Pharmacotherapy of Obesity: Practical Application for ... · Pharmacotherapy of Obesity: Practical Application for Clinical Care Caroline M. Apovian, MD, FACN, FACP, DABOM Professor

Pharmacotherapy of Obesity: Practical Application for Clinical Care

Caroline M. Apovian, MD, FACN, FACP, DABOMProfessor of Medicine and PediatricsBoston University School of MedicineDirector, Nutrition & Weight Management CenterSection of Endocrinology, Diabetes, and NutritionBoston Medical CenterBoston, Massachusetts

Scott Kahan, MD, MPH, FTOS, DABOMMedical Director, Strategies to Overcome and Prevent (STOP) Obesity AllianceGeorge Washington UniversityWashington, DC

Kimberly A. Gudzune, MD, MPHAssistant ProfessorJohns Hopkins University School of MedicineBaltimore, Maryland

2

Dr Apovian:

• Consultant: Merck; Nutrisystem; Zafgen; sanofi-aventis; Orexigen; EnteroMedics; Scientific Intake; Gelesis; Ferring; Takeda; Novo Nordisk

• Research funding: Aspire Bariatrics; GI Dynamics; Pfizer; Gelesis; Orexigen; MetaProteomics; Takeda; MYOS Corporation; The Dr. Robert C. and Veronica Atkins Foundation

• Stockholder: Science Smart, LLC

Dr Kahan:

• Consultant: Novo Nordisk; Takeda; Orexigen; Eisai

Dr Gudzune:

• Has no relevant financial relationships to disclose

Disclosures

3

Identify obesity as a disease, not a behavioral problem, and consider the implications of that paradigm shift on attitudes toward treating the condition

Identify indications that lifestyle interventions have not been sufficient to result in weight loss

Describe the pharmacology of, and indications for, the use of the currently available medications for chronic weight management

Describe ongoing management of people using anti-obesity medications, including means to gauge both therapeutic efficacy or the need to consider bariatric surgery

Learning Objectives

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Case Study Introduction

The Disease of Obesity

Obesity Etiology

Caroline M. Apovian, MD, FACN, FACP, DABOM

Clinical Overview of Anti-Obesity Medications for Weight Management

Scott Kahan, MD, MPH, FTOS, DABOM

Barriers to the use of Pharmacotherapy

When to Consider Bariatric Surgery

Kimberly Gudzune, MD, MPH

Program

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Public Health Crisis:69% of American Adults are Overweight or Obese

5

“The average American is now 23 pounds overweight.”~ Dr. Thomas R. Frieden, director of the U.S. Centers for Disease Control and Prevention

Ogden CL, et al. JAMA. 2014;312(2):189-190.

6

U.S. Adult Overweight/Obesity by BMI

BMI: <18.5 18.5-24.9 25.0-29.9 30.0-34.9 >35 >40

Underweight Normal Overweight Obesity I Obesity II Obesity III

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U.S. Adult Population 31% 34% 20.6%

69% Overweight and ObeseMore than two-thirds

8.1% 6.4%

Ogden CL, et al. JAMA. 2014;312(2):189-190.

35.1% Obese

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Extreme or Massive Obesity is Rapidly Expanding as a Subgroup BMI Increase by Category, 2001 to 2010

>10-fold increase

Sturn R, et al. Int J Obes (Lond). 2013;37(6):889-891.

Category BMI kg/m2

Underweight < 18.5

Normal weight 18.5–24.9

Overweight 25–29.9

Obese ≥ 30

Grade 1 30–34.9

Grade 2 35.0–39.9

Grade 3≥ 40 (severe, extreme,

or morbid obesity)

Grade 4 ≥ 50

Grade 5 ≥ 60

Poirier P, et al. Circulation 2009;120:86-95.

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Case: 52-year-old female

• CC: “I can’t lose weight.”

• Family history: type 2 diabetes and CAD

• Tried multiple diets; lifestyle interventions are not

currently achieving weight loss goals.

