03-Apr-17

1

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

03-Apr-17

2

-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

03-Apr-17

3

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.

03-Apr-17

4

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.

03-Apr-17

5

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

03-Apr-17

6

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

03-Apr-17

7

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

03-Apr-17

8

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

03-Apr-17

9

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