obesity. diet, exercise and drugs. how much pain? how much gain? patrick english consultant...
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Obesity. Diet, Obesity. Diet, Exercise and Exercise and
Drugs. How much Drugs. How much pain? How much pain? How much
gain?gain?Patrick EnglishPatrick EnglishConsultant Physician. DerrifordConsultant Physician. Derriford
OverviewOverview• 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
Dietary interventionsDietary interventions• Energy restriction
– VLCD– LCD– Liquid meal replacements
• Mediterranean • Low CHO/Low GI/Low
fat/Macronutrient restriction/freedom
Dietary interventionsDietary interventions• Goal is maintenance of weight loss
achieved• Few studies of good quality and long
duration• Energy restriction is ultimately the
key
Low GI: Cochrane Review 2009. Low Low GI: Cochrane Review 2009. Low glycaemic index or low glycaemic load diets glycaemic index or low glycaemic load diets
for overweight and obesityfor 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
Low CHO. Obesity Reviews Low CHO. Obesity Reviews 2009. Hession2009. 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
Mediterranean: Shai NEJM Mediterranean: Shai NEJM 20082008
• 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
Longer term studies: Douketis Longer term studies: Douketis IJO 2005IJO 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)
Liquid meal replacements. Liquid meal replacements. Flechtner-Mors Ob Res 2000Flechtner-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
Take HomeTake 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
– Dietary counselling has a modest effect as stand alone intervention (-1.9 BMI units 3)
1. Astrup Lancet 2004; 364:897-9 2. Dansinger JAMA 2005; 293:43-53 3. Dansinger Ann Int Med 2007: 147:41-50 4. Astrup Obes Rev 2000; 1:17-19 5. Anderson Am J Clin Nut 2001; 74:579-84
Exercise/Activity-Studied Exercise/Activity-Studied interventionsinterventions
• Resistance training• Aerobic training
– Long duration– Short duration
• HIT
Metabolic/Weight loss Metabolic/Weight loss effects of Resistance effects of Resistance
TrainingTraining• 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
1. Umpierre JAMA 2011 2. Strasser Obesity Reviews 2012
Metabolic/Weight Loss Metabolic/Weight Loss effects Aerobic training 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 Arch Intern Med 2005 5. Wing Med Sci Sports Exerc 2007
Metabolic/Weight Loss Metabolic/Weight Loss effects Aerobic training 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% combined1. Jakicic Obesity Dec 2009 2. Donnelly Arch Int Med 2003 3. Wood PD NEJM 1988 4. Hagan Med Sci Sports Exerc 1986
Effects of Physical activity Effects of Physical activity (aerobic) on long term weight (aerobic) on long term weight
loss/maintenanceloss/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
Exercise and prevention of Exercise and prevention of weight gainweight 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 M1. Ball K Int J Obes Relat Metab Disord 2002 2. French S Int J Obes Relat Metab
Disord 1994
HIT (Panorama)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 may help as fitness strategy
1. Gibala & Dean Exercise and Sports Sciences Reviews April 2008
Summary-Activity/Exercise and Summary-Activity/Exercise and obesityobesity
• 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
Studies that help us in real Studies that help us in real worldworld
Counterweight• www.counterweight.org• Primary care led• OMA training practice nurses
in 20 practices• Groups (1 hrs) and 1:1 (10-30
minutes each)• 6 appointments in 3 months,
then at least quarterly• Lifestyle but
pharmacotherapy available• Links with supporting
physician/dietitian
Look AHEAD• Diabetes Care 30:1374-1383,
2007• Obesity 14: 737-752 2006• Arch Int Med 170: 1566-75
2010• 0-6months: weekly visits, 3
group, 1x1:1.• 7-12 months: 3 visits/m, 2
group, 1x 1:1 (?Orlistat)• 2-4 yrs: 1 face to face 1:1/m,
1 x email/phone, refresher groups/ campaigns
• 5+yrs: monthly individualised contact/refresher groups/campaigns
What do they have in What do they have in Common?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
What did they achieve?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
What did they achieve?What did they achieve?Look AHEAD 1 yr• 97.1% 1 year follow up
exam• Mean 8.6% weight loss
(0.7% C)• 37.8% had > 10% weight
loss (3.2% control)• 68% > 5% weight loss• HbA1c 7.3 6.6%
(0.14% C), use of medicines 7.8% ( 2.2% C), BP 7/3, TG and cholesterol and % with MS 93.678.9%)
fitness 20.9 vs 5.8%
• Look AHEAD 4 year• 93% assessed in each of
the 4 years• Mean 6.15% WL (0.88%
control)• HbA1c 0.36% ( 0.09 %
controls)• Less medication use-if no
OHG at baseline only 42% using at 4 yrs vs 67% in controls
Look AHEAD good newsLook AHEAD good news• Percentage of people meeting all 3
treatment goals for BP, HbA1C and LDL– 10.823.6% 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
OK-some drugsOK-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
Orlistat licenseOrlistat 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
Proportion of patients achieving Proportion of patients achieving beneficial weight loss with Orlistat over beneficial weight loss with Orlistat over
one year (NGT)one year (NGT)
0
20
40
60
80
100
5% 10%
Patients (%)
68.5%
38.8%49.2%
17.7%
p<0.05
p<0.05
Adapted from Sjöström. Lancet 1998; 352: 167-172
Placebo + diet (n=340)Orlistat + diet (n=343)
Weight loss (%)
(ITT population)
Proportion of patients with T2D Proportion of patients with T2D achieving beneficial weight loss with achieving beneficial weight loss with
Orlistat over one yearOrlistat over one year
Taken from Miles JM, Diabetes Care 2002;25(7):1123-8 and Kelley DE, Diabetes Care 2002;25(6):1033-41.
Adapted from Khan et al. Reprinted with permission from theNorth American Association for the Study of Obesity © 2000. Obes Res 2000; 8: 43–8
0
–8
–10
–6
–2
–4
Drug-treateddiabetic
Diet-treateddiabeticNon-diabetic
Cha
nge
in B
MI (
kg/m
2 )Weight control is more difficult to Weight control is more difficult to
achieve in patients with type 2 diabetesachieve in patients with type 2 diabetes
p<0.01vs non-diabetic
UK Orlistat Multimorbidity UK Orlistat Multimorbidity Study Improvements in risk Study Improvements in risk
factorsfactorsTotalChol
LDLChol
SysBP
DiasBP
OGTTScore
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<0.05All differences at least p<0.05
Orlistat-SummaryOrlistat-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
Liraglutide Astrup Lancet Liraglutide Astrup Lancet 20092009
• 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 9.9 (NS)
• 69% vs 49% lost > 5% weight at 2 yrs
Topiramate/Phentermine-Topiramate/Phentermine-QnexaQnexa
• 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%)
TesofensineTesofensine• 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
BBuupprrooppiioonn
CCoommbbiinnaattiioonnss--UUnnddeerr
RRVV FFDDAA
• 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 II, Phase III awaited
PramlintidePramlintide• With Metreleptin-Phase II, 12.7% WL
at 20/52• With Sibutramine• With Phentermine• With Exenatide
Summary-DrugsSummary-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
Adiposity signallingAdiposity signalling
Schwarz Nature vol 404 6 April 2000
The hypothalamus in weight The hypothalamus in weight controlcontrol
Schwarz Nature vol 404 6 April 2000
Integrating adiposity and Integrating adiposity and satiety signalssatiety signals
Schwarz Nature vol 404 6 April 2000
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