AN OVERVEW OF OBESITY and ANTIOBESITY MEDICATIONS WITH

AN EMPHASIS ON CONTRAVE

Nicole Dean, Linh Huynh, and Dhara ShahPharmD candidates 2016, MCPHS University

February 9,2016

OBJECTIVES Identify risk factors and etiology of

obesityAnalyze different pharmacological

therapies for weight managementCompare CONTRAVE with other FDA-

approved anti-obesity drugs

INTRODUCTION⦿Obesity is a chronic disease associated with

excess body fat.⦿Obesity is the leading cause of mortality,

morbidity, disability, healthcare utilization, and healthcare costs in the United States.

⦿Obesity is a major risk factor for the top five diseases: cardiovascular disease, cancer, stroke, and type 2 diabetes.

⦿ In total about 68.8% of Americans are obese or overweight.

Please reference at bottom of slide….each bullet should be

referenced unless these bullets were derived from 1 source

WHO’S OBESE?

1. Obesity Prevalence Maps. (2015). Retrieved January 28, 2016, from http://www.cdc.gov/obesity/data/prevalence-maps.html

WHO’S OBESE? The Midwest had the highest prevalence of obesity (30.7%), followed by the South

(30.6%), the Northeast (27.3%), and the West (25.7%) 1

1. Obesity Prevalence Maps. (2015). Retrieved January 28, 2016, from http://www.cdc.gov/obesity/data/prevalence-maps.html

DOLLARS AND CENTS ⦿In 1998 cost of obesity was 78.5 billion ⦿Medicare and Medicaid paying for half of this cost who

pays the other half? Would be prepared to respond⦿Due to current trends, the cost of obesity costs 40 billion

dollars more every four years. Indent after the last bullet⦿ In 2008 the total cost of obesity increased to 147 billion.

Would make this bullet #2⦿Annually 7 Billion dollars is spent on medications for

complications associated with obesity. Bullet #3

Disability and Obesity. (2015). Retrieved February 05, 2016, from http://www.cdc.gov/ncbddd/disabilityandhealth/obesity.html

OBESITY RISK FACTORS Inadequate Diet /

Physical Activity Genetics / Family History

can play a minimum role if developing the disease.

Medication conditions can lead to weight gain.

Stress, diabetes, Crushing’s syndrome, hypothyroidism, Polycystic ovary syndrome (PCOS)

Drugs leading to weight gainInsulinCorticosteroidsAtypicals

Antipsychotics Olanzapine Clozapine

Tricyclic Antidepressants

Can Prescription Drugs Cause Weight Gain? (n.d.). Retrieved February 05, 2016, from http://www.drugs.com/article/weight-gain.html

9 medical reasons for putting on weight. (n.d.). Retrieved February 05, 2016, from http://www.nhs.uk/Livewell/loseweight/Pages/medical-reasons-for-putting-on-weight.aspx

PHARMACOLOGY OF CONTRAVE AND OTHER AVAILABLE ANTIOBESITY

DRUGS

Obesity Physiology

Pharmacological Weight Loss OptionsTenuate® Xenical®

Alli® (OTC)

Belviq® Qsymia® Saxenda® Contrave®

Generic Diethyl-propion

Orlistat Locaserin Phentermine &

Topiramate

Liraglutide Naltrexone &

Bupropion

Class Central Nervous

Stimulant

Lipase inhibitor

Serotonin (5HT2c) Receptor Agonist

Sympatho-mimetic &

Anti-convulsant

Glucagon-Like Peptide

(GPL-1) Receptor Agonist

Dopamine/Norepi-nephrine Reuptake

Inhibitor & Opioid

Antagonist

Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/27/16; accessed 01/27/16]

Neuropeptides Influence Appetite by exerting their effects within the Hypothalamus

What peptides suppresses appetite?Leptin, Insulin, GPL-1, PPY, MSH,

Melanocortins, CRH, CCK

What peptides stimulates appetite? Ghrelin, NPY, AgRP, Opiods (especially μ),

Galanin

Which of these drugs is a GPL-1 aagonist, Teunate, Xenical, Belviq, Qsymia, Saxenda, Contrave?Saxenda

