Bariatric Surgery- Insight into pathophysiology of Obesity ...
03-Apr-17 - Healthed 1 Managing Obesity ... Genetics and pathophysiology of human obesity. ......
Transcript of 03-Apr-17 - Healthed 1 Managing Obesity ... Genetics and pathophysiology of human obesity. ......
03-Apr-17
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Managing Obesity Beyond Lifestyle – Drugs,
Surgery and Other Evidence-based Options
Professor John B Dixon
Head of the Clinical Obesity Research Laboratory
Baker Heart and Diabetes Institute, Melbourne
National Obesity Forum – Sydney - Wednesday 29 March 2017
Apollo Endosurgery Consultant
Bariatric Advantage Consultant
BUPA Research Support
I-Nova Consultant
Medtronics Consultant
Nestle Health Science Consultant
NHMRC Research Support
Nova Nordisk Advisory board and speaker fees
Novartis Advisory board and speaker fees
RACGP Research Support
ResMed Research Support
Disclosures: Professor John B Dixon
Lifestyle interventions are fundamental to managing and preventing chronic disease
Cardiovascular risk – end organ damage and complications
But CDM - vascular intervention, pharmacotherapy, and devices have revolutionised health outcomes
Type 2 diabetes – end organ damage and complications
But CDM – statins, blood pressure control, glycaemic control have revolutionized health outcomes
Dyslipidaemia – end organ damage and complications
Pharmacotherapy – Statins, Fibrates and PCSK-9 inhibitors – are so superior to lifestyle
Obesity- end organ damage and complications
Now this is where lifestyle is so good? NOT - for the majority weight loss in minimal and poorly sustained
What I will cover
The complex determinants of obesity
The Brain is the key organ in the control of energy balance
Obesity is a disease of central dysregulation of energy balance
Why to be successful we must have therapies beyond lifestyle
• Very low energy diets
• Drug therapy
• GI devices
• Bariatric-metabolic surgery
The complex determinants of obesity: Nature and Nurture
Type Correlation
Men
Correlation
Women
Monozygotic
Reared apart
Reared Together
0.70
0.74
0.66
0.66
Dizygotic
Reared Apart
Reared Together
0.15
0.33
0.25
0.27
Early life programming is critical and we now focus on the first 1000 days following conception
Contributors beyond the BIG TWO
Reduced smoking rates
Infection and obesity
Epigenetic
Intrauterine and intergenerational effects
Maternal age
Non-random mating
Sleep debt
Endocrine disrupters
Iatrogenic
Ambient temperature
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-12
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24
Time (Weeks)
Ch
an
ge
fro
m B
as
eli
ne
(%
)
Placebo
Phentermine
Topiramate
Qnexa
Me
an %
We
igh
t Lo
ss
Weeks
-11%
-10%
-9%
-8%
-7%
-6%
-5%
-4%
-3%
-2%
-1%
0%
4 8 12 16 20 24
Study Week
Mean
Weig
ht
Lo
ss
Look at the groups that did not get effective therapy – Diet & Exercise and a placebo therapy
Effect of different feeding regimens on body weight in ratsWeight trajectories are set early in life and are difficult to change
Effect of tube feeding 50% excess (obese) and 20% deficit (thin) calories compared with pair-fed (average) and free feeding (control) animals on body weight.
Tube feeding stopped
Reference: Porte et al. Diabetologia 1998;41:863–81
The homeostatic response to calorie restriction in WT and MC4R-/-
Butler, A. A., et al. (2001). "Melanocortin-4 receptor is required for
acute homeostatic responses to increased dietary fat." Nat Neurosci4(6): 605-611.
Normal weight mouse and response to dietary restriction followed by two cycles of dietary restriction – Note the rapid correction of weight loss
Melanocortin-4 receptor KO mouse is obese because a pathway to control excessive weight gain is blocked, but weight loss still generates the homeostatic return to the much higher weight.
The balance between anabolic and catabolic pathways!
