OBESITY TREATMENT UPDATE

Juliana Simonetti, MD Assistant ProfessorDirector of Medical Bariatric Program University of Utah

DISCLOSURES

Juliana Simonetti, MD – NOTHING TO DISCLOSE

Outline:

Epidemiology of obesity in UT

Pathophysiology of obesity

Current treatments: Medical, surgical, non-surgical

Teaching Points:

Excess fat causes chronic inflammation which leads to metabolic dysfunction

Obesity’s leads to early mortality

Causes of obesity beyond diet and exercise: genetics, environment , biology

Treatment:

-Medical treatment is more effective than diet and exercise alone

-Devices, important to have options

-Surgical options for those with severe obesity

Wang YC, et al. Lancet. 2011 Aug 27;378(9793):815-25. Graph: 1Trust for America's Health and Robert Wood Johnson Foundation. The State of Obesity2016. Washington, D.C.: 2015.. Hum Reprod. 2009 Jul; 24(7): 1532–1537 5

Obesity: Rationale For Treatment

111 Million US Adults Are Obese or OverweightUTAH

In the USA, 40.4% of women and 35% of men

are obese (BMI ≥ 30)

Adipose tissue is an endocrine organ

Significant physiological functions of white adipose tissue:Appetite regulation, Immunity, glucose and lipid metabolism

Hiolski, E Feb. 16, 2017 http://www.sciencemag.org/news/2017/02. Coelho M, Oliveira T, etc Arch Med Sci. 2013 Apr 20; 9(2): 191–200.

Adiposopathy, sick fatFat hypertrophy causes direct and indirect adverse health consequences

Pathogenic Adipose Tissue

Deranged endocrine and immune response

Sick Fat Disease(Adiposopathy)

• Elevated glucose• Elevated BP• Dyslipidemia

• Other metabolic disease

Abnormal physical forces

Fat Mass Disease (FMD)

• Stress on weight bearing Joints• Immobility

• Tissue compression (sleep apnea, gastric reflux, high BP

• Tissue Friction (intertrigo)

Seger, J. C., et al. ASBP Obesity Algorithm 2013,(2016). H E Bays, et al. The Adiposopathy Working Group, Int J Clin Pract. 2008 Oct; 62(10): 1474–1483

Excess fat leads to chronic inflammation

Overnutrition

Increase demand for lipid storage

Adipocyte hyperplasia

and hypertrophy

••hypoxia

• cytokines

•acute phase proteins

•Recruitment of leukocytes

•Reparative tissue response

CHRONIC INFLAMMATION

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis

Coronary heart diseaseDiabetesDyslipidemiaHypertension

Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Osteoarthritis

Skin

Gallbladder disease

Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate

Phlebitisvenous stasis

Gout

Medical Complications of ObesityIdiopathic intracranial hypertension

StrokeCataracts

Severe pancreatitis

Significantly increases mortality

• A BMI of 30–35 reduces life expectancy by 2-4 years• Severe obesity (BMI > 40) reduces life expectancy by 10 years

http://www.nejm.org/doi/full/10.1056/NEJMoa055643#t=article,Epidemiologic Reviews 2014; 36:114-136.

Solution= Weight Loss

Small amount of weight loss 5-10% will lead to significant health improvements

IMPROVING HTN: both systolic and diastolic, decrease by 5 mmHg

on average

DM TYPE II: decrease in A1C 0.5-1%

HLD: can result in a 5 point increase in HDL and decrease triglycerides by an average of 40 mg/dl

Even a small weight loss (2%) in anovulatory obese infertile women resulted in improvements in ovulation, pregnancy rate, and pregnancy outcome

Hum Reprod. 1998;13:1502–5. http://www.obesityaction.org/educational-resources/resource-articles-2

Why is it so hard to lose weight?

