THE MEDICAL TREATMENT OF OBESITY

Session # 1

January 9th, 2020

January 9, 2020

DISCLOSURES

Disclosures:

Grants/Research Support: Novo Nordisk Canada, Valeant, Servier, Sanofi

Speaker’s Bureau/Honoraria: Boehringer-Ingelheim, Eli Lilly, Novo Nordisk Canada, Sanofi,

AstraZeneca, Jansen, Valeant, Bausch Health, Abbott, Sutherland Global Services Canada ULC

Consulting Fees: Boehringer-Ingelheim, Eli Lilly, Novo Nordisk Canada, Sanofi, AstraZeneca,

Jansen, Valeant, Bausch Health, Abbott

Liviu Danescu MD, FACE

These slides were prepared and originally presented by:

Dr. Stephen A. Glazer MD FRCPC FCCP Humber River Regional Hospital

*Slides have been modified for today’s sessionSpecial thanks to Jennifer Brown from the Ottawa BCOE

ACKNOWLEDGEMENTS

1) How do we define obesity?▪ Obesity as a chronic disease

▪ Assessment and management options

2) Patient engagement strategies▪ Bariatric centres of excellence

3) Medications for obesity management▪ Meal replacements: Optifast®

▪ Medications: Orlistat, Liraglutide, Buproprion/Naltrexone

4) Questions

OBJECTIVES

HOW DO WE DEFINE OBESITY?

OBESITY: HISTORICAL APPROACHES

ALT = alanine aminotransferase; BMI = body mass index; FPG = fasting plasma glucose; NAFLD = non-alcoholic fatty liver disease.Adapted from Jensen MD et al. J Am Coll Cardiol. 2014;63:2985-3023; Lau DCW et al. CMAJ. 2007;176:1103-6; CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212.

Body Mass Index (BMI)

Waist Circumference

Obesity-Related Health risk

Male Female

European, Sub-Saharan African, Eastern Mediterranean and Middle Eastern ≥94 cm ≥80 cm

South Asian, Chinese, Japanese, South and Central American ≥90 cm ≥80 cm

25 to <29.9 30 to <34.9 35 to <40 ≥40

Overweight Class I Class II Class III

Obesity

Diabetes FPG, A1c

Hypertension Blood pressure (BP)

Dyslipidemia Lipid profile

NAFLD ALT

Edmonton Obesity Staging System (EOSS) or King’s Criteria

Looks at the health and complication-based conditions (medical,mental and functional) not size or weight alone

OBESITY: NEW APPROACHES

FACTORS AFFECTING WEIGHT

http://kim.foresight.gov.uk/Obesity/Obesity.html

Biology

Food Production

Food Intake

Social InfluencesIndividual Physiology

Individual Activity

ActivityEnvironment

OBESITY IS A CHRONIC DISEASE

CMA. CMA recognizes obesity as a disease. 2015. https://www.cma.ca/En/Pages/cma-recognizes-obesity-as-a-disease.aspx.

Canadian Medical Association (CMA) declared obesity a chronic disease in 2015 ▪ Multiple factors contributing to body weight

(genetics, physiology/metabolism, environmental, psychosocial, etc)

▪ Excessive adipose tissue affecting health (medical, mental and functional health)

▪ Other organizations have also declared obesity a chronic disease: ▪ American Medical Association (AMA)

▪ World Health Organization (WHO)

▪ World Obesity Foundation (WOF)

OBESITY IS A COMPLEX CHRONIC DISEASE

CHF = congestive heart failure; GERD = gastroesophageal reflux disease; PCOS = polycystic ovarian syndrome.1. Catenacci VA et al. Clin Chest Med. 2009;30:415-444. 2. Wang C et al. Diabetes Care. 2011;34:1669-1675. 3. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-798.

HEALTH BENEFITS OF WEIGHT LOSS

Cefalu et al. Diabetes Care. 2015; 38:1567-1582.

OBESITY: EXPECTATIONS

Adapted from www.drsharma.ca & Ryan et al. Arch Intern Med. 2010 Jan 25;170(2):146-54.

MANAGING WEIGHT IS TRICKY

Thermogenic Adaptation

▪ Energy expenditure ↓ after weight loss

▪ Homeostatic drivers in brain adapt to want to conserve energy and increase body weight

Hormonal Adaptation

▪ Hunger hormones ↑▪ Satiety hormones ↓▪ Desire to eat highly

palatable foods ↑▪ All to defend against

weight loss (adipose loss)

Body weight conservation (adipose tissue): evolutionary protective mechanism to defend against weight loss

Morton GJ, et al. Nature. 2006;443:289-295. Leibel RL, et al. N Engl J Med. 1995;31:621-628. Schwartz A & Doucet É. Obes Rev. 2010;11:531–547. Sumithran P et al. N Engl J Med. 2011;365:1597–1604.

