Are drugs of any use in obesity management? Current and ...dwj9ys9q38f10.cloudfront.net/wp-content/... · Liraglutide 3.0 mg + diet and exercise 72% completed 56 weeks of treatment

The University of Sydney Page 1

Pharmacotherapy for

Obesity – Important New

Options

Are drugs of any use in

obesity management?

Presented by

Associate Professor Samantha Hocking

Sydney Medical School


– Obesity Advisory Board for Novo Nordisk and Inova

– Advisory Boards for Novo Nordisk, Lilly and Astra Zeneca

– Honoraria from Novo Nordisk, Astra Zeneca, Lilly, Boehringer

Ingelheim, Sanofi, Inova and Merke Sharp and Dohme

– Research support from Novo Nordisk and GSK

Conflicts of Interest


Key Learning Objectives

– Greatest challenge in obesity management is maintainingweight loss

– Few individuals successfully maintain weight loss with lifestyle

– Modest weight loss has metabolic benefit

– Pharmacotherapies for obesity in Australia

Phentermine Liraglutide

Orlistat Bupropion / Naltrexone

Prepare patients for side-effects & explain mechanism of action & expected weight loss


Maintaining weight loss is the greatest challenge in

obesity management

Franz et al. J Am Diet Assoc 2007:1755-1767


Why do most people tend

to regain weight after

weight loss?

5


6

The University of Sydney Page 750 patients who were overweight or had obesity lost weight on a 10-week very-low-calorie diet

References: 1. Sumithran P et al. N Engl J Med 2011; 365:1597–604.

7

Long-term persistence of hormonal adaptations to weight loss:

fasting hormonal changes


The result of hormonal adaptations to weight loss

– Increase in appetite

– Increase in preference for high-calorie food

– Reduction in energy expenditure

– Increased propensity to store fat

– Weight regain

8


Australian algorithm for the management of obesity

https://diabetessociety.com.au/documents/ObesityManagementAlgorithm18.10.2016FINAL.pdf The University of Sydney Page 10

Goal of weight loss: BMI centric vs complications centric

Increase

lifespan

Type 2 diabetesNon-alcoholic fatty

liver disease

Pulmonary embolism

HypertensionCoronary artery disease

Congestive heart failure

Cancer (various)Acid Reflux Disease

Asthma

OsteoarthritisGout

Back pain

Gallbladder disease

StrokeCognitive impairment

Depression

Sleep apnoea

Guh, DP et al. BMC Public Health 2009; 9:88

Improve

health

Improve

QOL


-20-15-10-50

Diabetes (Prevention)

Hypertension

Dyslipidaemia

Hyperglycaemia (elevated HbA1c)

Non-alcoholic fatty liver disease

Sleep apnoea

Osteoarthritis

Stress incontinence

Gastroesophageal reflux disease

Polycystic ovary syndrome

Health-related quality of life

Weight loss required for therapeutic benefit (%)

Obesi

ty c

om

plica

tion

Maximum benefit at 10%

Triglycerides still decreasing at >15%

HbA1C still decreasing at >15%

Improves steatosis, inflammation, and mild fibrosis

Improves symptoms and joint stress mechanics

5–10% in women; 10% in men

>10% optimal; lowers androgens, improves

ovulation, and increases insulin sensitivity

Continues to improve with weight-loss

Blood pressure still decreasing at >15%

Cefalu WT et al. Diabetes care 2015;38(8):1567-82.

Wright F et al. J Health Psychol. 2013;18:574-86.

‘dose-response’ relationships between weight loss

and obesity-related complications


1. Life-long lifestyle modification

– Weight loss maintainers from the National Weight Control Registry (NWCR)

• Moderate exercise for >60 min each day

• Low energy diet (1400 – 1700 kcal/day)

• Frequent self-monitoring of weight

2. Lifestyle modification plus pharmacotherapy

– Orlistat

– Phentermine

– Liraglutide 3mg

3. Surgery (endoluminal therapies)

– Not accessible for all

– Not desirable for all

Treatment options for Australians with obesity

Catenacci VA et al. Obesity 2008;16:153


Registered anti-obesity medications in Australia

1. Duromine™ Approved Product Information, July 1991. 2. Contrave Approved Product Information, August 2018.3. Xenical® Approved Product Information, April 2000. 4. Saxenda® Approved Product Information, December 2015

• Registered in 2000

• Inhibits intestinal lipase to reduce fat absorption

Orlistat3

• Registered in 1991/ 2004

• Sympathomimetic amine

• Appetite suppression

Phentermine1

Liraglutide 3.0 mg4

• Registered December 2015

• GLP-1 analogue

• Central action to reduce hunger

Naltrexone /

Bupropion2

• Registered August 2018

• Anti-addiction therapies

• Central action to reduce hunger & cravings

-4%

-6%

-6%

% Weight

loss

-5%


Liraglutide 3.0 mg – mechanism of action

Hypothalamus:Appetite regulation

Liraglutide lowers body weight through decreased caloric intake and loss of predominantly fat mass Prospective food

consumption

Fullness

Hunger

Energy intake

Satiety

Saxenda® Approved Product Information, December 2015


Liraglutide 3.0mg as an adjunct to lifestyle

modification over 52 weeks

Week

Change in w

eig

ht

from

baseline (

%)

p<0.0001

-8.0%

-2.6%

-9.2%

-12

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

-3.5%

Liraglutide 3.0 mg + diet and exercise72% completed 56 weeks of treatment

Diet and exercise alone64% completed 56 weeks of treatment

p<0.001

Adapted from Pi-Sunyer 2015. Circle represents weight-loss at week 56 using Last Observation Carried Forward

(LOCF) imputation. Square represents weight-loss at week 56 using completer data set

Pi-Sunyer X et al. N Engl J Med 2015;373:11–22. Saxenda® Approved Product Information, December 2015

Mean baseline weight: 106 kgMean baseline BMI: 38.3


-12

-10

-8

-6

-4

-2

0

0 16 28 40 56 68 80 92 104 116 128 140 152 160 172

Effect of liraglutide 3.0 mg on weight loss in individuals with

prediabetes over 3 years0–172 weeks

778

320

-2.1%

-5.2%

Full analysis set, fasting visit data only. Line graphs are observed means (±SE).