Current medications

• Multivitamin, calcium, vitamin B12, vitamin D

Vital statistics and laboratory results for this visit

• Height: 5’7”

• Weight: 190 lb

• BMI: 29 kg/m2 (overweight)

• Blood pressure: 145/95 mm Hg

• Fasting blood glucose: 97 mg/dl

• HbA1C: 5.9

• Vitals and labs: patient is hypertensive and

dyslipidemic, but no dysglycemia

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Q: What would you recommend for this patient?

A. Dietary and exercise lifestyle recommendations

B. Medication including off-label use of metformin

C.On-label use of Belviq (lorcaserin), Contrave (Bupropion/naltrexone), Qsymia (phentermine/topiramate), or Saxenda (liraglutide)

D. Off-label use of GLP-1 or SGLT-2 inhibitor

• BMI 29 with prediabetes and probably HTN • Family history positive for CAD and DM

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Designation of Obesity as a Disease

1. ASMBS, TOS, ASBP, AACE Joint Statement. Obesity is a disease: leading obesity groups agree. June 19, 2013.

http://asmbs.org/2013/06/obesity-is-a-disease-leading-obesity-groups-agree/. Accessed September 11, 2013.

2. American Medical Association. AMA Resolution No. 420 (A-13). June 19, 2013.

www.ama-assn.org/assets/meeting/2013a/a13-addendum-refcomm-d.pdf.

Medical Associations and Societies1

World / National Health Organizations1,2

• American Association of Clinical Endocrinologists

• American Academy of Family Physicians

• American College of Cardiology

• American College of Surgeons

• American Medical Association

• American Society for Reproductive Medicine

• American Urological Association

• The Endocrine Society

• The Obesity Society

• The Society for Cardiovascular Angiography and Interventions

• World Health Organization

• Food and Drug Administration

• National Institutes of Health

Obesity is a disease: leading obesity groups agree

June 19

2013

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Obesity: A Major Contributor to Disease

CHF=congestive heart failure; GERD=gastroesophageal reflux disease; PCOS=polycystic ovarian syndrome.

1. Catenacci VA, et al. Clin Chest Med. 2009;30(3):415-444. 2. Wang C, et al. Diabetes Care. 2011;34(7):1669-1675.

3. Lauby-Secretan B, et al. N Engl J Med. 2016;375(8):794-798.

Neurologic1

Stroke

Intracranial hypertension

Dementia

Gastrointestinal1

Nonalcoholic fatty liver disease

Gall bladder disease

GERD

Hernia

Cardiovascular1

Atherosclerosis

Hypertension

Dyslipidemia

CHF

Genitourinary1,2

PCOS

Abnormal menses

Infertility

Urinary incontinence

Low testosterone

Psychological1

Depression

Poor self-image

Poor quality of life

Eating disorder

Pulmonary1

Obstructive sleep apnea

Hypoventilation syndrome

Asthma

Pulmonary hypertension

Dyspnea

Cancer3

Esophagus

Stomach

Colorectal

Liver

Gallbladder

Pancreas

Breast

Musculoskeletal1

Low back pain

Osteoarthritis

Restrictive mobility

Metabolic1

Type 2 diabetes

Gout

Insulin resistance

Metabolic syndromeDermatologic1

Venous stasis

Cellulitis

Corpus uteri

Ovary

Kidney

Meningioma

Thyroid

Multiple myeloma

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How Obesity Causes Disease

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Ectopic Fat Deposits Associated with Metabolic Disorders

FFA = free fatty acid; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; RAS = renin angiotensin

system; TG = triglyceride; TNF- = tumor necrosis factor ; VLDL = very low density lipoprotein;

Gustafson B, et al. Atherosclerosis. 2015;241(1):27-35.