Neurotransmitters Influence Appetite by exerting their effects within the Hypothalamus

What neurotransmitters suppresses appetite?Norepinephrine α1 β2

Serotonin 5-HT1B and 5-HT2C

Histamine H1 and H3

Which serotonin subtype suppresses appetite?Norepinephrine α2 , Serotonin 5-HT1A

Neurotransmitters Influence Appetite by exerting their effects within the Hypothalamus

Which of these drugs can stimulate the NE receptor, Teunate, Xenical, Belviq,Qysmia, Saxenda, Contrave?Tenuate, Qymia, Contrave

Which of these drugs can stimulate the 5-HT2C receptor, Teunate, Xenical, Qsymia, Belviq, Saxenda, Contrave?Belviq

Enzymes Influence Appetite by exerting their affects within the Gastrointestinal

What is the function of the lipase?Hydrolyzes dietary triglycerides into

absorbable fatty acids

Which of these drugs inhibits lipase, Teunate, Xenical, Belviq, Saxenda, Qsymia, Contrave?Tenuate

Mechanism Of Action Belviq, Qsymia,Saxenda,Xenical, and Contrave

Amazonaws.com. 2016. Available at: https://s3.amazonaws.com/classconnection/984/flashcards/5918984/png/screen_shot_2015-04-11_at_10447_pm-14CA9DF33612FB6208F.png. Accessed January 29, 2016.

RECOMMENDED DOSING FOR OBESITY TREATMENT

Adapted from National Diabetes Education Initiative. Available online at: http://www.ndei.org/dsl/searchslide.aspx?Slideid=3835&keyword=

Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015.100(2):342–362.

QUIZ TIME!

WHAT ANTI-OBESITY AGENT IS AVAILABLE OTC?

A. CONTRAVE

B. XENICAL

C. ALLI

D. BELVIQ

A LITTLE MORE ABOUT CONTRAVE…

ContraveMechanism of Action

Christou G, Kiortsis D. The efficacy and safety of the naltrexone/bupropion combination for the treatment of obesity: an update. HJ. 2015. doi:10.14310/horm.2002.1600.

Adapted from https://dailymed.nlm.nih.gov/dailymed/image.cfm?id=138957&name=image-01%2Ejpg

CONTRAVE STARTER PACKAGE

Adapted from Medscape.com: http://img.medscape.com/news/2014/ht_140916_contrave_800x600.jpg

CONTRAVE CONTENT PACKAGE

Adapted from drugs.com: http://www.drugs.com/imprints/nb-890-22385.html

HOW CONTRAVE PILLS LOOK LIKE:CONTRAVE Appearance

Adapted from contrave.com: https://www.contrave.com/Images/pound-chart-2.png

WEIGHT REDUCTION WITH CONTRAVE

People taking Contrave along with diet and exercise counseling

People using diet and exercise counseling along

RESULTS - Lost 12lbs

(on average at 56 weeks with initial average weight of 220lbs)

- Lost 3 lbs

(on average at 56 weeks with initial average weight of 219lbs)

CONTRAVE TRIALS

TITLES IINTERVENTION

PRIMARY OUTCOME MEASURES

RESULTS LIMITATION

A Multicenter, Randomized, Double Blind, Placebo Controlled Study Comparing the Safety and Efficacy of Two Doses of Naltrexone Sustained Release (SR)/Bupropion Sustained Release (SR) and Placebo in Obese Subjects (COR-I)

- 16mg-360mg/day (NB16)- 32mg-360mg/day (NB32)- Placebo

- Mean percent change in body weight after 56 weeks (~ 1 year) from baseline- Proportion of subjects ≥5% decrease in body weight from baseline

- NB16: -5%NB32: -6.14%Placebo: -1.33%

- NB16: 39.49%NB32: 47.98%Placebo: 16.44%

- subjects were generally healthy middle-aged white women with completion rate of 50% in all groups- excluded individuals with diabetes or active cardiovascular disease - only compared with placebo (in all 4 studies)