ENERGY EXPENDITURE cortisol fat oxidation thyroid hormones

FOOD INTAKE GIPGhrelin Leptin PYYAmylin Insulin

APPETITE

Humans have evolved an energy regulation system that at its core is to protect against energy deprivation

Obesity is a highly heritable disease Heritability of obesity ranges between 65% to 70%

Image: http://scitechdaily.com/ucla-researchers-show-link-between-diet-genetics-and-obesity/Parks, B et al, Cell Metabolism , Volume 17 , Issue 1 , 141 - 152

http://www.cdc.gov/features/obesity/

• "thrifty genotype" hypothesis

Leptin Resistance

Environmental causes

http://dietdatabase.com/causes-of-obesity/

Per Capita Energy Intake in U.S. 1970-2009

Stress/Sleep Depravation->Weight Gain

CHRONIC STRESSOR

Hypothalamic-pituitary-adrenocortical (HPA) axis

Insulin Cortisol+ Appetite Anxiety, depression, apathyActivation of Lipoprotein

LipaseDeposition of Visceral fatCravings for fat and sugarFat break down

WEIGHT GAIN

Overweight and Obesity

Microbiome

http://www.nature.com/pr/journal/v77/n1-2/full/pr2014169a.

Weight promoting medications:CLASS DRUGS Affect on appetite and

satietyAntihypertensives Beta blockers -reduce metabolic rate

- slow utilization of nutrients

corticosteroids Prednisone(usually if taken for prolonged duration)

Multiple mechanisms: -fluid retention-stimulate appetite - Increase fat deposition

Anticonvulsants Sodium valproateCarbamazepinegabapentin

Increasing appetite

Psych meds -TCA antidepressant-Atypical antipsychotics-SSRIs

-antihistaminic activity and increase in appetite-Changes in serotonin may also lead to increase in appetite and decrease satiety

Contraceptives The progestin-only injectable-depo medroxyprogesterone

-DMPA users increased their weight (+5.1 kg), body fat (+4.1 kg), percent body fat (+3.4%) more than OC and NH users *- Weight gain has not been consistent with OCPs

http://www.medindia.net/patients/patientinfo/drugs-causing-weight-gain.htm, * Am J Obstet Gynecol. 2009 Mar

Weight centric approach to treat DMII Intervention A1C reduction

expected %Weight effects

Metformin 1-2 Loss 0.6-2.7 KgGLP-1 analogs (Liraglutide, Exenatide)

0.5-1.5 Loss 1.8-6.0 kg

Pramalinitide 0.5-0.7 Loss 1.5 KgDPP-4 inhibitor(Januvia)

0.5-0.8 Neutral

Sulfonylureas(Glipizide, glimepiride)

1-2 Gain 1.8-5.0 Kg

Thiazolidinediones 0.5-1.5 Gain 1.3-4.8 KgInsulin 1.5-3.5 Gain (variable) up to 10

kg

Intense Lifestyle intervetion 0.6 Loss 8.6 % of body weight

Igel LI, Powell AG. Curr Atheroscler Rep. 2012 Feb;14(1):60-9

20UKPDS. Lancet. 1998;352:854-856.

-1

01

23

45

67

8

Metformin

Diet Alone

Sulfonylureas

Insulin

Years after Randomization108642

Change in Body Weight with Antidiabetic Medications

Wei

ght C

hang

e (k

g)

• Metformin

• GLP-1 receptor agonist • SGLT2 inhibitor• DPP-4 inhibitor

• Insulins – cause weight gain

NEW AACE Guidelines – Weight Loss or Weight Neutral Medications FIRST

1st Line

2nd Line

Last

21

Requires Comprehensive Treatment Approach

Lifestyle Modification

Diet + Physical Activity+ BH

PharmacotherapyDevices

BMI ≥27 w/ comorbidities or BMI ≥30

Surgery

Foundation of all weight management approaches

-Anti-obesity:Phentermine, Qsymia, Contrave, Belviq, SaxendaDevices

For pts with BMI ≥35 w/ DM II or BMI >40

The Challenge85% of patients that diet and exercise fail….

What do you offer your patients for whom diet, exercise and behavioral therapy alone has not resulted in sustained weight loss?

