
15
1010
5
0
1975 1980 1985 1990 1995 2000 2005 2010 2015
1975 1985 1995 2005 2015
Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.

51. obesity trends - women
5060
50
40
40
% population
30
30
20
20
10
10
0
1975 1980 1985 1990 1995 2000 2005 2010 2015
1975 1985 1995 2005 2015
Adapted from The Information Centre. Statistics on Obesity, Physical Activity and Diet: England, 2006. London: TIC, 2006.