Systemic

effects

Increased

metabolic

risk factors

Local

effects

Increased

risk for

vascular

diseases

Pancreatic fat

Intramuscular fat

Fatty liver

Visceral fat

Perivascular fatEpi/pericardial

fatMyocardial steatosis

Renal sinus fat

-cell dysfunction, insulin resistance, impaired

glucose metabolism, inflammation, lipotoxicity

Hepatic insulin resistance, oxidative stress,

inflammation, lipogenic transcription factors,

VLDL-TG

Inflammation, macrophage infiltration, insulin

resistance, altered release of adipokines, altered

FFA metabolites, RAS activation, oxidative stress

Inflammation, TNF-, IL-6, leptin, MCP-1,

cell adhesion molecules, calcification,

decreased diastolic function, coagulation

defectsHypertension, vascular resistance,

glumerosclerosis, proteinuria, intra-renal

pressure

Systemic and intramuscular insulin resistance,

mitochondrial dysfunction, impaired lipid and

glucose metabolism

Meta

bo

lic

syn

dro

me

Ca

rdio

vas

cu

lar d

ise

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pe 2

dia

bete

s

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Pathogenesis of the Metabolic Syndrome Trait Complex

Central Adiposity

Dyslipidemia• Increased large VLDL• Increased small LDL• Decreased large HDL

Endothelial Dysfunction• Vascular reactivity• Dysfibrinolysis• Inflammation• Foam cell proliferation

Insulin Resistance• Glucose intolerance

Metabolic Consequences

• Adiponectin

• Leptin

• Resistin

• Free fatty acids

• PAI-1

• IL-6

• TNFα

• Angiotensinogen

• CETP

Secreted Adipocyte Factors:

CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IL-6 = interleukin 6; LDL = low-

density lipoprotein; PAI-1 = plasminogen activator inhibitor 1; TNF- = tumor necrosis factor ; VLDL = very-

low-density lipoprotein.

WT Garvey, 2013.

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Association Between Visceral Fat and Insulin Resistance

CT scans courtesy of Wilfred Y. Fujimoto, MD.

Carey DG, et al. Diabetes.1996;45(5):633-638.

Ins

uli

n S

en

sit

ivit

y(

mo

l/m

in p

er

kg

le

an

ma

ss

)

% Visceral Abdominal Fat

20

110

25 30 35 40 45 50

100

90

80

70

60

50

40

30

20

BMI <25 kg/m2

BMI 25 kg/m2

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Annual Prevalence of Obesity-Related Comorbidities, 2004-2013

Li Q, et al. J Med Econ. 2015 Sep 4:1-9. Li Q, et al. J Med Econ. 2015;4:1-9.

Three most prevalent

and expensive annually

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Possible Causes of Poor Weight Loss Maintenance

Ebbling CB, et al. JAMA. 2012;307(24):2627-2634.

One explanation for the poor long-term outcome of weight-loss diets relates to behavior:

Motivation to adhere to restrictive regimens typically diminishes with time

Adherence

Weight loss elicits biological adaptations that promote weight regain:

Specifically, a decline in energy expenditure (adaptive thermogenesis)

and an increase in hunger

Hypothalamic Injury

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Biological AdaptationHow long do these biological adaptations persist w/ calorie restriction?

Evidence suggests often indefinitely1

Biological pressure to restore bodyweight to the highest-sustained lifetime level gets stronger as weight loss increases.2

Then is a patient ever truly “recovered” from obesity?

Few individuals ever fully recover from obesity1,2

Individuals with obesity who lose weight are essentially in “remission” and biologically very different than their counterparts1,2,3

1. Ochner CN., et al. Physiol Behav 2013;120:106-113.

2. Rosenbaum M, et al. Int J Obes (London). 2010;34 (suppl 1) S47–S55.

3. Ochner CN, et al. Lancet. 2015;3(4):232-234.

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Obesity Associated with Hypothalamic Injury in Rodents and Humans

• Rodent models of obesity, induced by consuming high-fat diet (HFD), are characterized by inflammation both in peripheral tissues and hypothalamic areas critical for energy homeostasis

• Unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain

• Both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding

• Evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI

Thaler JP, et al. J Clin Invest. 2012;122(1):153-162.