PATIENT ENGAGEMENT

STRATEGIES

MYTHS SURROUNDING OBESITY:THE LIVED EXPERIENCE

“Food causes obesity”

“Obesity is a choice”

“Calories in, calories out”

“Who cares about why?Just eat less”

“It’s just a lack of will power”

UNDERSTAND & LISTEN

Ask for permission to discuss their weight and explore readinessAsk

Assess health status, obesity-related risks (BMI + EOSS) and root causes to their weight gain (metabolic, functional, mental health, environment) Assess

Advise on health risks and benefits of treatment options.

Aim for focus on improving HEALTH rather than simply weight lossAdvise

Agree on health outcomes and behaviour-related goalsAgree

Assist in accessing appropriate resources, providers, programs to support patients goals/behavioursAssist

Refer to the 5A‘s of Obesity Management for research and resources on use in Primary Care: https://obesitycanada.ca/resources/5as/

EXPECTATION MANAGEMENT: ALIGNING HCP/PATIENT EXPECTATIONS

HCP = healthcare professional.

Foster et al. Am J Clin Nutr. 2005;82(suppl):230S-235S.

-5-10%- 30%

Patient Expectations HCP Expectations

▪ Discuss patient goals prior to treatment to identify unrealistic expectations

▪ Discuss biological/physiological limitation

▪ Shift goals beyond weight loss▪ Improvement in metabolic and

cardiovascular measures▪ Improvements in quality of life measures

COUNSELLING WITHOUT PERCEIVED JUDGEMENT IMPROVES PATIENT OUTCOMES

Patients who received weight-management

counseling were

5xmore likely to attemptweight loss than those

who did not, and achieve clinically

significant weight loss

Patients who did notperceive judgment

during counseling were more likely to achieve

≥10% weight loss compared with patients who did

perceive judgment

aA US cross-sectional, internet-based survey in 600 adults with overweight/obesity (BMI ≥25 kg/m2) to assess differences

in weight-loss attempts and clinically significant weight loss (≥10%) based on receipt of HCP counseling and perceived judgment.

BMI = body mass index; HCP = health care professional.

Gudzune KA et al. Prev Med. 2014;62:103-107.

PUTTING THE PATIENT FIRST

DO SAY OR WRITE

DON’T SAY OR WRITE

“Patients living with…”

▪ Obesity▪ A higher weight▪ Weight problems

▪ Obese ▪ Fat*▪ Extremely obese▪ Super or morbid obese

~20%of patients who perceive weight stigma from their

health care provider would avoid future

appointments or seek out a new health care

provider

Obesity Action Coalition. http://www.obesityaction.org/wp-content/uploads/People-First.pdf. Accessed July 20, 2016; 2. Puhl R et al. Int J Obes (London). 2013;37:612-619.

CANADIAN CENTRES OF EXCELLENCE IN BARIATRIC MEDICINE

HOSPITAL MEDICAL PROGRAMS

Case Management

•Patient assessment by physicians or nurse practitioner with expertise in bariatric medicine

Registered Dietitian

Social Worker, Psychologist or Behaviourist

Kinesiologist, Exercise Physiologist, Physiotherapist, Occupational Therapist

Access to pharmacotherapy counselling

MEDICATIONS FOR OBESITY

MANAGEMENT

WHEN IS PHARMACOTHERAPY APPROPRIATE?

Pharmacotherapy (Based on 2006 CPG)

BMI ≥27 kg/m2 + risk factors orBMI ≥30km/m2

Adjunct to lifestyle modifications consider if patient has not lost 0.5kg (1lb) per week by 3 – 6 months after lifestyle changes

UPDATED Canadian CPG for

Obesity Management coming

early 2020

ORLISTAT

1.Heck et al. Pharmacotherapy. 2000; 20(3): 270-279. 2. Hadvary et al. Biochem J. 1988; 256:357-361. 3. Borgstrom et al. Biochim Biophys Acta. 1998; 962:308-316. 4. Hadvary et al. J Biol Chem. 1991; 266(4):2021-2027. 5.Ransac et al. Eur J Biochem. 1991; 202:395-400.

