1. Obesity. Diet,
Exercise and
Drugs. How much
pain? How much
Patrick English gain?
Consultant Physician. Derriford

2. Overview
• Dietary intervention
– Effectiveness of major studied
interventions
• Exercise
– Major studied interventions
– Metabolic effects
– Weight loss effects
• CombinedStrategies-LookAHEAD
• Pharmacotherapy
– GLP-1 and Orlistat
– Newer agents

3. Dietary interventions
• Energy restriction
– VLCD
– LCD
– Liquid meal replacements
• Mediterranean
• Low CHO/Low GI/Low
fat/Macronutrient restriction/freedom

4. Dietary interventions
• Goal is maintenance of weight loss
achieved
• Few studies of good quality and long
duration
• Energy restriction is ultimately the
key

5. Low GI: Cochrane Review 2009. Low
glycaemic index or low glycaemic load diets
for overweight and obesity
• 6 RCTs Low GI vs standard
with 202 participants,
5/52-26/52 duration
• Possible small benefit with low
GI
– 1 kg greater WL at 6/12
– TC -0.22mM
– LDL -0.24mM
• unconvincing

6. Low CHO. Obesity Reviews
2009. Hession
• Low CHO/High protein vs Low fat/Low Cal/Higher
CHO
• Systematic review 2000-2007
• Adults , Mean BMI ≥28, duration > 6/12
• 13 studies-longest 36/12, total number 1022
patients
• Attrition rate 36%
• At 6/12 favours Low CHO -4.02kg
• At 12/12 Favours low CHO -1.05 kg
• In the one trial to go to 3 yrs-no difference

7. Mediterranean: Shai NEJM
2008
• Low CHO vs LF vs Med diet (which was as low in
fat as LF)
• 2yrs
• 322 patients, 52 yo, BMI 31
• Adherence 95.4% 1yr, 84.6% 2y
• WL in LF vs Low CHO vs Med = 2.9kg vs 4.7kg*
vs 4.4 kg*
• inT2DM glucose  1.8mmol/L in Med with 
HOMA-IR

8. Longer term studies: Douketis
IJO 2005
• Systematic review-BMI ≥ 25, prespecified
approved WL intervention, clinical trial, > 2yrs, >
100 subjects
• 16 dietary/lifestyle interventions, 6 with FU =
4yrs. Results based on completers
• 5698 subjects, mean age:40-59, Mean wt
78-116kg, Attrition 31-64%
• 13 studies split induction (3-18/12) then
maintenance, 3 studies just induction over 2-4
yrs
• <5kg WL after 2-3yrs (3.5±2.4kg, range
0.9-10kg)
• <5kg after 4-7 yrs (3.6±2.6kg, range 1.8-10kg)

9. Liquid meal replacements.
Flechtner-Mors Ob Res 2000
• 100 patients BMI-25-40
• 1200-1500 kcal/d restriction with diet vs meal
replacement shakes x 2 for 12/52
• 1 x meal replacement shake and snack daily as
part of maintenance 4 yrs
• Attrition of 42 patients at 2 yrs, 32 persuaded to
rejoin
• WL 1.3 vs 7.1kg 12/52, 4.1kg vs 9.5kg at 4 y,
75% FU
• SBP  13.3 mmHg in intensive gp, glucose fell in
both by 0.6-0.65mM

10. Take Home
– Different dietary composition little effect long
term though suggestive for Low CHO/Med
– Adherence and energy content most important
– Adherence low with severely CHO restricted
diets at 1 year (< 50% vs 60=% with other
approaches)
– Interventions with large weight loss up front
with lifestyle change subsequently may have a
bigger effect
1. – Dietary counselling JAMA 2005; modest effect Int Med
Astrup Lancet 2004; 364:897-9 2. Dansinger has a 293:43-53 3. Dansinger Ann as
2007: 147:41-50 4. Astrup Obes Rev 2000; 1:17-19 5. Anderson Am J Clin Nut 2001; 74:579-84
stand alone intervention (-1.9 BMI units 3)

11. Exercise/Activity-Studied
interventions
• Resistance training
• Aerobic training
– Long duration
– Short duration
• HIT