LOCF, last observation carried forward; SE, standard error; ETD, estimated treatment difference

Mean baseline weight:

108 kg

1467 1295 1223 1161 1100 1030 971 885 849 830 780805911

734 635 576 544 508 465 436 375 365 354 327336399

n=

n=

747

322

Change in w

eig

ht (%

)

Observed mean LOCFObserved mean LOCF

Off-drug follow-up Off-drug follow-up

Liraglutide 3.0 mg Placebo

Week

-1.9%

-6.1%

ETD at week 160:

–4.3%

[–4.9; –3.7]

p<0.0001

-9.2%

-3.5%

-8.5%

-3.4%

-7.1%

-2.7%

le Roux et al. Lancet 2017; 389: 1399–409

45% completed the study


Obesity and prediabetespopulation achieved at week 561,2

Diabetes populationachieved at week 561,3

Obstructive sleep apnoea population achieved at week 321

p<0.0001 p<0.0001

Treatment arm = Liraglutide 3.0 mg plus diet and exercise;

Placebo = diet and exercise alone; Data are for patients in the full analysis set, with last observation carried forward; Changes

from baseline are estimated mean weight loss

63% 26.6%- VS - 50% 13.5%- VS -

p<0.0001

46% 18%- VS -

p<0.0001 p<0.0001

33% 10%- VS - 23% 4%- VS -

p<0.0001

22% 1.5%- VS -

p<0.001

14% 3.5%- VS -

1. Saxenda® Approved Product Information, December 2015 2. Pi-Sunyer X et al. N Engl J Med 2015;373:11–22.3. Davies ML et al. JAMA. 2015;314(7):687–699.

Weight loss achieved

≥5%


>10%


>15%

SCALE program – Liraglutide 3.0 mg


Fujioka K et al. Obesity. 24; 2278–2288, 2016.


Liraglutide – safety and tolerability

– Subcutaneous injection – 0.6 mg – 3.0 mg once daily

– Gastrointestinal side-effects

– Nausea and vomiting

– Gall bladder related events

– Elevated amylase and lipase levels

– Pancreatitis?

– Stopping rule if insufficient weight loss after 3 months on max. dose

α-MSH=α-melanocyte-stimulating hormone; MC4-R=melanocortin-4 receptor; POMC=proopiomelanocortin.

Billes SK et al. Pharmacol Res. 2014;84:1-11.

Hypothalamus

MC4-R

α-MSH▪ Released from POMC neuron▪ Binds to MC4-R to decrease food intake

↓ Appetite↑ Energy Expenditure

α-MSH

POMC neurons▪ Integrate multiple

energy balance signals

POMC neuron

β-endorphin (endogenous opioid)▪ Released from POMC neuron with α-MSH▪ Binds to µ-opioid receptor to inhibit POMC activation

µ-opioid receptor

POMC negative feedback loop

Naltrexone + bupropion – mechanism of action

Bupropion directly increases POMC activity

Naltrexone blocks negative feedback loop


Effect of naltrexone + bupropion* on weight

loss in overweight and obese adults (COR-I)

Completers, LOCF

analysis

Greenway FL, et al. Lancet 2010;376:595–605.

*

Wei

ght

chan

ge f

rom

bas

elin

e (%

)

–6.7%

–8.1%

p=0.0079*p<0.0001 vs. placebo

*

*

**

**

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

−10

−8

−6

−4

−2

0

Week0 4 8 12 16 20 24 28 32 36 40 44 48 52 52

–1.8%

Placebo (n=511)

NB16 (n=471)

NB32 (n=471)

* Fixed dose combination not TGA approved for obesity in Australia


*P<0.01 vs placebo; **P<0.001 vs placebo.

BMOD=behavior modification; DM=diabetes mellitus;

ITT=intent-to-treat;

LOCF=last observation carried forward; LS=least squares.

Greenway FL et al. Lancet. 2010;376:595-605. Wadden TA et al. Obesity. 2011;19:110-120. Hollander P et al. Diabetes Care. 2013;36:4022-4029.

Naltrexone / Bupropion Clinical Trial Program


Naltrexone + bupropion – safety and tolerability

– Oral medication given twice a day

– Titrate from 1 to 4 tablets with weekly dose increases

– Contraindications: chronic opioid use, seizure disorder, HT, Bipolardisorder, severe haptic impairment, severe renal impairment

– Side-effects

– Nausea, vomiting, constipation

– Headache

– Insomnia

– Dry mouth

– Stopping rule if insufficient weight loss after 16 weeks



Key Learning Objectives

– Greatest challenge in obesity management is maintainingweight loss

– Few individuals successfully maintain weight loss with lifestyle

– Modest weight loss has metabolic benefit

– Pharmacotherapies for obesity in Australia

Phentermine Liraglutide

Orlistat Bupropion / Naltrexone

Prepare patients for side-effects & explain mechanism of action & expected weight loss


Thanks for your attention

Documents

Are drugs of any use in obesity management? Current and ...dwj9ys9q38f10.cloudfront.net/wp-content/... · Liraglutide 3.0 mg + diet and exercise 72% completed 56 weeks of treatment