▪ Pancreatic and gastric lipase inhibitor

▪ Naturally produced by Stephomyces toxytricini

▪ Mechanism of action: ▪ Forms covalent bond with active serine site of gastric and

pancreatic lipases in lumen of GI tract

▪ Prevents enzymes from hydrolyzing dietary fat (triglycerides) into absorbable free fatty acids and monoglycerols

▪ Undigested triglycerides are eliminated in feces

▪ Lipase inhibition decreases dietary fat absorption (contributing to lower caloric intake → weight loss)

▪ Peripheral administration of GLP-1 receptor agonists ▪ Reduces short term oral intake

▪ Promotes satiety

▪ Decreases energy intake

▪ Net effect = decreases body weight

▪ Mechanisms of action: ▪ GLP-1 receptors are expressed in the stomach on gastric parietal

cells

▪ Interact with receptors localized to hypothalamic CNS centers that

regulate eating behaviors

▪ Activating neurons in the CNS coupled to gastrointestinal motility

and gastric emptying (ascending neural pathways; vagal afferent

fibers)

LIRAGLUTIDE

1. Shaefer et al. Postgrad Med. 2015; 127(8): 818-826; 2. Elrick et al. J Clin Endocrinol Metab. 1964; 24:1076-1082; 3.Baggio et al. Gastroenterology. 2007; 132: 2131-2157; 4.Nauck et al. J Clin

Endocrinol Metab. 1986;63:492-498; 5.Baggio et al. J Clin Invest. 2014;124(10):4223-4226.

COMBINATION: NALTREXONE AND BUPROPION

1. Naltrexone product information; 2. Wellbutrin SR Product Information.

The hypothalamus (hunger center) to reduce hunger

The mesolimbic reward system to help control cravings

REGULATION OF HUNGER: ROLE OF HYPOTHALAMIC POMC NEURONS

1. Billes SK et al. Pharmacol Res. 2014;84:1-11. 2. Modi, Renuca. Pharmacotherapy III: Contrave for Chronic Weight Management

Hypothalamus

POMC neurons▪ Integrate multiple energy

balance signals

POMC stimulus

POMC neuron

β-endorphin (endogenous opioid)

▪ Released from POMC neuron with α-MSH▪ Binds to µ-opioid receptor to increase food intake and conserve energy (negative feedback

loop)

µ-opioid receptorPOMC negative feedback loop

↓ Appetite↑ Energy Expenditure

α-MSH

MC4-R

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

intake

SYNERGISTIC ACTION OF NALTREXONE & BUPROPION TO ACTIVATE POMC NEURONS TO SUPPRESS APPETITE

1. Billes SK et al. Pharmacol Res. 2014;84:1-11. 2. Modi, Renuca. Pharmacotherapy III: Contrave for Chronic Weight Management

Figure adapted from Billes et al,1 © 2014, and Modi R2, 2018

Hypothalamus

POMC neuron

↑ POMC activity ↓ Hunger↓ Weight

Directly ↑ POMC activity

Indirectly ↑ POMC activity

CHOOSING A MEDICATION: CONTRAINDICATIONS

Orlistat

• Chronic Malabosprtion, Cholestasis, Cyclosporin

Liraglutide

• PHx/FHx medullary thyroid Ca, Multiple endocrine neoplasia syndrome type 2 (MEN2)

• Females – actively trying to conceive

Bupropion/Naltrexone

• HTN, Seizures, Eating Disorder(s), Severe Hepatic Impairment, End-stage Renal Failure

• Use of opiods or opioid agonists, Thioridazine, MAOIs, Tamoxifen

• Abrupt d/c of etoh, sedative and/or antiepileptic drugs

CHOOSING A MEDICATION: CAUTIONS

Orlistat

▪ Nephrolithisais (Ca oxalate)

Liraglutide

▪ Pancreatitis, Gallstones, Arrhythmias

Bupropion/Naltrexone

▪ CYP2B6 inhibitors: Clopidogrel, ticlopidine

▪ Inhibits CYP2D6: SSRI, SNRI, B-Blockers, Type 1 C Antiarrhythmic (proprafenone, flecainaide)

▪ Anxiety, Insomnia, Arrhythmia

CHOOSING A MEDICATION: PATIENT CONSIDERATIONS

Considerations Orlistat Liraglutide Bupropion/Naltrexone

ComorbiditiesPre-diabetesConstipationDyslipidemia

Pre-diabetesType 2 Diabetes

SmokerDesire to decrease ETOH

Depression

Hunger None Yes Yes

Cravings None None to Mild Mild to Strong

▪ Obesity is a complex, chronic disease defined by having excess or abnormal adipose tissue that impairs health

▪ Use comprehensive medical assessment of health factors (medical, mental and functional health) → EOSS instead of BMI alone

▪ Use 5As to obesity management

▪ Medications can be part of obesity management

▪ Lifelong management

SUMMARY

QUESTIONS &

DISCUSSION

REFERENCES

Jensen MD et al. J Am Coll Cardiol. 2014;63:2985-3023;

Lau DCW et al. CMAJ. 2007;176:1103-6;

CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212

NCD Risk Factor Collaboration. Lancet. 2016;387:1377-96.

