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Medical Treatments in ObesityJoseph Leung, BSc (Hons), MD, FRCPC, ABIM

UBC Endocrinology Fellow PGY-5

Thursday, April 19th, 2018

Disclosures

• I have no current or past relationships with commercial entities

• I have received a speaker’s fee from CSHP for this learning activity

Objectives

• By the end of this session, the learner will be able to: • Describe the history, definitions, epidemiology, pathophysiology and

classification of obesity

• Formulate an approach to the medical treatment of obesity

• List and classify the different types of weight loss medications

• Discuss landmark papers in the medical treatment of obesity

Obesity: The BasicsHistory

DefinitionsEpidemiology

PathophysiologyClassification

Obesity History

• Obesity was recognized as a disease in 1948 by the World Health Organization at its inception (see ICD-6); however, because of various reasons, there was little government action

• Over the last few decades, increased research in this field has established consensus on the causes and consequences of obesity, although there is still much ongoing study

• In 2013, the American Medical Association declared obesity to be a chronic disease

• In 2015, the Canadian Medical Association declared obesity to be a chronic disease

James. Int J Obes (Lond). 2008. 32(Suppl 7): S120-126.

Obesity Definitions

• BMI is the most widely used method to gauge obesity, although there are other approaches to quantifying obesity

• BMI definitions:• <18.5 kg/m2 Underweight

• 18.5-24.9 kg/m2 Normal weight

• 25.0-29.9 kg/m2 Overweight

• ≥30.0 kg/m2 Obesity• 30.0-34.9 kg/m2 Class I Obesity

• 35.0-39.9 kg/m2 Class II Obesity

• ≥40 kg/m2 Class III Obesity

Bray and Perreault. Obesity in adults: Prevalence, screening, and evaluation. Uptodate, Topic 5372, Version 18.0.

Flier and Maratos-Flier. In: Kasper et al. Harrison’s Principles of Internal Medicine. 2015. 19th edition.

Obesity Epidemiology

• Developed countries• In 2013, obesity prevalence:

• 18-20% in men and women

• US• In 2013-4, obesity prevalence:

• ~35% in men

• 40.4% in women

• Canada• In 2013, obesity prevalence:

• >22% in men

• 20% in women

• In 2014, obesity prevalence:• Class I: 3,758,100

• Class II: 1,070,200

• Class III: 497,300

CON-RCO. Report Card on Access to Obesity Treatment for Adults in Canada. 2017.


• Physiological System• Afferent signals sense energy status

• Integrating brain centres determine efferent response

• Efferent signals regulate hunger intensity and energy expenditure

• Pathophysiology• Disruption of this physiological system causes caloric intake to exceed

caloric expenditure, leading to increased energy stored as fat, resulting in obesity

• Genetics• A variety of genes and genetic syndromes are also important in the

pathophysiology of obesity

Obesity Pathophysiology

Kanaya and Vaisse. In: Gardiner and Shoback. Greenspan’s Basic and Clinical Endocrinology. 2018. 10th edition.


• Afferent Signals

Farooqi et al. J Clin Invest. 2002. 110(8):1093-1103.

Münzberg and Morrison. Metabolism. 2015. 64(1):13-23.

Hormone Main Site of Synthesis Secretion Pattern Effect on Food Intake

Ghrelin Gastric X/A-like cells Increases prior to meal;

decreased by food

food intake

Cholecystokinin

(CCK)

Proximal intestinal I

cells

Stimulated by duodenal

fat and protein

Promotes meal termin.,

meal size

Peptide YY3-36

(PYY)

Distal intestinal L cells Stimulated by presence

of fat in the lumen

appetite and food

intake

Glucagon-like peptide 1

(GLP-1)

Distal intestinal L cells Stimulated by presence

of nutrients in the lumen

Short-term inhibition of

food intake

Pancreatic polypeptide

(PP)

Pancreatic F cells Released in proportion

to calories ingested

appetite and food

intake


• Afferent Signals• GI and pancreatic signals



• Integrating Brain Centres

Apovian et al. J Clin Endocrinol Metab. 2015. 100(2):342-362.


• Efferent Signals


Heymsfield and Wadden. N Engl J Med. 2017. 376(3): 254-266.

• Genetic variants that increase the risk of obesity• Chromosomal loci: 16q12, 18q21, 2, 16p11, 1p31, 11p14

• Genetic syndromes that cause human obesity• Prader-Willi, Bardet-Biedl, Alström, Börjeson-Forssman-Lehman,

Cohen, Carpenter

• Leptin-melanocortin genes associated with monogenic obesity• Leptin, Leptin-R, POMC, PC-1, NTRK2, SIM1, MC4R



Obesity Classification

Sharma and Kushner. Int J Obes. 2009. 33(3):289-295.

