Nonsurgical Treatment of Obesity and the...
Transcript of Nonsurgical Treatment of Obesity and the...
Frank L. Greenway, MD
Nonsurgical Treatment of Obesity and the Gastroenterologist
Frank L. Greenway, MDACG/LGS Postgraduate CourseNew Orleans, March 5, 2016
What Will be Discussed
• Obesity is a chronic physiologic disease• When to treat obesity with medication• Approved obesity medication options• Off-label combination use of two approved
medications.• Using obesity medications in the context of
obesity surgery
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Weight Loss Curve
Sumithran et al. NEJM 2011; 365:1597-1604.
Gut Hormone Changes Persistently Oppose Diet-induced Weight Loss
Sumithran et al. NEJM 2011; 365:1597-1604.
PY
YC
CK
Am
ylin
Ghr
elin
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Frank L. Greenway, MD
Fenfluramine1-Year Rx & 1-Year Follow-up
0
5
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15
20
25
30
0 mo.
2 mo.
4 mo.
6 mo.
8 mo.
10 m
o.
12 m
o.
14 m
o.
16 m
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18 m
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20 m
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22 m
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24 m
o.
Pounds
Diet, Activity, and Other Interventions with Drugs
• Diet and Activity
• Types of nutrients
• Eating schedules
• Physical activity
• Sleep health
• Drugs and medications
• Local stressors
Amenable to individual action
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Frank L. Greenway, MD
No Behavior Modification
-7
-6
-5
-4
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-2
-1
0
10 1 wk. 2 wk. 3 wk. 4 wk. 5 wk. 6 wk.
Poun
ds MazindolPlacebo
Walker BR et al. J Int Med Res. 1977;5(2):85-90
With Behavior Modification
-9-8-7-6-5-4-3-2-10
0 1wk. 2 wk. 3 wk. 4 wk. 5 wk. 6 wk.
Poun
ds MazindolPlacebo
Walker BR et al. J Int Med Res. 1977;5(2):85-90
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Frank L. Greenway, MD
Relationship Between Mortality & BMI
Lew EA: Mortality and weight: insured lives and the American Cancer Society studies. Ann Intern Med 103:1024-1029, 1985.
Very Low
Low Moderate High Very High
20 25 30 35 40
2.5
2.0
1.5
1.0
0
MenWomen
Mor
talit
y Ra
tio
Body Mass Index, kg/m2
Mortality: Diastolic Blood Pressure
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Mortality: Body Mass Index
Edmonton Obesity Staging System
• Stage 0: No obesity related risk factors
• Stage 1: Subclinical risk factors – borderline HTN or DM, minor aches or psychopathology
• Stage 2: Established obesity-related disease –HTN, DM, PCO, moderate limitations ADL
• Stage 3: Established organ damage – MI, CHF, DM comp, significant limitations of ADL
• Stage 4: Severe disabilities – end stage and limitations like wheelchair use
Sharma AM and Kushner RF. Int J Obes. 2009;33:289-95
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
EOSS Predicts Mortality in NHANES III
Padwal R et al. CMAJ 2011;183(14):E1059-66
Phentermine
• Approved in 1959 when obesity was thought to be bad habits at doses from 15 to 30 mg/d.
• Tested and approved for up to 12 weeks.• Extensive experience with longer use and
apparently well tolerated.• Blood pressure does not drop as much as
placebo, and can give adrenergic symptoms• In DEA class IV with diethylpropion, but abuse
has been low.
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Frank L. Greenway, MD
0
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32
0 4 8 12 16 20 24 28 32 36
Time in Weeks
Continuous PhentermineAlternate Phentermine & PlaceboPlacebo
5
10
Wei
ght
loss
(kg
)
Wei
ght
loss
(lb
s)0
Phentermine: A Noradrenergic Drug Reduces Body Weight
Munro JF et al BMJ 1968;1:352-4
Orlistat
• Approved for long-term use to treat obesity at 120 mg tid and causes 33% of dietary fat to be lost into the stool.
• Safety is good, but side effects of anal leakage, passage of oil with flatus and incontinence have dampened enthusiasm by patients.
• Sold now without a prescription at half the dose which gives about 80% of the weight loss seen with the higher dose.
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Torgerson et al., Diabetes Care. 2004;27(1):155-61
Orlistat 120 mg tid Induces Weight Loss
Placebo
Orlistat
0 52 104 156 208-12
-9
-6
-3
0
Time (weeks)
Wei
ght C
hang
e (k
g)
Orlistat 60 mg tid Compared to Prescription Orlistat
Percent Change from Initial Body Weight Over Two Years
Integrated Database
EF64.XLS
-10
-9
-8
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-2
-1
0
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104
Week
% Change
Placebo
120 mg
60 mg
Hauptman Data on file Hoffmann-La Roche Figure 6
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Lorcaserin
• Phentermine and fenfluramine gave additive weight loss, but fenfluramine was withdrawn due to cardiac valvulopathy.
• Lorcaserin is a selective serotonin (5HT) 2c agonist (suppresses hunger centrally) without valve problems related to 5HT2b.
• Well tolerated with few adverse events (headache, dizziness), DEA IV but low addictive potential and drops HgbA1c 0.5%.
Phase III Study (BLOOM)Body Weight Over Years 1 and 2
Study Week
Smith SR, et al. N Engl J Med. 2010;363:245-256.