Target underlying pathways that contribute to hunger, satiety, and reward

23Kraschnewski, JL et al. Long-term weight loss maintenance in the United States. International Journal of Obesity 2010; 1-11

Anti-obesity Medications

1. NIH Clinical Guidelines Evidence Report, Sept 1998.

Agents may be used in those >18 yo.There is a lack of clinical trial data to support use in patients >65 yo

Non-drug interventions should be attempted for at least 6 months before considering pharmacotherapy1

For patients with BMI > 30

For patients with BMI > 27 w/ concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea)1

Medications plus lifestyle changes can result in weight loss of about 3.5-10kg more than lifestyle interventions alone.

AHA/TOS/ACC Guidelines for Selecting Treatment

1. NIH Clinical Guidelines Evidence Report, Sept 1998.

Comparison of Obesity Treatments

AgentBrand

Name

Drug(kg)

Placebo (kg)

Net Weight Loss (kg) Duration FDA Approval

Phentermine Adipex 12.2 4.8 7.4 36 weeks 1959

Orlistat Xenical 5.8 3.0 2.8 4 years 1999

PhentermineTopiramate Qsymia 10.2 1.4 8.8 56 weeks 2012

Lorcaserin Belviq 8.2 3.4 4.8 52 weeks 2012

BupropionNaltrexone Contrave 8.2 1.9 6.2 48 weeks 2014

Liraglutide Saxenda 7.2 2.8 4.4;5.8 20;56 weeks Sept 2014

Phentermine Sympathomimetic; controls appetite

Schedule IV; approved for short term use (3 months)

COST $6-40/month

Dose:15mg or 37.5mg can be given daily, or 8mg BID or TID to control hunger.

(start at low dose either 8mg, 15 mg or 18.25mg)

Contraindications: CVD, uncontrolled HTN, tachycardia, CKD, hyperthyroidism, agitation, angle-closure glaucoma, pulmonary HTN, Hx of drug abuse/dependence, bipolar, mania

Common SE: dry mouth, constipation, insomnia, palpitations, anxiety, euphoria•Monitor BP and HR, baseline creatine

Yanovski SZ, Yanovski JA. Long-term Drug Treatment for Obesity: A Systematic and Clinical Review. JAMA : the journal of the American Medical Association. 2014;311(1):74-86

Phentermine / Topiramate Approved July 2012

Once a day combination of phentermine and extended release topiramate

REMS program, only available by registered pharmacies

Cost of $150/month

Use of two existing medications-Phentermine -Topiramate approved for seizure and migraine ppx

Dose has to be titrated up and max dose of 15mg/92 mgYanovski SZ, Yanovski JA. Long-term Drug Treatment for Obesity: A Systematic and Clinical Review. JAMA : the journal of the American

Medical Association. 2014;311(1):74-86

Topiramate Phentermine

Reduction in compulsive or addictive food cravings via antagonism of AMPA receptors

Decreased lipogenesis and modification of food taste via inhibition of carbonic anhydrase

Increased energy expenditurevia activation of GABA receptors

Off label for binge eating

Reduction in hunger via sympathomimetic signals

Full-dose

-13.2%, 30 lbs10% more than placebo

15 mg phentermine/92 mg topiramate

Phentermine / Topiramate Contraindications: Hyperthyroidism, tachycardia, SI, angle-

closure glaucoma, cognitive impairment, metabolic acidosis, hypokalemia, MAOIs

SE: paresthesia, dizziness, taste alteration, insomnia, constipation, dry mouth, memory or cognitive changes. HR increase due to phentermine

Topiramate can cause HYPOKALEMIA if pt is on potassium wasting diuretic (i.e. HCTZ) consider more frequent lab monitoring

Teratogenic Risk-Women of child bearing potential should have pregnancy test and ensure adequate contraception (2 forms of birth control)

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

Phentermine/Topiramate

7.5 mg phentermine/ 46 mg topiramate

15 mg phentermine/92 mg topiramate

Mid-dose-10.5%, 24 lbs

CONQUER Trial: Weight Loss Over Time

Full-dose-13.2%, 30 lbs

Placebo-2.4%, 6 lbs

Mea

n %

Wei

ght L

oss

WeeksPatients Placebo Mid FullCompleters(% of randomized)

