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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
elin
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
ge F
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.
Chart1
8.1
8
Category
-0.9‡
-0.4
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Sheet1
Category
8.10-0.9
8.00-0.4
Chart1
163.3
160
Category
-27.4‡
-11.9
-27.4
-11.9
Sheet1
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163.3-27.4
160-11.9
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