Findings suggest obesity is associated with neuronal injury

in a brain area crucial for body weight control

in both humans and rodent models

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Hypothalamus is a Regulation Center of Appetite and Energy Expenditure

• Integrates peripheral and CNS signals that collectively modulate feeding behavior and energy balance1-3

• A primary regulation center is the arcuate nucleus (ARC)1

ARC of the

Hypothalamus

1. Yu JH et al. Diabetes Metab J. 2012;36:391-398.

2. Morton GJ et al. Nature. 2006; 443:289-295.

3. Cone RD. Nat Neurosci. 2005; 8:571-578.

4. NetterImages. http://www.netterimages.com/image/4742.htm. Accessed October 2, 2013.

CNS, central nervous system

ARC, arcuate nucleus

Primarily based on data from animal studies.

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Hypothalamic Injury Diminishes Signaling to Cortex and NTS*, Leading to Greater Weight Gain

AGRP: agouti-related peptide; α-MSH: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor;

LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; PYY: peptide YY; Y1R; neuropeptide Y1 receptor;

Y2R: neuropeptide Y2 receptor.

Apovian CM, et al. J Clin Endocrinol Metab. 2015;100(2):342-362. *NTS: nucleus tractus solitarius

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The Fat Trap

22Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.

Body continues to fight against weight loss long after dieting has stopped

• 2009, 50 obese men and women

• Men 233 lbs/average; women 200 lbs/average

• Extreme low-calorie diet

• Optifast shakes + 2 cups of low-starch vegetables

• Total 500-550 kcal/d for eight weeks

• Reported feeling more hungry and preoccupied with food than before the weight loss

30-lb LOSS

11-lb GAIN

10 week weight-loss program

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14% Weight Loss Produced Changes in 8 Hormones That Encourage Weight Regain

15% Weight Loss

Reduced: Increased:

Leptin - 65%

Peptide YY

Cholecystokinin

Insulin

Amylin

Ghrelin

Pancreatic polypeptide

Gastric inhibitory polypeptide

Measures of appetite

10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones

Mean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks

NET RESULT OF THESE HORMONAL CHANGES is WEIGHT GAIN!

Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.

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Sustained Changes in Peripheral Signals for Up to One Year Following Weight LossMean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks

10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones

Appetite Stimulating

Hormone was Higher

Appetite Suppressing Hormone was Lower


Gh

relin

, p

g/m

L

0 180 24030 60 120

200

100

0

Postprandial Time, min Pep

tid

e Y

Y, p

g/m

L

0 180 24030 60 120

60

20

0

Postprandial Time, min

CC

K,

fmo

l/m

L


Week 62

BaselineWeek 62

Baseline

0 180 24030 60 120

4

2

0

1

3

Week 62

Baseline

Am

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n,

pg

/mL


0 180 24030 60 120

200

100

0Week 62

Baseline


(chole

cysto

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in)


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Sustained Changes in Peripheral Signals for Up to One Year Following Weight Loss

Mean fasting and postprandial ratings of hunger and desire to eat at baseline and weeks 10 and 62

Changes were accompanied by significant increases in appetite

based on self-reported ratings (P<0.001)

Hunger Desire to Eat


26

Obesity is an epidemic with massive obesity being the fastest growing subgroup

Obesity was designated a disease by multiple medical organizations in 2013

– Increased expression of some hormones, suppression of others, leads to inflammation and disease

Neurological injury in the brain and hormonal changes account for weight regain, not lack of willpower

Summary

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Obesity Etiology

Caroline M Apovian, MD, FACN, FACP, DABOM






Program

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Q: When do you prescribe obesity pharmacotherapy in your practice?

A. I prescribe obesity medications in all my patients

B. I do not prescribe obesity medications in my practice

C. I prescribe only in patients who have severe obesity

D. I prescribe only in patients who have obesity comorbidities

E. I am not sure what are appropriate guidelines for prescribing

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Intensive Behavioral Therapy for Obesity

Look AHEAD Research Group. Obesity. 2014;22(1):5-13.