56457%

34469%1

63464%1

1. Statistically greater number of patients completing study on Qnexa vs. placebo, p

Lorcaserin (Belviq)

Approved in 2012

Selective 5-HT2c receptor agonist improves satiety

1997- Fenfluramine withdrawn

nonspecific 5HT receptor agonist5-HT2b receptor subtype on cardiac

valves valvulopathy

Lorcaserin has 11x affinity toward 2C than 2B

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

2C

Lorcaserin

Dosing 10mg BID; no titration

New dose of 20mg ER once daily

Most common side effects: headache, nausea, fatigue and dizziness

Contraindications: Avoid concurrent use of SSRI– risk of serotonin syndrome. Caution with those who have valvular heart disease

At Week 52, the mean weight loss was 8.0% with BELVIQ vs 3.7% with placebo

Smith S, Weissman et al. N Engl J Med 2010; 363:245-256

BLOOM: Evaluation of 2 Years of Treatment

Response to therapy should be evaluated by Week 12. If a patient has not lost at least 5% body weight, discontinue BELVIQ

Cha

nge

From

Bas

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e (k

g)

0

-2

-4

-6

-8

-104 8 12 24 36 52 60 72 84 96 104

Study Week

-6.0 kg

-3.8 kg

-2.6 kg

BLOOM (2-year completer data)

Placebo Year 1 and Year 2 (N=507)BELVIQ Year 1/Placebo Year 2 (N=195)BELVIQ Year 1 and Year 2 (N=426)

33

Mean Weight Change Over Time1

Smith S, Weissman et al. N Engl J Med 2010; 363:245-256

BELVIQ Provided Improvement in Glycemic Control Parameters Compared to Placebo

BLOOM-DM (ITT population)*

34

Chan

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rom

B

asel

ine

(%)†

HbA1c

Chan

ge F

rom

B

asel

ine

(mg/

dL)†

Fasting Plasma Glucose

BELVIQ (N=256) Placebo (N=252)

All Patients Received Lifestyle Modification Counseling

BL (%): BL (mg/dL):

O'Neil PM, Smith SR, Weissman NJ et al. Obesity (Silver Spring). 2012 Jul;20(7):1426-36.

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Buproprion/Naltrexone (Contrave)

Approved, Sept 10, 2014

Naltrexone- opioid receptor antagonist

May reduce preference for highly palatable foods, especially foods that are high in fat and sugar

Buproprionnorepinephrine -dopamine reuptake inhibitor;

Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study). 2012.; Clinicaltrials.gov.

Buproprion/Naltrexone (Contrave)

Dosing 8mg Naltrexone HCL/90mg Buproprion HCL. Therapeutic dose of 32mg/360 mg

Common side effects: Nausea (29%), constipation (19%), headache (17%), dizziness(9%), vomiting(10%), dry mouth

No increased risk of SI/Depression

Weight loss of 8.2% vs. 1.4% placeboApovian, Aronne, et al Obesity (Silver Spring) 2013 May; 21(5): 935–943

Gomez G, Stanford FC. Int J Obes (Lond). 2017 Nov 20.

COR-I/II Trials: 56 week Completer Data

3 Phase III Trials

NB32 (Naltrexone SR 32mg, BuproprionSR 360mg) 1.4-1.8%

8.1%

Apovian C et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity 2013 May;21(5):935-43

Liraglutide (Saxenda™)

September 11, 2014

Glucagon-Like Peptide 1 Analog

Secreted in L cells of the intestine

delays gastric emptying and enhances satiety

binds and activates GLP-1 receptor in hypothalamus involved in appetite regulation Image from Shashikiran Umakanth, Published on Dec 13, 2015 Health and Medicine

Liraglutide 3 mg-SCALE Obesity and Prediabetes study 3,731 patients with BMI>30 or BMI>27 with 1 co-morbidity

-2.6%

-8.0%

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

QUESTION

24-year-old female with past medical history of PCOS, Impaired glucose tolerance, HTN, and overweight with BMI of 29 comes to discuss her weight.