12. Metabolic/Weight loss
effects of Resistance
Training
• Resistance training
– Poorly studied for weight loss2
– Intensity and duration not clearly
defined
– Better studied in type 2 diabetes and
lowers HbA1c 0.57% (6 mmol/mol)1
– Has greater effect if > 150 mins
week1
– Combined with AET may be more
effective than AET alone (muscle
mass) in reducing VAT2
– New trial underway-Washburn et al
Contemp Clin Trials July 2012

13. Metabolic/Weight Loss
effects Aerobic training
• The more you do, the harder you go, the more
you get1, 2 but effects are modest2
• Increased physical activity and fitness improves
health risk independent of weight1,2 but does
not completely alleviate effects of weight1
• Unfit lean men double risk mortality vs fit lean
men3 (1.8/1000 man yrs vs 3.6)
• Unfit men with waist <87cm higher mortality
than fit men waist > 99cm (7.8/1000 man
years vs 1.9)3
• In DM unfit men of all weight categories
2.7-2.8 x mortality of those with high fitness
levels and normal weight4
• Limited data on those with BMI > 354, 5
1. Jakicic Obesity Dec 2009 2. Shaw K. Cochrane Database
Syst Rev 2009 3. Lee CD Am J Clin Nutr 1999. 4. Church

14. Metabolic/Weight Loss
effects Aerobic training
• Typically 0.5-3kg weight loss with physical
activity alone1
• If supervised activity 45mins/daily for 16 months
M lost 5.2kg v 0.5kg no exercise, W 0.6kg
increase vs 2.9kg increase2
• Effect of exercise interventions less than that if
dietary interventions, 4kg vs 7.2kg at 1 year 1, 3
• Combined intervention more effective still in short
term studies 1, 4 0.6% placebo vs 8.4%/5.5% (M/
F) exercise vs 11.4%/7.5% combined
1. Jakicic Obesity Dec 2009 2. Donnelly Arch Int Med 2003 3. Wood PD
NEJM 1988 4. Hagan Med Sci Sports Exerc 1986

15. Effects of Physical activity
(aerobic) on long term weight
loss/maintenance
• Following weight loss 33-50% lost weight is regained in
12-18 months1
• Physical activity may be critical in weight loss maintenance2
• Those maintaining 10% weight loss at 24 months reported
performing 275 minutes of activity above baseline levels2
(338 mins vs 63 mins)
• Those who failed to maintain weight loss increased by 74
mins/week (128 mins vs 54 mins)2.
• NWCR-those who maintained 13.6kg WL > 12 months
reported >2,800kcal/wk of LTPA3
• 76% of those who maintain weight loss report using
physical activity as a WL strategy4
1. Jakicic Obesity Dec 2009 2. Jakicic Arch Int Med 2008 3. KlemAm J Clin
Nutr 1997 4. Kayman Am J Clin Nut 1990

16. Exercise and prevention of
weight gain
• Australian Longitudinal study of womens health1:
– 8726 18-23 yo F followed for 4 yrs
– 41% gained ≥ 5% BW
– Sitting > 33hrs/wk increased risk of weight
gain by 20%
• Healthy Worker Project2
– avge weight gain 0.6kg F and 0.4kg M over 2 yrs
– 1 extra walking session/week reduced wt of 0.8kg F and
0.4kg M
1. Ball K Int J Obes Relat Metab Disord 2002 2. French S Int J Obes Relat
Metab Disord 1994

17. HIT (Panorama)
• All out intervals > 90% VO2 peak,
seconds to minutes with recovery
period
• Classically Wingate Test-30s all out vs
high force on cycle ergometer 4-6 rpts
with 4 min recovery
• Used 3x weekly for 2-6/52
– At 2/52 2x duration effort at 80% base VO2
peak (26-51 mins)
– Improves oxidative capacity mitochondrial
enzymes 15-35% (euivalent to 10.5 hrs
endurance training), increases GLUT-4
expression and muscle glycogen
• Not used as weight loss strategy but

18. Summary-Activity/Exercise and
obesity
• The more you do and the harder you do it the
more weight loss you get
• Health benefits accrue from improved fitness as
well as weight loss
• Required levels of activity are more than most
suppose
• Most people struggle to achieve activity targets
so strategies targeted at improving adherence
required
• The more contact people have the better they do