92.8

68.0

37.7

15.6

73.6

50.3

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60

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YEAR 1 YEAR 8

>0% ≥5% ≥10% ≥15% >0% ≥5% ≥10% ≥15%

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Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss

Wadden TA, et al. Obesity. 2011;19(1):110-120.

31


Pucci A, et al. Can J Cardiol. 2015;31(2):142-152.

Astrup A, et al. Int J Obes (Lond). 2012;36(6):843-854.

PBO ORL LOR PHEN/TPM ER BN LIRA

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32


le Roux C, et al. Poster presented at: TOS 2015; November 2-7, 2015; Los Angeles, CA. Poster T-P-LB-3843.

33

Pharmacotherapy Improves Weight Maintenance

Wadden TA, et al. Intl J Obes (London). 2013;37(11):1443-1451.

34

Key Obesity Pharmacotherapy Guidelines

Use pharmacotherapy as adjunct to diet, exercise, and behavioral counseling for individuals…• with BMI 30+; or 27+ with comorbidity• who are unable to lose and successfully maintain weight• who meet label indications

Use medications to promote long-term weight loss maintenance

Assess efficacy and safety monthly for the first 3 months, then every 3 months thereafter

At 3 months, if loss is 5% or more, continue; if not, discontinue and seek alternative approaches

Pharmacological Management of Obesity: An Endocrine Society

Clinical Practice Guideline. J Clin Endocrinol Metab, 2015.

35

Outcomes by Responder Status

Smith SR, et al. Obesity (Silver Spring). 2014;22(10):2137-2146.

36

• 5 FDA-approved medications for long-term use

• Orlistat (Xenical/Alli)

• Phentermine/topiramate ER (Qsymia)

• Lorcaserin (Belviq)

• Naltrexone/Bupropion SR (Contrave)

• Liraglutide 3.0 mg (Saxenda)

• Phentermine (Lomaira/Adipex) approved for short-term use

Obesity Pharmacotherapy

37

Mechanism of action (MOA): Sympathomimetic amine, norepinephrine (NE) release

Blunts appetite

Approved in 1959 for short-term use, schedule IV

Dosing: 8 mg to 37.5 mg qAM; use lowest effective dose

Contraindications: pregnancy, nursing, MAOIs, glaucoma, drug abuse history, hyperthyroidism

Relative contraindications: uncontrolled hypertension, tachycardia, CAD, CHF, stroke, arrhythmia

Warnings: primary pulmonary hypertension, valvular heart disease, tolerance, risk of abuse, alcohol use

Phentermine

Phentermine [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; 2009

38

MOA: Lipase inhibitor, decreases fat absorption

Approved 1999; long-term use

Not scheduled

Dosing: 120 mg TID with meals (Rx) or 60 mg TID (OTC)

Use multivitamin supplement (MVI) with fat-soluble vitamins at bedtime

Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis

Possible gastrointestinal adverse events

Orlistat

Xenical [package insert]. Nutley, NJ: Roche Laboratories, Inc.; 2009.

39

MOA: Selective 5-HT2C receptor agonist; increases satiety

Approved in 2012 for long-term use; schedule IV

Single dose: 10 mg BID

Discontinue if less than 5% weight loss after 12 weeks of use

Contraindications: pregnancy

Warnings: co-administration with serotonergic agents, valvular heart disease, psychiatric disorders (euphoria, suicidal thoughts, depression), priapism

Lorcaserin

Belviq [package insert]. Woodcliff Lake, NJ: Eisai, Inc.; 2012.

40

Phentermine MOA: sympathomimetic amine; blunts appetite

Topiramate MOA: increases GABA activity, carbonic anhydrase inhibitor, and other actions; prolongs satiety

Approved in 2012 for long-term use; schedule IV

“Recommended” dose: 7.5/46 mg; max: 15/92 mg

Discontinue if less than 3% weight loss after 12 weeks

Contraindications: pregnancy, glaucoma, MAOIs, hyperthyroidism

Phentermine/ Topiramate Extended Release

Qysmia. [package insert]. Mountain View, CA: Vivus; 2012.

