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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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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Fenfluramine1-Year Rx & 1-Year Follow-up

0

5

10

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

o.

18 m

o.

20 m

o.

22 m

o.

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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No Behavior Modification

-7

-6

-5

-4

-3

-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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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


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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


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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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0

4

8

12

16

20

24

28

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.


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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

-7

-6

-5

-4

-3

-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


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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

94

92

90

10472 806448 564024 32160 8 88 96


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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.


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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)


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Bupropion 360 & Naltrexone 32 mgPlacebo

(N=511)NB32 (N=471)NB16 (N=471)

0 8 16 24 32 40 48 56-10

-8

-6

-4

-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.


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Completers on Liraglutide 3 mg

-12

-10

-8

-6

-4

-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


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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)


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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


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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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nonsurgical treatment of obesity and the...

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