19. Studies that help us in real
world
Counterweight Look AHEAD
• www.counterweight.org • Diabetes Care 30:1374-1383,
• Primary care led 2007
• OMA training practice nurses • Obesity 14: 737-752 2006
in 20 practices • Arch Int Med 170: 1566-75
• Groups (1 hrs) and 1:1 2010
(10-30 minutes each) • 0-6months: weekly visits, 3
• 6 appointments in 3 months, group, 1x1:1.
then at least quarterly • 7-12 months: 3 visits/m, 2
• Lifestyle but pharmacotherapy group, 1x 1:1 (?Orlistat)
available • 2-4 yrs: 1 face to face 1:1/m,
• Links with supporting 1 x email/phone, refresher
physician/dietitian groups/ campaigns
• 5+yrs: monthly individualised
contact/refresher
groups/campaigns

20. What do they have in
Common?
• Based on evidence of what works
• Clear structure to programme
• Emphasis on motivation and engagement of
patient
• Use of goal setting and structured meal plans
with calculated energy deficits
• More frequent contact than usually afforded in
everyday practice
• The use of pharmaceutical agents if lifestyle alone
did not achieve goals

21. What did they achieve?
Counterweight
• 47.9% with 1 year follow up data
• Mean weight change -3.0kg
• 30% had 5% weight loss (40% high attenders)
• Estimated ↓ 6.3% of prescribing costs (8.4% in
high attenders)
• Savings cover 40% of programme costs

22. What did they achieve?
Look AHEAD 1 yr • Look AHEAD 4 year
• 97.1% 1 year follow up • 93% assessed in each of
exam the 4 years
• Mean 8.6% weight loss • Mean 6.15% WL (0.88%
(0.7% C) control)
• 37.8% had > 10% weight • HbA1c  0.36% ( 0.09 %
loss (3.2% control) controls)
• 68% > 5% weight loss • Less medication use-if no
• HbA1c ↓ 7.3→ 6.6% OHG at baseline only 42%
(↓0.14% C), use of using at 4 yrs vs 67% in
medicines ↓ 7.8% (↑ 2.2% controls
C), ↓ BP 7/3, ↓TG and
cholesterol and ↓ % with
MS 93.6→78.9%)
∀ ↑ fitness 20.9 vs 5.8%

23. Look AHEAD good news
• Percentage of people meeting all 3
treatment goals for BP, HbA1C and
LDL
– 10.8→23.6% ILI vs 9.5→ 16.0% C
↑ fitness and ↓ weight in controls
– Controls got baseline education and 3
group sessions in one year and this was
enough for substantial improvements
from baseline

24. OK-some drugs
• GLP-1
• Orlistat
• Phentermine/Topiramate Phase 3 studies
underway-awaiting approval
• Tesofensine –phase 3 x2 underway
• Bupropion/Naltrexone, Buproprion/Zonisamide-
awaiting approval
• Pramlintide & combinations

25. Orlistat license
• BMI > 30 or >28 with risk factors
• Need to lose 2.5kg prior to treatment
removed from license
• Need to lose 5% bodyweight at three
months to continue treatment long-
term
• Reconsider if significant regain
occurs at any time
• NICE recommendation in 2001

26. Proportion of patients achieving
beneficial weight loss with Orlistat over
one year (NGT)
Patients (%)
100 Placebo + diet (n=340)
p<0.05 Orlistat + diet (n=343)
80
68.5% (ITT population)
p<0.05
60
49.2%
38.8%
40
17.7%
20
0
≥5% ≥10%
Weight loss (%)
Adapted from Sjöström. Lancet 1998; 352: 167-172

27. Proportion of patients with T2D
achieving beneficial weight loss with
Orlistat over one year
Taken from Miles JM, Diabetes Care 2002;25(7):1123-8 and Kelley
DE, Diabetes Care 2002;25(6):1033-41.