41

Bupropion MOA: dopamine/noradrenaline reuptake inhibitor

Naltrexone MOA: opioid receptor antagonist

Not a controlled substance

Standard dose: 32/360 mg (2 tablets BID)

Consider discontinuation if <5% weight loss after 16 weeks

Black box warning for suicidal thoughts in adolescents

Contraindications: pregnancy, uncontrolled hypertension, seizure disorders, chronic opioid use, MAOIs

Naltrexone/Bupropion Extended Release

Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014.

42

MOA: Glucagon-like peptide 1 (GLP-1) receptor agonist

Multiple actions; effect on weight is primarily via hypothalamus neurons

Liraglutide 1.8 mg approved for T2DM in 2010

Liraglutide 3.0 mg approved for obesity in 2014

Not a controlled substance

Dosing: weekly escalation by 0.6 mg SC

Discontinue if <4% weight loss at 16 weeks

REMs: medullary thyroid carcinoma, acute pancreatitis

Liraglutide 3.0 mg

Saxenda [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.; 2016.

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Improvements in Risk Factors and Comorbidities

Orlistat Lorcaserin Phentermine/topiramate ER

Naltrexone/bupropion SR

Liraglutide3.0 mg

WC

BP

LDL

HDL

TG

A1C

HR 0

Diabetes

44



Obesity Etiology

Caroline M Apovian, MD, FACN, FACP, DABOM






Program

45

Weight-Favorable Medications for Management of Other Conditions (1)

ConditionPromoteWeight Gain

Weight-NeutralPromote Weight Loss

Diabetes mellitus Insulin*SulfonylureasTZDsMetiglinides

DPP-4 Inhibitors MetforminPramlintideGLP-1 AgonistsSGLT2 InhibitorsAcarboseMiglitol

Cardiovascular disease β Blockers**α Blockers

ACE InhibitorsARBsCCBs

--

*Weight gain differs by type of insulin regimen used. Basal insulin only typically has less weight gain than premixed or combination therapy. **If needed, certain agents may have less weight gain effects including carvedilol, nebivolol, and bisoprolol.

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

46




Contraception Medroxyprogesteroneinjection

Combination OCPsBarrier methods IUDs

--

Allergies Antihistamines* Decongestants Steroid inhalers

--

Chronic inflammatorydisease (e.g., RA)

Corticosteroids NSAIDs --

*Most common with sedating anti-histamines.


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Depression ParoxetineFluvoxamineAmytriptylineDoxepinImipramineNortriptylineTrimipramineMirtazapineLithium

Fluoxetine*Sertraline*

Bupropion

*Weight loss may occur with short-term use.


48




Serious mental illness ClozapineRisperidoneOlanzapineQuetiapineHaloperidol PerphenazineQuetiapine

ZiprasidoneAripiprazole

--

Epilepsy CarbamazepineGabapentinValproate

Lamotrigine TopiramateZonisamide


49

Q: What has prevented you from prescribing weight loss medications?

A.I have concerns about the long-term safety of these medications

B. The side effects and risks of these medications are too great

C.Patients have been dissatisfied with the weight loss results with these medications

D.Patients should have the will power to lose weight without medications

E.Patients don’t stick with taking the medications and just regain weight

50

Few patients with obesity prescribed a weight loss medication• Range 1-2% in large cohorts of insured patients

More likely to pursue nonprescription options• 4-18% report using herbs, supplements or OTC

meds

• OTC products have no association with clinically significant weight loss

• Safety data often unknown and reports of previous serious adverse effects

Prescribing Habits for Weight-Loss Medications

Bolen SD, et al., Obesity 2010; 18:206-9. Samaranayake NR et al., Ann Epidemiol. 2012;22:349-53. Xia Y, et al. Obesity.

2015;23:1721-1728. Nicklas JM, et al. Am J Prev Med. 2012;42:481-485. Bertisch SM, et al. Obesity (Silver Spring).

2008;16(7):1610-1615. Bray GA. Obesity (Silver Spring). 2008;16(3):509-514.