Both pathways can be altered to respond to over and under feeding, but the bias is to actively respond to weight loss
This response is physiologically essential and of
course supports survival
Genetics and pathophysiology of human obesity.
Annu Rev Med. 2003;54:453-471
The balance between anabolic and catabolic pathways!
Both pathways can be altered to respond to over and under feeding, but the bias is to actively respond to weight loss
This response is physiologically essential and of
course supports survival
Proietto, J. (2011). "Why is treating obesity so difficult? Justification for the role of bariatric surgery." Med J Aust 195(3): 144-146
“We have 9 hormones to switch off hungerAnd just one to turn it on”
Schematic diagram showing the major factors determining neural control of appetite and regulation of energy balance
Huiyuan Zheng, and Hans-Rudi Berthoud Physiology 2008;23:75-83
Unfortunately a rise in weight (fat) is defended
just as a rise in blood pressure is defended
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Oh, if it were as simple as energy in energy out and will power!
This notion is fundamentally flawed, for one simple reason: it assumes that weight is the “dependent” variable in this equation.
Indeed, everything we know about human physiology points to the fact that it is as much (if not more) body weight itself that determines energy intake and output as vice versa.
Controversies in ObesityHaslam, David W., Sharma, Arya M., le Roux, Carel W. (Eds.)
First law of thermodynamics – Conservation of energy True
Biological systems are regulated
Decreased energy expenditure with weight loss
There is a 20% increase in muscular efficiency and a change in fuel
preference to efficient fat burning. Fuel efficient at low levels of
activity
Goldsmith, R., D. R. Joanisse, et al. (2010). Am J Physiol Regul Integr Comp Physiol 298(1): R79-88.
Adaptive thermogenesis – our patients feel the cold but do not
adapt by moving they just layer up and turn the thermostat higher
Muller, M. J. and A. Bosy-Westphal (2013). "Adaptive thermogenesis with weight loss in humans." Obesity (Silver Spring) 21(2): 218-228.
Reduced sympathetic tone
Reduced thyroid function T3 and T4
Rosenbaum, M., et al. (2005). J Clin Invest 115(12): 3579-3586.
Reduced resting energy expenditure, and voluntary and involuntary movement energy expenditure
In the weight loss state
Perceptions of fullness are altered and more is needed to satisfy
Perceptions of how much is consumed is also altered – you perceive to have eaten less
Reward pathways are sensitized – food tastes great
There is an increase in emotional response to food and reduced cognitive restraint
These effects can be shown on using visual cues and fMRI
Weight loss - Activation in attention, visual processing, reward and memory regions in
response to receipt and anticipated receipt of palatable food relative to those in neutral
or positive energy balance.
Rosenbaum, M., M. Sy, et al. (2008). J Clin Invest 118(7): 2583-2591
Stice, E., et al. (2013). Neuroimage67: 322-330.
Results confirm that self-imposed caloric deprivation increases responsivity of attention, reward, and
motivation regions to food, which may explain why caloric deprivation weight loss diets typically do not
produce lasting weight loss.
Obesity a disease of central dysregulation of energy balance
FAT TEMPERATURE BLOOD PRESSURE
Dose response curve“A change in regulation”
LEAN
Satiety
OBESE
Bariatric-metabolic surgery and drugs
Meal Size
Physio
logic
al
range
Miras, A. D. and C. W. le Roux (2013). Nat Rev Gastroenterol Hepatol 10(10): 575-584.
VLCD Program < 800 kcal/ dayVery low calorie diets
Average VLCD (replacing 3 meals/day) typically provides:
Energy: 1.9 – 2.6 MJ/day
Carbohydrate: 45 – 60g Carbohydrate distributed evenly throughout the day
Protein: 50 – 60g Protein/day
VLCD are designed to meet 100% daily recommendations for vitamins, minerals, trace elements and essential fatty acids.