Medical Treatment of Obesity

Surgical Treatment of Obesity

Schauer et al. Diabetes Care. 2016. 39(6):902-911.

Medical Treatment of Obesity

1. Lifestyle Modification• Diet

• Exercise

• Behaviour

2. Medication Modification• Discontinuation of medications

that are associated with weight gain

3. Weight Loss Medications• Orlistat (Rx)

• Orlistat (OTC)

• Liraglutide

• Diethylpropion

• Phentermine

• Phentermine/topiramate

• Lorcaserin

• Bupropion/naltrexone

1. Lifestyle Modification

• Endocrine Society Guideline Recommendations:• 1.1 We recommend:

• BMI ≥25 Diet, exercise, behavioural Δ

• BMI ≥27 w/ comorbidity Diet, exercise, behavioural Δ, pharmacotherapy

• BMI ≥30 Diet, exercise, behavioural Δ, pharmacotherapy

• BMI ≥35 w/ comorbidity Diet, exercise, behavioural Δ, bariatric surgery

• BMI ≥40 Diet, exercise, behavioural Δ, bariatric surgery

• Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially

• Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications



• Medications act to amplify the effect of the behavioural changes to consume fewer calories; they do not “work on their own”

• Obesity drugs should be used as adjuncts to lifestyle change therapy, and in some cases, weight loss is limited without lifestyle change



Garvey et al. Endocr Pract. 2016. 22(Suppl 3):1-203.

2. Medication Modification

• Current and past medications can contribute to weight gain and obesity (see upcoming slides)

• Insulin, SUs, TZDs, and antipsychotics are common causes of weight gain

• Smoking cessation is also associated with weight gain

• While discontinuation of these medications is an obvious modification to reduce weight gain, it may not be possible due to other comorbidities



• Antidepressants:• Paroxetine

• Citalopram

• Amitriptyline

• Nortriptyline

• Imipramine

• Mirtazapine

• First-gen antipsychotics: • Thioridazine

• Second-gen antipsychotics: • Risperidone

• Olanzapine

• Clozapine

• Quetiapine

• Mood stabilizers:• Carbamazepine

• Gabapentin

• Lithium

• Valproate



• Glucocorticoids: • Prednisone

• Antihyperglycemics:• Insulin

• Sulfonylureas

• Thiazolidinediones

• Meglitinides

• Hormones:• Especially progestins such as

medroxyprogesterone

• Antihistamines:• Especially cyproheptadine

• Alpha-blockers:• Especially terazosin

• Beta-blockers:• Especially propranolol



• Endocrine Society Guideline Recommendations:• ACE/ARB/CCBs over BBs as first-line HTN agent in DM + obesity

• Weight-neutral antipsychotics over those that cause weight gain

• NSAIDs/DMARDs over corticosteroids in inflammatory diseases

• Antihistamines with less CNS activity to reduce weight gain


3. Weight Loss Medications

• In Canada, orlistat, liraglutide, and bupropion/naltrexone are approved by Health Canada for weight loss

• In the US, there are 7 FDA approved meds for weight loss

CON-RCO. Report Card on Access to Obesity Treatment for Adults in Canada. 2017.


Generic Drug Brand Name FDA Approval Health Can Approval

Orlistat Xenical® 1999 1999

Liraglutide Saxenda® 2014 2015

Diethylproprion Tenuate® 1960s

Phentermine ApidexP®, Ionamin® 1960s

Phentermine/topiramate Qsymia® 2012

Lorcaserin Belviq® 2012

Bupropion/naltrexone Contrave® 2014 2018

• Mechanism of Action: Pancreatic/gastric lipase inhibitor

dietary fat absorption by 30%

Drug Dosage Common Side Effects Contraindications Cost for 1 yr

Orlistat

(prescription)120 mg TID

↓ absorption of fat-

soluble vitamins,

steatorrhea, oily

spotting/evacuation,

flatulence w/ discharge,

fecal urgency, ↑

defecation, fecal

incontinence

Cyclosporine, chronic

malabsorption sx,

pregnancy,

breastfeeding,

cholestasis,

levothyroxine, warfarin,

antiepileptics

$8439.96

USD

~$725 CAN

Orlistat

(OTC)60-120 mg TID See above See above

$633.48

USD

3a. Orlistat

Orlistat: Drug Information. Uptodate, Topic 10179, Version 118.0.