51

80% of providers in a 2016 NEJM poll voted against prescribing an FDA-approved medication • Preferred maximizing lifestyle modification first

• “Short-sighted to simply treat obesity with a prescription medication”

Past history may be influencing current perceptions• Amphetamine “diet pills,” fenfluramine, sibutramine

• Prompt us to look carefully at the safety profile of anti-obesity drugs

– Inappropriate to generalize and think that any potential anti-obesity drug is unacceptably harmful

Prescriber Perceptions of Pharmacotherapy

Yeh JS, et al. N Engl J Med. 2016;375(12):1187-1189.

Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2):185-189.

52

Weight bias and stigma may also play a role

• Majority of physicians report limited efficacy in weight management

• Many feel unprepared with respect to training, in addition to limited time and reimbursement for services

• Weight management considered unrewarding or futile

• Avoid discussing weight and weight loss entirely when trying to balance multiple priorities during the visit

Prescriber Perceptions of Pharmacotherapy

Kristeller JL, et al. Prev Med.1997;26(4):542-549; Foster GD, et al. Obes Res. 2003;11(10):1168-1177;

Fogelman Y, et al. Int J Obes Relat Metab Disord. 2002;26(10):1393-1397; Kushner RF, et al. Prev Med.

1995;23:546-552; Gudzune KA, et al. Patient Educ Couns. 2012;89(1):152-157.

53

Barriers to Pharmacotherapy

Yeh JS, et al. N Engl J Med. 2016;375(12):1187-1189.

Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2):185-189.

Fujioka K. Obesity (Silver Spring). 2015;23(Suppl 1):S7-S11.

Lack of long-term data efficacy and safety data• Clinicians want to wait for

definitive long-term data for weight-loss pharmacotherapy – Not economically feasible for

manufacturers– Delays potentially useful options

for decades

• Other chronic diseases the long-term use of medications is well accepted – why is obesity different?– Long-term surveillance necessary

with any chronic medication– Apply stopping rules if no benefit

at ~12 weeks

Concern about adverse effects

• Benefits do not outweigh the possible side effects– Weight loss achieved highly

variable between individuals• Some may have substantial

benefit

• Side effects an issue for any medication– Counseling about side effects

and risks important component of medication discussion to guide selection

• Shared decision-making process with patient

54

Barriers to Pharmacotherapy

Nicklas JM, et al. Am J Prev Med. 2012;42(5):481-485.; Risser JA, et al. Obes Res. 2005;13(1):86-92.; Wee

CC, et al. J Gen Intern Med. 2004;19(12):1206-1211.; Bray GA. Obesity (Silver Spring). 2008;16(3):509-514.

Patient Non-adherence

• Patients are more likely to achieve clinically significant weight loss if they use prescription meds– Medication persistence tends

to be low

• Medications can be costly & few have insurance coverage– Costs drives non-adherence for

many patients

– Insurance coverage improves adherence and weight loss

Patient Dissatisfaction with Results

• Most patients do not value modest weight loss– Many misperceive the

amount of weight loss that they are likely to achieve with medications

– Counseling on weight loss that may be achieved along with other health benefits may help manage expectations

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Approved for use in patients with:

• BMI ≥40 kg/m2

• BMI ≥35 kg/m2 + obesity-related condition such as CVD, OSA, uncontrolled T2DM or severe OA

Surgery Mechanism Mean Weight Loss - 1 Year Mean Weight Loss - 3 Years

Adjustable Gastric Banding

Restriction 30.2 kg 34.8 kg

Sleeve Gastrectomy Restriction 40.4 kg 37.2 kg

Roux-en-Y GastricBypass

Restriction + Malabsorption

43.5 kg 41.5 kg

BiliopancreaticDiversion

Malabsorption 51.9 kg 53.1 kg

Mechanick JI, et al. Obesity (Silver Spring). 2009;17 Suppl 1:S1-S70.; Maggard MA, et al. Ann Intern Med.