A Multicenter, Randomized, Double Blind, Placebo Controlled Study Comparing the Safety and Efficacy of Naltrexone Sustained Release (SR)/Bupropion Sustained Release (SR) and Placebo in Subjects with Obese and Weight-related Risk Factor (COR-II)

- NB32- Placebo

- Mean percent change in body weight after 28 weeks (~ 1 year) from baseline- Proportion of subjects ≥5% decrease in body weight from baseline

- NB32: -6.45%Placebo: -1.89%

- NB32: 55.64%Placebo: 17.54%

- subjects were generally healthy middle-aged white women with completion rate of 54% in all groups- individuals with diabetes were excluded- duration of study was only 28 weeks

A Multicenter, Randomized, Double Blind, Placebo Controlled Study Comparing the Safety and Efficacy of Naltrexone 32 mg Sustained Release (SR)/Bupropion 360 mg Sustained Release (SR) and Placebo in Obese Subjects With Type 2 Diabetes Mellitus (COR-Diabetes)

-NB32-Placebo

- Mean percent change in body weight after 56 weeks (~ 1 year) from baseline- Proportion of subjects ≥5% decrease in body weight from baseline

- NB32: -5.03%Placebo: -1.75%

- NB32: 44.53%Placebo: 18.87%

- study excluded subjects who were taking insulin therapy (which can promote weight gain) and GLP-1 (which is asscoiated with mild weight loss) - relatively high drop-out rate

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Efficacy of Naltrexone Sustained Release (SR)/Bupropion SR and Placebo in Subjects With Obesity Participating in a Behavior Modification Program (COR-BMOD)

- NB32- Placebo

- Mean percent change in body weight after 56 weeks (~ 1 year) from baseline- Proportion of subjects ≥5% decrease in body weight from baseline

- NB32: -9.02%Placebo: -5.08%

- NB32: 66.39%Placebo: 42.49%

- lack of male participants and participants with significant comorbidities

RECOMMENDATIONS and COMPARISON

Adapted from National Diabetes Education Initiatives. Available at: http://www.ndei.org/dsl/searchslide.aspx?Slideid=3833&keyword=

Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015.100(2):342–362.

WHAT TO PICK??...

TENUATE XENICAL BELVIQ QSYMIA SAXENDA CONTRAVE

Long-term vs short-term

Short-term management

Long-term management

Long-term management

Long-term management

Long-term management

Long-term management

Mean weight loss

After 10 weeks, 14.8 lb vs 9.0 lb of placebo

After 4 years, 12.8 lb vs 6.6lb of placebo 1

After 1 year, 12.8 lb (6%) vs 4.8 lb (3%) of placebo 3

- 4.5% decrease in weight in T2DM 4

After 1 year,17.8 lb (9%) in 7.5-46mg group and 22.4lb (11%) in 15-92mg group compared to placebo (2%) 5

- Mean of 10.9% weight loss also seen in class II, III obesity 6

After 2 years, patients on 2.4 or 3mg had an average weight loss of 23.8 lb (10.8 kg) 7

After 1 year, (with recommended dosing of 32-360mg/day), 6.14% weight loss compared to placebo (1.33%)

- In

patients with T2DM, 5.03% weight loss compared to placebo (1.75%),

Patient-specific

For short-term weight loss up to 12 weeks

Patients who usually have fat-containing meals

At least one weight-related comorbidity*and not contraindicated

At least one weight-related comorbidity* and not contraindicated

At least one weight-related comorbidity* and not contraindicated

At least one weight-related comorbidity* and not contraindicated

TENUATE XENICAL BELVIQ QSYMIA SAXENDA CONTRAVE

Contraindication

ArteriosclerosisSubstance abuseGlaucomaHTNHyperthyroidismMAOI therapy

CholestasisMalabsorption syndrome

N/A GlaucomaHyperthyroidismMAOI therapy

Personal or family history of medullary thyroid carcinoma

Concomitant use of bupropion, opiates or alcoholUncontrolled HTNSeizure disorders or past history of seizure

Pregnancy X X X X X X

Price (source: Lexicomp)