Bo
dy
Wei
gh
t (k
g)
Year 1
Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1, placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)
Year 2
0
102
100
98
96
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90
10472 806448 564024 32160 8 88 96
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Fasting Plasma Glucose
BLOOM-DMChange in Glycemic Parameters
HbA1C, -0.5%
O’Neil PM, et al. Obesity. 2012;20:1426-1436.
Ch
ang
e F
rom
Bas
elin
e (m
g/d
L)
Ch
ang
e F
rom
Bas
elin
e (%
)
Study WeekStudy Week
PlaceboLorcaserin 10 mg twice a day
* * **
*†
*
Phentermine/Topiramate
• Approved at 3.75/23 mg/am for 2 weeks then 7.5/46 mg, but at 12 weeks if weight loss <3%, stop or 15/92 mg. Stop (taper) if <5% loss after 12 weeks.
• Safety: fetal cleft palate - pregnancy test q mo. Elevated heart rate, suicidal ideation, glaucoma, sleep disorders, impaired cognition, metabolic acidosis. DEA Class IV and REMS program
• Adverse events >5% and 1.5 times greater than placebo: paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Topiramate-Phentermine Phase III TrialPlacebo, 48mg/7mg & 96mg/15mg
Allison DB et al. Obesity. 20(2):330-42, 2012
Naltrexone/Bupropion• A 3-week dose escalation to 16/180 mg SR
bid
• HgbA1c dropped 0.5% in diabetics
• Adverse events >5% and >1.5 times control: Nausea, headache, constipation, dizziness, vomiting, insomnia, dry mouth & hot flashes
• Not scheduled by DEA, reduces cravings and cardiovascular safety trial stopped and will be reinitiated (to evaluate BP & pulse rate)
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Bupropion 360 & Naltrexone 32 mgPlacebo
(N=511)NB32 (N=471)NB16 (N=471)
0 8 16 24 32 40 48 56-10
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-2
0
-1.3%
-5.0%-6.1%†
Week
Chan
ge fr
om b
asel
ine
(%)
0 8 16 24 32 40 48 56-10
-8
-6
-4
-2
0
-1.8%
-6.7%
-8.1%
Week
Chan
ge fr
om b
asel
ine
(%)
ITT-LOCF Observed
Placebo-subtracted weight lossWeek 56NB16: -3.7%NB32: -4.8%
Placebo-subtracted weight lossCompletersNB16: -4.9%NB32: -6.2%
P<0.001 for NB16 and NB32 vs. Placebo at all time points
PlaceboCompleters (N=290)
NB32Completers (N=296)
NB16Completers (N=284)
Completers
Greenway FL et al. Lancet. 376(9741):595-605, 2010
Liraglutide 3 mg
• Same parenteral drug used to treat diabetes, but at a higher dose. The dose is escalated 0.6 mg/wk to 3mg.
• Common side effects were nausea, vomiting, diarrhea, and constipation usually mild to moderate and transient.
• Incidence of pancreatitis, gall stones and breast neoplasms were low but greater in the liraglutide group.
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Completers on Liraglutide 3 mg
-12
-10
-8
-6
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-2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Liraglutide 3mg
9.2%
% W
tLos
s
Weeks
Placebo
3.9%
Greenway FL et al. Presentation Obesity Week, Boston, Nov, 2014
Zonisamide 360 mg & Bupropion 360 mg)Weight Loss at 1 Year of Treatment
-1.2%
-11.6%-12.1%
-12.5%-12.9%
-10.9%
-14.9%-16%
-15%
-14%
-13%
-12%
-11%
-10%
-9%
-8%
-7%
-6%
-5%
-4%
-3%
-2%
-1%
0%
Mea
n W
eig
ht
Lo
ss
Placebo (a)
(N=72)
Z120/B280
(N=27)
Z120/B360
(N=36)
Z240/B280
(N=36)
Z240/B360
(N=26)
Z360/B280
(N=32)
Z360/B360
(N=39)
(a) Placebo weight loss through 24 weeks
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Phentermine Adds to LorcaserinWeight Loss
A. LOCF Lorcaserin 10mg/Phentermine 15mg BID B. Completer analysis projects to weight loss projects to 10.8% 13%
Smith SR et al. ASPB Poster presented Washington DC, Sept/Oct 2015.
Efficacy of Obesity Drugs• Drug• Phentermine• Orlistat• Lorcaserin• Topiramate-Phentermine• Bupropion-Naltrexone• Liraglutide• Lorcaserin-Phentermine• Bupropion-Zonisamide
(Off-label Use)
Average Weight Loss LOCF• 3.6% > placebo• 2.75% > placebo• 3.3% > placebo• 9% > placebo• 4.8% > placebo• 5% > placebo• 5.9% > placebo• 9% > placebo
(Off-label Use)
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Gastric Bypass Weight Loss Requires the Melanocortin-4 Receptor
A. Wild-type mice with Roux-en-Y B. MC-4 receptor knockout mice with Gastric Bypass or Sham surgery Roux-en-Y Gastric Bypass or Sham surgery
Hatoum IJ et al. J Clin Endocrinol Metab. 2012;97(6):E1023-31
Serotonin Agonists Add to Gastric Bypass Weight Loss – Not Topiramate
Carmody JS et al. Endocrinology. 2015;156(9):3183-91
2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Frank L. Greenway, MD
Conclusions
• Obesity is a chronic disease, and long-term weight loss usually requires changing physiology, but lifestyle programs help, are safe, and should be part of treatment
• Obesity trials evaluate the drug & lifestyle Rx• Treatment requires weighing risks & benefits• Many more obesity medication options now
exist and treating obesity after obesity surgery requires more research.
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