2005;142(7):547-559.; Carlin AM, et al. Ann Surg. 2013;257(5):791-797.

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Bariatric Surgery Pros & Cons

Benefits

• Improved obesity-related comorbidities– T2DM – up to 77% resolve

– HTN – up to 62% resolve

– OSA – up to 84% resolve

• Improved quality of life

• Reduce mortality– 40% in overall mortality

– 50% in CVD deaths

Complications

• Risk of death from procedures low– <5%

• Variable by procedure type– GI symptoms 7-38%

– Nutrition/electrolyte imbalances 3-17%

– Reoperation 2-12%

– Weight regain 9-25%

Buchwald H, et al. JAMA. 2004;292(14):1724-1737.; Levy P, et al. Obes Surg. 2007;17(9):1248-1256.;

Sjostrom L, et al. N Engl J Med. 2004;351(26):2683-2693.; Sjostrom L, et al. JAMA. 2012;307(1):56-

65.; Chang SH, et al. JAMA Surg. 2014;149(3):275-287.

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Summary

Obesity was designated a disease by multiple medical organizations in 2013

Causes of poor long-term weight loss include both behavioral and physiologic factors

Several obesity pharmacotherapy options are approved for use, including long-term use, and have strong data on efficacy and safety

Examining patients’ current medication lists is critical to identify weight-gain promoting medications and discuss weight-favorable alternatives

For patients who fail lifestyle modifications +/- weight loss medications, bariatric surgery should be considered

Q&A

Thank You

BACKUP SLIDES

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Effects of Phentermine Plus Topiramate on Bodyweight

Gadde KM et al. Lancet. 2011;377:1341-52.

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Effects of Sustained-Release Naltrexone/Bupropion on Bodyweight

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

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Weight Loss Observed with Liraglutide

Pi-Sunyer X et al., N Engl J Med. 2015; 373:11-22.

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Impact of Liraglutide on Plasma Glucose, and Prevalence of Prediabetes


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Rate of T2DM Development


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Drug Common AE Contraindication Safety Consideration Tolerability

Phentermine InsomniaDry mouthAgitationConstipation

CVD, CHF, arrhythmiasUncontrolled hypertensionMAOI useHyperthyroidismGlaucomaPregnancy

Primary pulmonary hypertension Discontinuation (CNS):Phentermine – 17%Placebo – 3%

Orlistat GI complaints Chronic malabsorptionGallbladder disease

May increase cyclosporine exposure; Liver failureMultivitamin administration

Discontinuation:Orlistat – 8.8%Placebo – 5%

Phentermine/topiramate ER

Dry mouthParesthesiasHeadacheInsomnia

GlaucomaHyperthyroidismMAOI usePregnancy

TeratogenicityMetabolic acidosisGlaucoma

Discontinuation:Top dose – 17% Low doses – 12%Placebo – 8%

Lorcaserin HeadacheDizzinessFatigueDry mouth

MAOI useUse with caution with serotonergic drugsPregnancy

Serotonin syndromeValvular heart diseaseDepressionPriapism

Discontinuation:Lorcaserin – 8.6%Placebo – 6.7%

Naltrexone/bupropion SR

NauseaGI complaintsHeadacheInsomnia

Seizure disorderUncontrolled hypertensionChronic opioid useMAOI usePregnancy

Suicidality in adolescentsElevated blood pressure, pulseGlaucomaHepatotoxicity

Discontinuation: Naltrexone/bupropion –24% Placebo – 12%

Liraglutide 3.0 NauseaGI complaints

Personal/family history of medullary thyroid carcinoma or MEN2History of pancreatitisPregnancy

Thyroid c-cell tumors (rodents)Acute pancreatitisGallbladder diseaseHypoglycemiaTachycardiaRenal impairmentSuicidal behavior

Discontinuation: Liraglutide – 9.8%Placebo – 4.3%

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Pharmacotherapy of Obesity: Practical Application for ... · Pharmacotherapy of Obesity: Practical Application for Clinical Care Caroline M. Apovian, MD, FACN, FACP, DABOM Professor