Obesity is a treatable chronic disease. With nearly 2 billion individuals worldwide classified as being overweight and 650 million as having obesity, it is critical to optimize implementation of existing treatment interventions and develop novel therapies to mitigate the obesity pandemic. Anti-obesity medications are one of the essential tools in our medical toolbox to help patients achieve their health and weight goals. In this webinar, Dr. Jastreboff discusses current use of anti-obesity pharmacotherapy, mechanisms involved, and agents in various stages of development with considerations for next steps. The presentation aims to inspire development of innovative therapeutics while optimizing use of existing agents to address the urgent need to effectively and sustainably treat millions of individuals with obesity around the world. Key Topics Include: - Understand the role of anti-obesity pharmacotherapy in the treatment of obesity - Describe current anti-obesity pharmacotherapy - Discuss anti-obesity medications under development

1. Obesity Series 2020
Anti-Obesity Pharmacotherapy:
Where are we now?
Where are we going?
Ania Jastreboff, MD, PhD
Associate Professor of Medicine
(Endocrinology & Metabolism) and
Pediatrics (Pediatric Endocrinology),
Yale University School of Medicine

2. Obesity Series 2020
Anti-Obesity Pharmacotherapy:
Where are we now?
Where are we going?
Dr. Ania Jastreboff discusses the current use of
anti-obesity pharmacotherapy, mechanisms
involved, and agents in various stages of
development with considerations for next steps.

3. S L I D E 2
Anti-Obesity Pharmacotherapy
Where are we now? Where are we going?
Ania M. Jastreboff, MD, PhD
Associate Professor, Yale University
Internal Medicine, Endocrinology & Metabolism
Pediatrics, Pediatric Endocrinology
American Board of Obesity Medicine, Diplomate
American Physiological Society
October 22, 2020

4. Disclosures
• Consultant: Novo Nordisk and Eli Lilly
• Research Support: American Diabetes Association,
Novo Nordisk, Eli Lilly, NIH/NIDDK

5. Obesity
…..

6. Obesity
62 yo firefighter
BMI 47kg/m2
Pmhx:
T2DM (A1c 8.5%)
hypertension
hyperlipidemia
Medications:
pioglitazone, sitagliptin
lisinopril, atorvastatin, aspirin
Fmhx: CVD/CAD
25 yo preschool teacher
BMI 57kg/m2
Pmhx:
PreDM (A1c 5.9%)
Medications:
OCP
Fmhx:
Strong family h/o T2DM
Both parents have T2DM

7. A majority of individuals in the United States
are overweight or have obesity
> 42% of adults in U.S. have obesity (BMI ≥30kg/m2)
NCHS Data Brief, No 288, October 2017
>71% of adults in U.S. are overweight (BMI ≥25kg/m2)
or have obesity (BMI ≥30kg/m2)
Body mass index (BMI kg/m2)
BMI ≥ 30 Obesity
BMI 25-29.9 Overweight
BMI 18.5-24.9 Lean

8. • excess fat accumulation that represents a risk to health
Obesity: a chronic disease
Obesity-related diseases
Adapted from : Daniel, Soleymani, Garvey, 2013 and slides Tim Garvey

9. Obesity and COVID-19
Characteristics:
• Mean age 62
• 63% Men
• 72% any chronic condition
• 40% Obesity
• 37% Hypertension
• 26% Hyperlipidemia
• 25% Diabetes
Required
Hospitalization
1) Age
(OR 66.8 / OR 10.9)
2) Obesity
(OR 6.2 / OR 4.3)
3) Heart Failure
(OR 4.3)
Strongest risk for
hospitalization
Petrilli C et al, medRxiv, 2020
NYC
Prevalence of
Obesity: 22%

10. Lifestyle Change (Professionally-directed)
Surgery
Post-surgical combinations
Lifestyle Change (Self-directed )
Treatment of obesity
Pharmacotherapy
Figure Adapted from L. Kaplan, Blackburn 2018; Apovian CM Aronne LJ
Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.

11. Timeline of recent Anti-Obesity Medications (AOMs)
1999 2008 2012
1997 2014
Orlistat
(Xenical)
Lorcaserin
Naltrexone/Bupropion
(Contrave)
Phentermine/Topiramate
(Qsymia)
Liraglutide
(Saxenda)
1959
Phentermine
Rimonabant Sibutramine
Fen-Phen
2010
X X X
Slide: Ania M. Jastreboff, MD, PhD
X

12. Anti-Obesity Medications (AOMs)
FDA-approved
Phentermine
(Adipex™, Ionamin™)
Phentermine / Topiramate
(Qsymia™)
Bupropion / Naltrexone
(Contrave™)
Liraglutide
(Saxenda™)
Orlistat
(Xenical™)
Medications that
promote weight loss
(off-label)
Metformin
Topiramate
Zonisamide
Bupropion
Naltrexone
Dulaglutide
Liraglutide
Exenatide
Semaglutide
Lixisenatide
Albiglutide
Pramlintide
Canagliflozin
Dapagliflozin
Empagliflozin
GLP-1a
SGLT2i

13. Anti-Obesity Medications (AOMs)
FDA-approved
Phentermine
(Adipex™, Ionamin™)
Phentermine / Topiramate
(Qsymia™)
Bupropion / Naltrexone
(Contrave™)
Liraglutide
(Saxenda™)
Orlistat
(Xenical™)
Indication for AOMs:
• BMI >30kg/m2
• BMI >27kg/m2 with
co-morbidities
(T2DM, HTN, HLD)