NCD Risk Factor Collaboration. http://www.ncdrisc.org/d-adiposity.html.

Twells et al. CMAJ OPEN. 2014; 2(1): 18-26.

Thomas CE et al. Obesity. 2016;24:1955-1961.

Catenacci VA et al. Clin Chest Med. 2009;30:415-444.

Wang C et al. Diabetes Care. 2011;34:1669-1675.

Lauby-Secretan B et al. N Engl J Med. 2016;375:794-798.

Mathew B, et al. J Am Board Fam Med. 2008;21:562-568.

Mokdad AH, et al. JaMA. 2003;289:76-79.

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

Hollander P, et al. Diabetes Care. 2013;36:4022-4029.

Apovian CM, et al. Obesity..13;21:935-943

Luppino FS, et al. Arch Gen Psychiatry. 2010;67:220-229.

Parkin DM, et al. Br J Cancer. 2011;105(suppl 2):S77-S81

Calle, EE., et al. N Engl J Med. 1999;341:1097-1105.

CMA. CMA recognizes obesity as a disease. 2015. https://www.cma.ca/En/Pages/cma-recognizes-obesity-as-a-disease.aspx.

Whitlock G, et al. Lancet. 2009;373:1083-1096

Garvey WT, et al. [published online May 24, 2016]. Endocr Pract.

Jensen, MD et al. Circulation 2014: 129;5102-38.

National Heart, Lung, and Blood Institute. 2002. https://www.nhlbi.nih.gov/files/docs/resources/heart/steps.pdf. Accessed July 26, 2016.

Obesity Society. http://www.obesity.org/obesity/resources/facts-about-obesity/infographics/potential-contributors-to-obesity. Accessed April 4, 2017.

Foster et al. Am J Clin Nutr. 2005;82(suppl):230S-235S.

CONTRAVE [product monograph], February 12, 2018, Valeant Canada LP; Laval, QC.

Obesity Action Coalition. http://www.obesityaction.org/wp-content/uploads/People-First.pdf. Accessed July 20, 2016; 2. Puhl R et al. Int J Obes (London). 2013;37:612-619.

Gudzune KA et al. Prev Med. 2014;62:103-107.

Morton GJ, et al. Nature. 2006;443:289-295. 2. Leibel RL, et al. N Engl J Med. 1995;31:621-628.

Schwartz A & Doucet É. Obes Rev. 2010;11:531–547.

Sumithran P et al. N Engl J Med. 2011;365:1597–1604.

Rosenbaum M et al. Am J Physiol Regul Integr Comp Physiol. 2003;285:R183–R192.

Rosenbaum M & Leibel R. L. Int J Obes (Lond). 2010 October ; 34(0 1): S47–S55.

Ryan et al. Arch Intern Med. 2010 Jan 25;170(2):146-54

Lau, et al. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children. CMAJ. 2007;176(8 suppl):Online-1-117.

Heck et al. Pharmacotherapy. 2000; 20(3): 270-279

22

REFERENCES

Hadvary et al. Biochem J. 1988; 256:357-361.

Borgstrom et al. Biochim Biophys Acta. 1998; 962:308-316.

Hadvary et al. J Biol Chem. 1991; 266(4):2021-2027.

Ransac et al. Eur J Biochem. 1991; 202:395-400.

Xenical (product monograph), November 18, 2015, Hoffmann-La Roche Limited, Mississauga, ON.

Shaefer et al. Postgrad Med. 2015; 127(8): 818-826

Elrick et al. J Clin Endocrinol Metab. 1964; 24:1076-1082

Baggio et al. Gastroenterology. 2007; 132: 2131-2157

Nauck et al. J Clin Endocrinol Metab. 1986;63:492-498

Baggio et al. J Clin Invest. 2014;124(10):4223-4226.

Saxenda (product monograph), July 12, 2017, Novo Nordisk Canada Inc, Mississauga, ON.

CONTRAVE [product monograph], February 12, 2018, Valeant Canada LP; Laval, QC.

Naltrexone product information; Wellbutrin SR Product Information.

Greenway FL, et al. Lancet. 2010;376:595-605;3. Wadden TA, et al. Obesity. 2011;19:110-120

2

REFERENCES