VLCD’s are designed to promote ketosis – using fat stores for energy in preference to carbohydrate, while providing nutritional adequacy with a reduced kilojoule intake.
The production of ketones reduces hunger.
Therefore any additional food (i.e. allowed foods) should be very low / no carbohydrate.
Foods containing carbohydrate should be re-introduced in a structured way during transitional phases of management.
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Indications
Adults with:
▪ BMI >30kg/m2
▪ BMI >27kg/m2 with medical co-morbidities
Where rapid weight loss is desired (eg. pre-surgery)
Contraindications
Pregnancy
Older age (Relative)
Recent MI or unstable angina
Organ failure
Severe psychological disturbance
Alcohol/illicit drug abuse
Caution: Type 1 diabetes, Gout, Impaired renal function.
Who is suitable for a VLCD program?
Precautions: Knowledge of the how to modify their use is important in managing some comorbidities.
Non surgical weight loss therapy
Results at 4-5 yrs follow-up
VLCDWeight-loss maintenance :
7.1 kg (95% CI: 6.1, 8.1 kg)
Percentage weight-loss maintenance:
29% (25%, 33%)
Reduced weight:
6.6% (5.7%, 7.5%)
LED
2.0 (1.5, 2.5) kg
17% (13%, 22%);
2.1% (1.6%, 2.7%).
Anderson, J. W et al. Am J Clin Nutr 2001;74:579-584
Common adverse events - Complications
Dry mouth
Constipation
Head aches, dizziness and fatigue
Orthostatic hypotension
Cold intolerance
Dry skin
Menstrual irregularities
Hair loss (10%) of patients
Ketosis – Halitosis
Muscle cramping
Anemia
Cholelithiasis
Increase Uric acid - gout attacks (rare)
Bone mineral loss
Acute psychosis (rare)
Decreased Metabolic rate
Decrease voluntary exercise
Early
Late
Phase II- Weight Stabilization
Re-calculate daily energy requirement (minus 300 calories).
Aim for weight maintenance eating a wide variety of foods.
Expect 1-2kg weight regain as glycogen stores are replenished in muscle and liver.
Cefalu WT, Bray GA, Home PD, et al. Diabetes care. Aug 2015;38(8):1567-1582.
Medications
Pharmacotherapy used in obesity management in Australia.
Drug Starting dose Available doses Weight loss vs
placebo (% or kg)
Side effects Contraindications
Phentermine 15mg 15 – 30 – 40mg 3.6 kg at 6
months
Dry mouth, insomnia, agitation,
constipation, and tachycardia.
Severe hypertension, cardiovascular
disease, glaucoma, history of
drug/alcohol abuse, MAO inhibitors, SSRI
use, pregnancy.
Orlistat 120mg TDS 120mg 2.9–3.4% at 1
year
Steatorrhea, oily spotting, flatulence
with discharge, faecal incontinence,
fat-soluble vitamin malabsorption.
Pregnancy.
Liraglutide 0.6mg 0.6 - 3.0mg 5.4% at 1 year Nausea, vomiting, diarrhoea,
constipation
Rare: Pancreatitis, cholecystitis
Severe renal or hepatic insufficiency,
pregnancy, past history of pancreatitis
and major depression or psychiatric
disorder.
Off-label pharmacotherapy (not approved by TGA for weight loss)
Topiramate 12.5 mg mane 25 – 50 – 100 mg 3.4 – 5.0 kg Paraesthesia, dry mouth,
constipation, altered taste
sensation, insomnia, dizziness,
cognitive effects.
Rare: closed angle glaucoma,
depression/suicidal ideation
Glaucoma, renal stones, pregnancy (if
used for weight loss)
Phentermine
(Phe)/ topiramate
(Top)
Phe 15 mg mane
Top. 12.5 mg
mane
Phe. 15 mg
Top. 12.5 – 25 – 50
– 100 mg
5 - 6.6% at 1
year
Side effects of phentermine and
topiramate.
Contraindications to phentermine or
topiramate.