WEIGHT HISTORY: She has struggled with her weight since she "can remember" and had multiple prior weight loss attempts including several years in Weight Watchers and working out with a trainer which have been unsuccessful. She feels that she loses and regains the same 10 lbs over the years.

Her BP has been well controlled on Hydrochlorothiazide

On Metformin 1500mg daily for PCOS and IGT

- She is interested in starting medication for weight loss. Her insurance does not cover these medications, and she has limited

financial resources since she is a student.

What would you recommend for this patient?

A) Advice on diet and exercise changes to help with weight loss and recommend that she follows-up in 6 months

B) Place referral to nutrition

C) Start patient on phentermine 37.5mg once daily for only 3 months

D) Start patient on phentermine 15 mg once daily. Have patient return every 4 weeks for follow-up. Keep her on this medication and/or add topiramate until she reaches her goal weight

E) Both B and D

Svetkey LP, Stevens VJ, Brantley PJ, et al. Comparison of strategies for sustaining weight loss. JAMA. 2008;299(10):1139–1148Thomas et al4; 2014 – National Weight Control Registry

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777230/#b4-dmso-9-037

Weight Loss Devices: BMI

BARIATRIC SURGERY: BMI >35 W/ COMPLICATIONS/ BMI >40

WWW. Bariatric-surgery-source.com

Weight Loss with bariatric surgery

Control

Banding

Vertical-banded gastroplasty

Gastric Bypass Cha

nge

in w

eigh

t (%

)

Years

Sjöström, L et. Al Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects, N Engl J Med 2007; 357:741-752

25%

16%

14%

HR adjusted for sex, age, and risk factors was 0.71 for surgery compared to the control(P=0.01)

How can we help?

1-Kimberly A. Gudzunea, Wendy L. Bennetta, etc. Preventive Medicine, Volume 62, May 2014, Pages 103–1072- S A Rose, P S Poynter, etc- International Journal of Obesity (2013) 37, 118–128; doi:10.1038/ijo.2012.24

weight loss 5-10% will lead to significant health improvements

Be non-judgmentalObese patients who experience stigma in health-care settings

may delay or forgo age-appropriate screenings

Discuss how this is a chronic disease and offer treatment

Set realistic expectations

In Summary

Obesity is a complex chronic disease that is difficult to treat

It requires a multidisciplinary comprehensive approach with multiple

options of treatment

Even a small amount of weight loss 5-10% will lead to

significant health improvements

Anti-obesity medications in addition to lifestyle changes can result in

more significant weight loss (3.5-10kg > lifestyle interventions alone)

Surgical options are now safer, leading to many comorbidity resolution

and long term weight loss

QUESTIONS AND COMMENTS?

��������OBESITY TREATMENT UPDATE �DISCLOSURESOutline: Teaching Points:Obesity: Rationale For TreatmentAdipose tissue is an endocrine organ Adiposopathy, sick fatExcess fat leads to chronic inflammation �Medical Complications of ObesitySignificantly increases mortalitySolution= Weight Loss Slide Number 12Slide Number 13Obesity is a highly heritable disease Environmental causesStress/Sleep Depravation->Weight GainMicrobiomeWeight promoting medications:Weight centric approach to treat DMII Change in Body Weight �with Antidiabetic MedicationsNEW AACE Guidelines – Weight Loss or Weight Neutral Medications FIRST�Requires Comprehensive Treatment Approach The Challenge�Anti-obesity Medications�Comparison of Obesity TreatmentsPhentermine Phentermine / TopiramateTopiramate PhenterminePhentermine / Topiramate CONQUER Trial: Weight Loss Over Time Lorcaserin (Belviq)LorcaserinBLOOM: Evaluation of 2 Years of TreatmentBELVIQ Provided Improvement in Glycemic Control Parameters Compared to PlaceboBuproprion/Naltrexone (Contrave)Buproprion/Naltrexone (Contrave)COR-I/II Trials: 56 week Completer Data Liraglutide (Saxenda™)Liraglutide 3 mg-SCALE Obesity and Prediabetes studyQUESTIONWeight Loss Devices: BMI 35 W/ COMPLICATIONS/ BMI >40Slide Number 43How can we help?In Summary Slide Number 46