25mg (100) - $51.85 100mg (ER) (100) - $130.17

Xenical 120mg (90): $614.53 Alli 60mg (90): $52.79

10mg (60): $263.22

REMS3.75-23 mg (30): $216.12 7.5-46 mg (30): $223.20 11.25-69 mg (30): $239.40 15-92 mg (30): $239.40

Injection:18mg/3mL: $236.59

8-90 mg (120): $239.40

Insurance Coverage

BC/BS = NCHarvard Pilgrim = NCMassHealth = NC

BC/BS = PAHarvard = NCMassHealth = NC

BC/BS = PAHarvard = NCMassHealth = NC

BC/BS = NCHarvard = NCMassHealth = NC

BC/BS = PAHarvard = NCMassHealth = NC

BC/BS = PAHarvard = NCMassHealth = NC

QUIZ TIME!

NOT ALL MEDICATIONS REQUIRE A DIET PLAN !

TRUE

FALSE

QUIZ TIME!

CONTRAVE HAS BEEN SHOWN TO BE SUPERIOR THAN OTHER ANTI-OBESITY MEDICATIONS !

TRUE

FALSE

QUIZ TIME!

IT IS USUALLY SAFE FOR OBESE PATIENTS, WHO ARE ON ZYBAN FOR SMOKING CESSATION, TO TAKE CONTRAVE.

TRUE

FALSE

Clinical Pearls of CONTRAVE “Powerful drug not to be taken lightly” !!

REFERENCES Contrave. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/27/16; accessed

01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/5338462

Tenuate. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/19/16; accessed 01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/6740

Xenical. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/27/16; accessed 01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/7402  

Belviq. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/27/16; accessed 01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/3808862

Qsymia. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/19/16; accessed 01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/3832942

Saxenda. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 01/27/16; accessed 01/27/16]. http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/2144379

Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27(1):155–161.

Fidler MC, Sanchez M, Raether B, Weissman NJ, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: The BLOSSOM trial. J Clin Endocrinol Metab 2011;96(10):3067–3077.  

O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: The BLOOM-DM study. Obesity 2012;20(7):1426–1436.  

Gadde KM, Allison DB, Ryan DH, Peterson CA, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): A randomized, placebo-controlled, phase 3 trial. Lancet 2011;377:1341–1352.  

Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: A randomized controlled trial (EQUIP). Obesity 2012;20(2)330–342.

Clements, J. N., & Shealy, K. M. (2015). Liraglutide An Injectable Option for the Management of Obesity. Annals of Pharmacotherapy, 1060028015586806.

REFERENCES (cont) Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in

overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2010;376(9741):595–605.

Apovian CM, Aronne L, Rubino D, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21(5):935–943.

Hollander P, Gupta AK, Plodkowski R, et al. Effects of Naltrexone Sustained-Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes. Diabetes Care 2013;36:4022-4029. Diabetes Care. 2014;37(2):587–587.

Wadden TA, Foreyt JP, Foster GD, et al. Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an Adjunct to Behavior Modification: The COR-BMOD Trial. Obesity. 2010;19(1):110–120.

Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015.100(2):342–362.

Obesity Prevalence Maps. (2015). Retrieved January 28, 2016, from http://www.cdc.gov/obesity/data/prevalence-maps.html

Christou G, Kiortsis D. The efficacy and safety of the naltrexone/bupropion combination for the treatment of obesity: an update. HJ. 2015. doi:10.14310/horm.2002.1600.

Sumnerdietrx.com. 2016. Available at: http://www.sumnerdietrx.com/files/2014/12/Contrave-Ad_Portfolio-2014.png. Accessed January 29, 2016.

Amazonaws.com. 2016. Available at: https://s3.amazonaws.com/classconnection/984/flashcards/5918984/png/screen_shot_2015-04-11_at_10447_pm-14CA9DF33612FB6208F.png. Accessed January 29, 2016.

Google.com. bupropion pomc - Google Search. 2016. Available at: https://www.google.com/search?q=bupropion+pomc&biw=1188&bih=563&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjMmMGY18_KAhUCPT4KHfuNBwcQ_AUIBigB#imgrc=H_juLQCeCoX6zM%3A. Accessed January 29, 2016.