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0
5
10
15
20
0 2 4 6 8 10 12Time (months)
Wei
ght
Loss
(%
)
Medication, behavior modification and meal replacements
*
*
Additive Effects of Behavior and Meal Replacement Therapy With
Pharmacotherapy for Obesity
*P<0.05 vs medication alone.Wadden et al. Arch Intern Med 2001;161:218.
Medication and behavior modification
Medication alone
Medication, behavior modification and meal replacements
Pharmacotherapy
-12
-9
-6
-3
0
Effect of Long-term Orlistat Therapy on Body Weight
0
Weeks
52
Torgenson et al. Diabetes Care 2004;27:155
Ch
ange
in W
eigh
t (k
g)
104 156 208
P<0.001 vs placebo
-4.1 kg
-6.9 kg
Placebo
Orlistat
Li, Z. et. al. Ann Intern Med 2005;142:532-546
Weight loss with orlistat versus placebo at 12 months
Phentermine
It is primarily a central acting sympathomimetic
It’s effects on dopamine and serotonin are trivial
Therefore it has little addictive potential
While it may be expected in some to raise blood pressure there is no clear evidence that it does so
No evidence of increased CV risk
There is generally the expected fall in BP associated with weight loss
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Phentermine Treatment
Start with Duromine 15 mg or 30 mg.
Most adult patients tolerate 30 mg/day.
Evaluate for adverse effects.
Evaluate for effectiveness
▪ Weight loss
▪ Eating behavior
Titrate dose to effectiveness
▪ Tachyphylaxis with lower effect
▪ Higher doses can be used
Side Effects
Common
▪ Dry mouth - usually tolerable
▪ Insomnia – typically fades quickly
▪ Increased energy
▪ Other anti-cholenergic effects – e.g. constipation
Less Common
▪ Impotence, decreased sex drive
▪ Irritability
▪ Mood elevation
If phentermine is effective and there are no adverse effects it can be continued – If not at intermediate to high CV risk
Liraglutide
Saxenda, Novo Nordisk
Status: Approved Australia 2016
Weight Loss 1 Year: -7%
Mechanism of action: Glucagon-like-protein receptor (GLP-1R) agonist. Decreased energy uptake.
Responder rate (≥10% wt. loss): 33%
Synthesis and Secretion of GLP-1
L-Cell
(ileum)
ProG
GLP-1
M Nauck, Diabetologia, 2010
GLP-2OXNTPYY
Liraglutide – SaxendaMean change in body weightBy prediabetes status: 0-56 weeks
-12
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Change in b
ody w
eig
ht
(%)
Weeks
LOCF
LOCF
Adapted from: Pi-Sunyer X et al. NEJM 2015;373:11–22; Saxenda® Approved Product Information, December 2015
Liraglutide 3.0 mg Placebo
Liraglutide 3.0 mg Placebo
Normoglycaemia:
With prediabetes: c
Data are observed means with standard error bars, and the symbols at the right represent the 56-week weight change using LOCF imputation
LOCF, last observation carried forward
-2.59
-2.68
-7.92-8.01
AEs reported in ≥5% of individuals0–56 weeks
0 20 40 60 80 100
Lipase increased
Hypoglycaemia
Constipation
Abdominal pain upper
Abdominal distension
Abdominal pain
Dyspepsia
Vomiting
Diarrhoea
Decreased appetite
Flatulence
Nausea Liraglutide 3.0 mg
Liraglutide 1.8 mg
Placebo
6.6
27.8
6.1
0.9
1.4
4.2
2.4
5.7
12.7
1.9
1.9
13.7
Placebo
%
% of individuals
11.8
44.3
16.1
3.6
6.2
6.2
11.1
15.6
25.6
9.5
5.2
32.7
%
Liraglutide3.0 mg
10.5
40.0
9.5
6.7
31.4
4.8
1.9
6.7
10.0
17.6
11.0
3.8
Liraglutide1.8 mg
%
Davies MJ et al. JAMA 2015;314:687–99
Safety analysis set
AE, adverse event
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Topiramate
Approved for seizures in 1996
Approved for migraine prevention in 2004
Mono-therapy not approved for obesity
Doses
▪ Epilepsy: 400 mg/day
▪ Migraine prevention: 25 - 100 mg/day
▪ Obesity: 25 – 100 mg/day
Starting Rx 12.5 - 25 mg/day, titrate dose slowly
Start low and go slow
Topiramate Weight Loss by Week
Bray, Obes Res. 2003;11(6):722-33
Meta-analysis of Topirimate RCTs Topiramate, ASEs
Paraesthesias, Dysgusia
Attention difficulty, Memory loss
Fatigue, Somnolence
Depression, Anxiety, Suicidal Ideation
Acute Myopia & Angle Closure Glaucoma
Increased risk of oral clefts if taken during pregnancy in first trimester
Note this is off label for weight management
Neoh, S. L., et al. (2014). "Combination phentermine and topiramate for weight maintenance: the first Australian experience." Med J Aust 201(4): 224-226.