28. Weight control is more difficult to
achieve in patients with type 2 diabetes
Diet-treated Drug-treated
Non-diabetic diabetic diabetic
0
Change in BMI (kg/m2)
–2
–4
–6 p<0.01
vs non-diabetic
–8
–10
Adapted from Khan et al. Reprinted with permission from the
North American Association for the Study of Obesity © 2000. Obes Res 2000; 8: 43–8

29. UK Orlistat Multimorbidity
Study Improvements in risk
factors
Total LDL Sys Dias OGTT
Chol Chol BP BP Score
Orlistat -0.12 -0.3 -6.0 -5.5 -0.37
Placebo +0.16 -0.02 -2.3 -3.1 +0.09
All differences at least p<0.05

30. Orlistat-Summary
• In NGT patients approx 4-6kg extra weight loss
with orlistat vs. placebo short term.
• 70% ≥ 5% WL and 40% ≥ 10% WL
• In T2DM approx 50% of this
• 10, 631 patietns in 16 studies 1-4 yrs in
Cochrane review 2009, with WL approx 2.9 kg v
placebo in these1
• Improves cardiovascular risk factors, glycaemia
to small extent1.
• No CV or mortality data1
1.Padwal; Cochrane Database Syst Rev 2009

31. Liraglutide Astrup Lancet
2009
• GLP-1 analogue
• 1.2-3.0mg vs placebo and orlistat over
20/52
• WL = 4.8kg (1.2mg) vs 5.5.kg
(1.8mg) vs 6.3kg (2.4mg) vs 7.2 kg
(3.0mg) vs 2.8kg (placebo) vs 4.1 kg
(orlistat) at 20/52
• 76% with 3.0mg lost > 5%, vs 41%
orlistat vs 30% placebo
• Withdrawal rates 19% placebo, 11-22%
liraglutide and 17% orlistat. Nausea in
24-47% in those on liraglutide
• At 2yrs WL 7.8 vs 5.4 kg Liraglutide vs
Orlistat (p=0.09) with SBP 12.5 vs

32. Topiramate/Phentermine-
Qnexa
• Topiramate-GABA agonist, unkown action in obesity.  SE
monotherapy
• Phentermine-NA lateral hypothalamus, β2-stumulation,
appetite
• Combination at 92mg/15mg and 46mg/7.5mg preparations
in Phase 3 studies-EQUATE, EQUIP, CONQUER
• CONQUER Lancet 2011, Gadde et al
• 2487 patients, BMI 27-45 plus 2 comorbidiities
• WL 1.4 kg vs 8.1 kg vs 10.2kg (9.8%) with 70% > 5% WL
vs 21% placebo
  depression and anxiety A/Es in high dose group vs low
dose group vs placebo (7% vs 4% vs 4%)

33. Tesofensine
• Tesofensine
– inhibits NA/DA, 5HT re-uptake
presynaptically and studied in AD and
PD
– Phase IIb studies 10.6% WL 24 weeks
in 1 mg dose but increased heart rate
7.4bpm

34. Bupropion Combinations-Under RV
FDA
• Buproprion inhibits reuptake DA and NA and
activates POMC neurons,  α-MSH release, 
appetite
• Naltrexone blocks β-endorphin inhibition of
POMC α-MSH release
• Zonisamide-anit-epilepsy with DA and 5HT
activity
• Combined with Naltrexone SR 32mg/Bupropion
SR 360 mg = Contrave
• Phase III studies: COR-I (Greenaway Lancet
2010), II; COR-BMOD, COR-Diabetes
– 552 with DM and obesity, A1c 7-10%
– WL 5% vs 1.8%
– A1c  0.6%
• With Zonisamide ? Greater WL in Phase

35. Pramlintide
• With Metreleptin-Phase II, 12.7% WL
at 20/52
• With Sibutramine
• With Phentermine
• With Exenatide

36. Summary-Drugs
• Orlistat only drug with long term license
and profile
• Liraglutide looks promising
• Others coming through but not greatly
increased weight loss over current agents
to date. Newer centrally acting drugs in
development
• Long term use is required and attrition
limits effectiveness
• Need for hard endpoint studies

37. Adiposity signalling
Schwarz Nature vol 404 6 April 2000

38. The hypothalamus in weight
control
Schwarz Nature vol 404 6 April 2000

39. Integrating adiposity and
satiety signals
Schwarz Nature vol 404 6 April 2000