• Mechanism of Action: GLP-1 agonist

glucose-dep insulin secretion

β-cell growth/replication

gastric emptying, food intake

3b. Liraglutide


Liraglutide 3 mg SC dailyNausea, vomiting,

pancreatitis

MTC history, MEN2

history

$16,898.22 USD

for Saxenda

$19,682.87 USD

for Victoza

$5055 CAN

For Victoza

Liraglutide: Drug Information. Uptodate, Topic 9522, Version 160.0.


• Mechanism of Action: Sympathomimetic amine

Appetite suppress d/t CNS effects

Stim norepi release from hypothal

3c. Diethylpropion


Diethylpropion 75 mg daily

CNS: dizzy, insomnia,

eu/dysphoria, tremor,

HA, psychosis, anxiety

CV: BP/HR, ischemia

GI: dry mouth, diarrhea,

constipation

Allergic: urticaria

Endo: ED, libido Δ’s

Anxiety d/o, heart dz,

HTN, seizure, MAOi,

pregnancy,

breastfeeding,

hyperthyroidism,

glaucoma, drug abuse,

sympathomimetic

amines

$520.68 USD

Diethylpropion: Drug Information. Uptodate, Topic 9354, Version 121.0.


3d. Phentermine


Diethylpropion 75 mg daily

CNS: dizzy, insomnia,

eu/dysphoria, tremor,

HA, psychosis, anxiety

CV: BP/HR, ischemia

GI: dry mouth, diarrhea,

constipation

Allergic: urticaria

Endo: ED, libido Δ’s

Anxiety d/o, heart dz,

HTN, seizure, MAOi,

pregnancy,

breastfeeding,

hyperthyroidism,

glaucoma, drug abuse,

sympathomimetic

amines

$1016.60

USD for

Apidex-P

$609.00

USD for

generic

Phentermine: Drug Information. Uptodate, Topic 9765, Version 194.0.


• Mechanism of Action: Sympathomimetic amine

Appetite suppress d/t CNS effects

Stim norepi release from hypothal

• MOA (Phentermine): As previously discussed

• MOA (Topiramate): Blocks Na channels in neurons

Enhances GABA activity

Antagonizes glutamate receptors

3e. Phentermine/topiramate

Phentermine and topiramate: Drug Information. Uptodate, Topic 85870, Version 132.0.



Phentermine

and Topiramate

3.75-23 mg ER

daily (initial)

7.5-46 mg ER

daily (usual)

15-92 mg ER

daily (max)

Insomnia, dry mouth,

constipation,

paresthesia, dizziness,

dysgeusia

Pregnancy,

breastfeeding,

hyperthyroidism,

glaucoma, MAOi,

sympathomimetic

amines

$2678.40

USD for 7.5-

46 mg

$2872.80

USD for 15-

92 mg

• Mechanism of Action 5-HT2C agonist

Stimulates POMC neurons in AN

α-MSH at MC4R

satiety and food intake

3f. Lorcaserin

Lorcaserin: Drug Information. Uptodate, Topic 85674, Version 91.0.



Lorcaserin 10 mg BID

Headache, nausea, dry

mouth, dizziness,

fatigue, constipation

Pregnancy,

breastfeeding

Use with caution: SSRI,

SNRI, MAOi, St. John’s

wort, triptan, bupropion,

dextromethorphan

$3815.16

USD

• MOA (Bupropion): NDRI

• MOA (Naltrexone): Pure opioid antagonist

• MOA (Both): Not fully understood, ? related to effects

on hypothal &mesolimbic dopamine circuit

3g. Bupropion/naltrexone


Bupropion and

naltrexone

90-8 mg tablets

1 tablet daily

(initial)

2 tablets BID

(max)

Nausea, constipation,

headache, vomiting,

dizziness

Uncontrolled HTN,

seizure disorders,

anorexia nervosa,

bulimia, drug or alcohol

withdrawal, MAOi

$3480.96

USD

Bupropion and naltrexone: Drug Information. Uptodate, Topic 97033, Version 70.0.


Garvey et al. Endocr Pract. 2016. 22(Suppl 3):1-203.


Heymsfield and Wadden. N Engl J Med. 2017. 376(3): 254-266.

Landmark Trials

DIRECT Study

• n = 322, mean BMI 31, mean age 52 years, 86% male

• Randomized to:• Low-fat calorie-restricted diet

• Mediterranean calorie-restricted diet

• Low carbohydrate non-calorie-restricted diet

• Outcomes included: weight change (primary outcome), BMI, waist circumference, BP, and metabolic bloodwork over 24 mos

• Patients followed for 2 years

Shai et al. N Engl J Med. 2008. 359(3): 229-241.