Emerging Anti-obesity Drugs and Drug Combinations
Phentermine and topiramate
Lorcaserin, a selective 5-HT2C receptor agonist
Naltrexone + bupropion (-2.2 Kg)
(-5.3 Kg)
(-6.6 Kg)
(-11.4 Kg) *-12
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24
Time (Weeks)
Ch
an
ge
fro
m B
as
eli
ne
(%
)
Placebo
Phentermine
Topiramate
Qnexa
* <0.0001 vs. placebo and each active component
Qsymia®: 24 Week Weight Loss
(-2.2 Kg)Placebo
(-5.3 Kg)Phentermine
(-6.6 Kg)Topiramate
(-11.4 Kg) *Qnexa®
http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933
Topiramate and Phentermine (ITT)
42
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Contrave™ COR-I Phase 3
Mean Weight Loss 56 Weeks – Completer Population
Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4.
Naltrexone SR/Bupropion SR
43
Behavioral Modification and Lorcaserin for Obesity and Overweight Management (BLOOM)
Lorcaserin (Lorc) vs placebo (PBO): P < .0001 at all timepointsLorc/Lorc vs Lorc/PBO: P < .0001 at all year 2 timepoints
8 16 24 32 40 48
-10
-8
-6
-4
-2
064 72 80 88 96 104
Lorc/LorcPBO/PBO Lorc/PBO
ITT/LOCF
ITT/LOCF
Per
Protocol
Study Week
Weig
ht
ch
an
ge (
kg
)
N = 344 N = 140 N = 308
Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.
Current accepted bariatric-metabolic surgical procedures
This has always been a clear message from non-surgeons
All have their own risks and benefits
There are now multiple new “diabetes” procedures, however in Australia we appear to be largely followers not leaders in new self-styled variants
Diabetes Care 2016;39: 861–877
AGB-Adjustable gastric band SG – Sleeve Gastrectomy RYGB- Roux-en Y Gastric Bypass
Description Adjustable silicone band placed just below the
gastroesophageal junction, apply gentle pressure that
supresses hunger. Level of restriction can be adjusted by
varying the amount of fluid placed in the band.
Greater portion of the fundus and body of the stomach
is removed. Gastric volume is reduced by about 80%.
Combination procedure:
1. Small stomach pouch created, thereby reducing gastric
volume
2. This pouch is joined to the jejunum, hence diverting
nutrients from lower stomach, duodenum and proximal
jejunum.
Mean total body weight loss 17-20% 20-30% 25-35%
Mortality rate (at 30 days) 0.03-0.1% 0.3-0.5% 0.1-0.4%
Morbidity at 1 year 4.6% 10.8% 14.9%
Nutritional concerns Low (deficiencies in iron, vitamin B12, folate, thiamine) Moderate (deficiencies in iron, vitamin B12, folate,
calcium, vitamin D, thiamine, copper, zinc)
Moderate (deficiencies in iron, vitamin B12, folate,
calcium, vitamin D, thiamine, copper, zinc)
Advantages Effective, with good long term weight maintenance.
