are drugs of any use in obesity...

The University of Sydney

Are drugs of any use in obesity management?Current and emerging pharmacotherapy for obesity

Presented byAssociate Professor Samantha HockingSydney Medical School


– Obesity Advisory Board for Novo Nordisk

– Honoraria from Novo Nordisk

– Research support from Novo Nordisk

Conflicts of Interest


Maintaining weight loss is the greatest challenge in obesity management

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


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 people with obesity

Catenacci VA et al. Obesity 2008;16:153


Treatment options for weight management and recommendations

Treatment intensification

Low

Mea

n w

eigh

t lo

ssH

igh

Med

ium

BMI 25-26.9

BMI 27-29.9with risk factors and/or

comorbidities orBMI > 30

Grima M and Dixon JB AFP 2013;42(8):532-41; National Health and Medical Research Council (2013) Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. Melbourne: National Health and Medical Research Council.

Lifestyle & Behavioural changes: Healthy eating, physical activity and psychological intervention

Reduced calorie diet/Very Low Energy diet

Anti-obesity medications with weight loss of 5–10%

Bariatric surgery

BMI 35-39.9with risk factors and/or

comorbidities orBMI ≥40


Approved anti-obesity medications in Australia

1. Duromine™ Approved Product Information, July 1991. 2. Metermine Approved Product Information, July 2004. 3. Xenical® Approved Product Information, April 2000

• Approved in 2000• S3• Private script; available on the PBS under the Repatriation

Pharmaceutical Benefits Scheme• Potent, specific and reversible long acting inhibitor of

gastrointestinal lipases required for the systemic absorption of dietary triglycerides

Xenical® (Orlistat)3

• Approved in 1991/ 2004• S4 • Private script• Sympathomimetic amine

Duromine™ / Metermine(Phentermine)1,2


Approved anti-obesity medications in Australia

• Approved December 2015• S4• Liraglutide is a human glucagon-like peptide (GLP-1)

analogue, with 97% amino acid sequence homology to endogenous human GLP-1

• Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor (GLP-1R)

• GLP-1 is a physiological regulator of appetite and calorie intake

Saxenda® (Liraglutide 3.0 mg)

Saxenda® Approved Product Information, December 2015


Orlistat – mechanism of action

C. S. Elangbam. Vet Pathol. 46, 10, 2009


4-Year RCT of orlistat as an adjunct to lifestyle for the prevention of type 2 diabetes in obese at-risk patients

Torgerson JS, et al. Diabetes Care. 2004;27:155–161.

“DPP-type”intervention:

–3.0kg

Orlistat +“DPP-type”intervention:

–5.8kg

DPP=DiabetesPreventionProgram


Orlistat – safety and tolerability

– Oral medication given three times daily– Perceived as a safer option due to its peripheral mechanism of

action in the intestinal lumen.– Unpleasant gastrointestinal side effects (eg faecal incontinence

and fatty or oily stools).– Rare cases of severe liver injury; potential risk of kidney injury,

pancreatitis and renal stones.


Phentermine – mechanism of action

Dietrich & Horvath . Nature Reviews Drug Discovery 11, 675-691, September 2012


Phentermine: continuous vs intermittent dosing

Munro JF, et al. Br Med J. 1968;1(5588):352–54.


Phentermine – safety and tolerability

– Oral medication given once daily – 15mg / 30mg / 40 mg

– Recommended for short-term use – 12 weeks.

– Cardiovascular side effects: hypertension and tachycardia

– Dry mouth

– CNS side effects: insomnia, restlessness, alters sexual behaviour,

hormonal secretion and mood.


Phentermine/topiramate – mechanism of action

Kim GW, et al Clinical Pharmacology & Therapeutics. doi: 10.1038/clpt.2013.204 Dietrich & Horvath . Nature Reviews Drug Discovery 11, 675-691, September 2012


Phentermine/topiramate – mechanism of action


Topiramate not TGA approved for obesity in Australia


Phentermine with topiramate – Australian experience

Neoh, S et al. MJA. 201, 224-226, 2014

40% ceased therapy due to adverse effects


Phentermine with topiramate – Australian experience

Neoh, S et al. MJA. 201, 224-226, 2014


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

Cha

nge

in w

eigh

t fr

om

base

line

(%)

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

Patients maintained a clinically meaningful weight loss over 56 weeks with liraglutide 3.0 mg

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

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%

Weight loss achieved>10%

Weight loss achieved>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


Phentermine/topiramate fixed dose combination –mechanism of action



Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER)

Gadde et al. Lancet 2011; 377: 1341–52


Effect of phentermine/topiramate extended release on weight loss in obese adults over 2 years: SEQUEL

Garvey WT, et al. Am J Clin Nutr 2012;95:297–308.

-10.5%*

0

–12

–14

–16

–10

–8

–6

–4

–2

Weeks

LS m

ean

wei

ght l

oss

(%)

0 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 LOCF

-1.8%

-9.3%*

*p<0.0001 vs. placebo

Placebo PHEN/TPM ER 7.5/46 PHEN/TPM ER 15/92

Resultsareforthecompleterpopulation;presentedasleast-squaresmean(95%CI).DatatotherightarefortheITTLOCFpopulation.PHEN/TPMER,phentermine/topiramate combinationtherapy;ITT,intenttotreat;LOCF,lastobservationcarriedforward


Phentermine plus topiramate ER – safety and tolerability

– relate to the side effect profiles of its constituent monotherapies

– paraesthesiae

– dry mouth

– dizziness

– generally well tolerated – therapy cessation due to adverse effects of 8-16%

– not recommended in those with recent or unstable vascular disease, significant

depression or active suicidal ideation and is contraindicated in those with

glaucoma and hyperthyroidism.

– Fetal toxicity – pregnancy category X

’– headache

– insomnia

– constipation

..

.


Lorcaserin – mechanism of action

Kim GW, et al Clinical Pharmacology & Therapeutics. doi: 10.1038/clpt.2013.204


Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management (BLOOM)

Smith et al. N Engl J Med 2010;363:245-56


Lorcaserin – safety and tolerability

– Oral medication given twice a day– No titration– Initial rejection: limited efficacy, carcinogenesis, cardiovascular events,

cognitive impairment, and psychiatric disorders– Contraindications: Pregnancy– Warnings:

serotonin or neuroleptic malignant syndromecognitive impairmentpsychiatric disorders,depression, suicidal thoughts, use of antidiabetic medications


Naltrexone + bupropion – mechanism of action

Kim GW, et al Clinical Pharmacology & Therapeutics. doi: 10.1038/clpt.2013.204


Effect of naltrexone + bupropion on weight loss in overweight and obese adults (COR-I)

MITT, LOCFanalysis

GreenwayFL,etal.Lancet2010;376:595–605.

*

Weightcha

ngefrom

baseline(%

)

–5.0%

–6.1%

p=0.0079*p<0.0001 vs. placebo

*

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−10

−8

−6

−4

−2

0

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

–1.3%

Placebo(n=511)NB16(n=471)NB32(n=471)


Naltrexone + bupropion – safety and tolerability

– Oral medication given twice a day– Complex titration algorithm– Contraindications: Pregnancy, chronic opioid use, seizure disorder– Warnings

Suicidal thoughts, suicidal behavior.Neuropsychiatric reactionsIncrease in BP and HRRisk of seizurehepatotoxicityangle-closure glaucomahypoglycemia with use of antidiabetic medications


Placebo adjusted weight loss with pharmacotherapy


0

5

10

15

20

25

30

35

Withdrawals due to AE (% participants)

Participants withdrawing due to adverse effects


Thanks for your attention

are drugs of any use in obesity...

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