DIRECT Study

Shai et al. N Engl J Med. 2008. 359(3): 229-241.

COR-I Trial

• n = 1,742, BMI 30-45 no complications, BMI 27-45 with HTN or dyslipidemia, no DM, mean age 43.7 years, 85% female

• Double-blind RCT comparing naltrexone-bupropion (32 mg-360 mg) vs. naltrexone-bupropion (16 mg-360 mg) vs. placebo

• All patients had regular counselling on lifestyle modification

• Co-primary endpoints• Percentage change in body weight

• Proportion achieving weight loss ≥5%

• Patients followed for 56 weeks

Greenway et al. Lancet. 2010. 376(9741): 595-605.

COR-I Trial

Greenway et al. Lancet. 2010. 376(9741): 595-605.

CONQUER Trial

• n = 2,487, BMI 27-45, ≥2 comorbidities (HTN, DM/pre-DM, dyslipidemia, abdo obesity), mean age 51.2 years, 70% female

• Double-blind RCT placebo vs. half-dose phentermine-topiramate (7.5 mg/46 mg) vs. full-dose phentermine-topiramate (15 mg/92 mg)





Gadde et al. Lancet. 2011. 377(9774): 1341-52.

CONQUER Trial

Gadde et al. Lancet. 2011. 377(9774): 1341-52.

SCALE Trial

• n = 3,731, BMI ≥30, no DM, mean age 45.2 years, 79% female

• Double-blind RCT liraglutide 3 mg SC daily vs. placebo






Pi-Sunyer et al. N Engl J Med. 2015. 373(1): 11-22.

SCALE Trial

Pi-Sunyer et al. N Engl J Med. 2015. 373(1): 11-22.

Quiz Question 1

• 28M PhD student presents in clinic with new onset DM2 on screening bloodwork. He has no PMHx and is on no medications. His BMI is 42. He eats frequent fast food and does not exercise. Which of the following is the most appropriate next step?

a. Monitor A1C with no specific recommendations

b. Order glyburide BID

c. Refer for bariatric surgery

d. Start basal insulin injections

e. Write a prescription for exercise

Quiz Question 2

• 56F with HTN is admitted for pneumonia. She has no other medical history. On her Pharmanet is a Compounded Product, but you are unsure of its identity. On questioning the patient, she says it is for her obesity in order to bridge her to bariatric surgery. What could be the identity of this medication?

a. Buprenorphine/naloxone

b. Liraglutide

c. Orlistat

d. Phentermine

e. Phentermine/topiramate

Quiz Question 3

• 39M with schizoaffective disorder presents to ER with DKA. He is known to have diabetes managed with metformin and glyburide. He is on olanzapine, flupenthixol, and lithium. His BMI is 37. He smokes 1 PPD x20 years. In additional to starting insulin, which of the following would you recommend prior to his discharge?

a. Consider less diabetogenic antipsychotics

b. Discontinue olanzapine and flupenthixol

c. Order bupropion/naltrexone

d. Prescribe lorcaserin

e. Start phentermine/topiramate

Conclusions

• Obesity is a chronic medical condition with emerging evidence on its causes and consequences

• Obesity is treated with: • Lifestyle measures: diet, exercise, behaviour modification

• Medications (and/or discontinuing medications)

• Surgery

• Consider medication choices carefully in a patient with obesity (or at risk of developing obesity)

• Awareness of medications for treating obesity is advised, as they are becoming more common in clinical practice

Resources

• Local Clinics: • LIVE WELL Clinics – Dr. Ali Zentner (www.livewellclinic.ca)

• Medical Weight Management Program – Dr. Michael Lyon (www.medweight.ca)

• Richmond Metabolic and Bariatric Surgery Centre – Dr. David Harris (www.rmbsurgery.com)

• Private Endocrinology Practice – Dr. Jordanna Kapeluto

• Clinical Practice Guidelines• Endocrine Society Guidelines: Apovian et al. J Clin Endocrinol Metab.

2015. 100(2):342-362.

• AACE/ACE: Garvey et al. Endocr Pract. 2016. 22(Suppl 3):1-203.

http://www.livewellclinic.ca/

http://www.medweight.ca/

http://www.rmbsurgery.com/

Objectives

• By the end of this session, the learner will be able to: • Describe the history, definitions, epidemiology, pathophysiology and

classification of obesity

• Formulate an approach to the medical treatment of obesity

• List and classify the different types of weight loss medications

• Discuss landmark papers in the medical treatment of obesity

medical treatments in obesity - bccshp.files.wordpress.com · medical treatments in obesity joseph...

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