Degree of restriction adjustable.
Reversible.
Lowest morbidity and mortality rate.
Very effective with good mid-term weight
maintenance.
Largest amount of weight loss with good long-term weight
maintenance.
Highest rate of diabetes remission (for patients with pre-
existing T2DM).
Disadvantages and key complications Highest long-term reoperation rate.
Gastric pouch dilatation, erosion of band into the
stomach, leaks to the AGB system, weight regain.
Staple line leak, gastroesophageal reflux disease,
dilatation of the gastric remnant, weight regain.
Poor long term data.
Staple line leak, dumping, stomal ulcer, intestinal
obstruction, gallstones, nutritional deficiency, weight
regain.
Adapted from: Dixon, JB et al. Bariatric surgery for type 2 diabetes. Lancet, (2012). 379(9833): p. 2300-11.
National and international guidelines for eligibility for bariatric surgery (adults)
The guidelines above are qualified by the following common elements: Appropriate
Non-surgical weight loss measures have been tried and failed; there is the provision
for, and a commitment to, long term follow-up; and individual risk to benefit ratio
needs to be evaluated
NIH (USA) NICE (UK) European ADA (USA) SIGN (Scotland) NHMRC (Australia)
Year 1991 2006 2007 2010 2010 2013
Recommended >50
Eligible (A):BMI >40 >40 >40 >40 >40
Eligible (B):BMI 35 - 40 with 1
serious weight
loss responsive
comorbidity
35-40 with
disease that
could improve
with weight loss
35 - 40 with 1
weight loss
responsive
comorbidity
35-40 if control
of diabetes and
comorbidity is
difficult
>35 with 1 serious
weight loss responsive
comorbidity
35 - 40 with 1
serious weight loss
responsive
comorbidity
Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes
Algorithm for the treatment of T2D, as recommended by DSS-II voting delegates
Diabetes Care 2016;39: 861–877
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Sjostrom, L. (2012). J Intern Med.
14 studies; 29,208 underwent bariatric surgery and 166,200 nonsurgical controls
Kwok CS et al. Int J Cardiol 2016
Hazard Ratio
0.6 (0.34 to 0.74)
50% reduction in CV deaths
50% reduction in cancer deaths
Bariatric-Metabolic Surgery
Sustained weight loss
Stunning safety profile – A shock
Sustained comorbidity change
QOL and psychosocial outcomes
Reduced mortality
Health economic – return on investment
Issues of equity and chronic disease follow-up
Who should be prioritized?
Conclusion: Take home messages
The Brain has a key role in the control of energy balance
Obesity is a complex disease of central dysregulation of energy balance
Lifestyle change can generate little sustained weight loss for the majority of obese people – Reason Physiology – Not lack of willpower or compliance
Effectively treating obesity means going beyond the lifestyle mantra
Diet Physical Activity
Pharmacotherapy
Surgery
Lifestyle Modification
Diet Physical Activity
Lifestyle Modification
Combination Pharmacotherapy
Surgery
DevicesLap Band
Endobarrier
Diet Physical Activity
Lifestyle Modification
Combination Pharmacotherapy
Obesity Treatment Pyramid
Current Interim Future
Chronic Care Management Model
3. Self-Management
Support
4. Delivery 5. Decision 6. Clinical
System Support Information
Design Systems
2. Health SystemHealth Care Organization
1. CommunityResources and Policies
Informed,
Activated
Patient
Prepared,
Proactive
Practice TeamProductive Interactions
Improved
Outcomes
Wagner, E.H. Chronic Disease Management: What Will It Take to Improve Care for Chronic Illness? Effective Clinical Practice 1998; 1:2-4.
Right thing
Right patient
Right time