14. Obesity remains undertreated with medical therapy
• Nearly half (46%) of adults in the U.S. meet recommendations for anti-
obesity pharmacotherapy (BMI ≥30 or BMI ≥27 kg/m2 with comorbidity)
• 2% of those adults receive proper pharmacotherapy treatment
Thomas CE et al, Obesity, 2016; Figure Lou Aronne Blackburn 2018.
Obesity Type 2 Diabetes
US
Adult
Population
(%)

15. Mechanisms of anti-obesity medications
⬆️ energy
expenditure
⬇️ energy
intake
⬇️ energy
absorption
Anti-Obesity
Medications
19th century
thyroid hormone
1920s
dinitrophenol
(DNP)
Fat
orlistat
Glucose
SGLT2 inhibitors

16. Figure Adapted from Zheng & Berthoud et al. Physiology. 2008;23 75-83.
Energy regulation and obesity pathophysiology
Genetic
Central
Peripheral
GLP-1
GIP
glucagon
leptin

17. neural
circuitry
Cognitive/
Executive
Hedonic/
Salience
Regions of the brain working in concert to control
eating behavior
Homeostatic

18. Cognitive/
Executive
Hedonic/
Salience
Regions of the brain working in concert to control
eating behavior: Homeostatic
Recognizes hunger
 ablation
anorectic state
Recognizes fullness
ablation 
obesity
hypothalamus
Homeostatic

19. Energy regulation: hypothalamus
Figure Adapted Barsh & Schwartz, Nature Reviews Genetics 3, 589-600 (2002).
paraventricular nucleus (PVN)
lateral hypothalmus (LH)
arcuate nucleus (ARC)
hypothalmus
second-
order
neurons
first-
order
neurons
AgRP/NPY
Orexigenic
increase food intake
decrease energy expenditure
POMC/CART
Anorexigenic
decrease food intake
increase energy expenditure
Ghrelin
Leptin
+
+
Neuropeptides:
• AgRP (agouti-related protein)
• NPY (neuropeptide Y)
• CART (cocaine- and amphetamine-regulated transcript)
• α-melanocyte stimulating hormone (post-translational derivative of proopiomelanocortin, POMC)
-
Leptin
Ghrelin
Homeostatic

20. Effects of recombinant human
leptin treatment in leptin deficiency
Endocr Rev. 2006;27(7):710-718. doi:10.1210/er.2006-0040
Congenital Leptin Deficiency
• Mutation in ob gene
(ob/ob mouse)
• Undetectable leptin
levels
• Early-onset severe obesity
• Hyperphagia
• Hyperinsulinism
• Delayed puberty
(hypothalamic hypogonadism)
• Altered immunity
(T-cell number and function)
BEFORE treatment
with leptin
AFTER treatment
with leptin

21. Energy regulation: hypothalamus
Figure Adapted Barsh & Schwartz, Nature Reviews Genetics 3, 589-600 (2002).
paraventricular nucleus (PVN)
lateral hypothalmus (LH)
arcuate nucleus (ARC)
hypothalmus
second-
order
neurons
first-
order
neurons
AgRP/NPY
Orexigenic
increase food intake
decrease energy expenditure
POMC/CART
Anorexigenic
decrease food intake
increase energy expenditure
Ghrelin
Leptin
+
+
Neuropeptides:
• AgRP (agouti-related protein)
• NPY (neuropeptide Y)
• CART (cocaine- and amphetamine-regulated transcript)
• α-melanocyte stimulating hormone (post-translational derivative of proopiomelanocortin, POMC)
-
Leptin
Ghrelin
Homeostatic

22. Melanocortin 4 receptor
(MC4R) mutation
• Obesity
• High growth velocity
• Tall stature
• Insulin resistance
Proopiomelanocortin
(POMC) mutation
• Early-onset obesity
• Hyperphagia
• Hypopigmentation, red hair
• ACTH deficiency
– adrenal crisis as neonates
(Adrenal Insufficiency)
Monogenic obesity

23. Kuhnen P et al. NEJM 2016
Setmelanotide:
MC4R agonist treatment of POMC deficiency

24. Setmelanotide:
MC4R agonist treatment of POMC deficiency
Kuhnen P et al. NEJM 2016
POMC deficiency
Mean weight loss: 70 lbs
(25% TBW) (N=10)
July 2020 - FDA granted
rare pediatric disease
designations for the
treatment of POMC deficiency
obesity and leptin receptor
(LEPR) deficiency obesity
Currently under review by FDA
November 2020

25. neural
circuitry
Cognitive/
Executive
Regions of the brain working in concert to control
eating behavior: Hedonic/Salience
Homeostatic
Hedonic/
Salience

26. CNS and anti-obesity medications
dorsal striatum
D2 receptor availability
is significantly lower in
individuals w/ obesity
obese
lean
Wang, Volkow et al, Lancet, 2001; Figure of brain adapted Robertson, NMLS, Shutterstock, 2016.
lorcaserin
phentermine
Norepinephrine
bupropion
Opioid
naltrexone
GABA
topiramate
Hedonic/
Salience

27. neural
circuitry
Regions of the brain working in concert to control
eating behavior: Cognitive/Executive
Homeostatic
Hedonic/
Salience
Cognitive/
Executive

28. Cognitive/executive: Prefrontal cortex
• Executive function
• Decision-making
• Impulse control
• Visceromotor
• Choices (food)
Arnsten A. Nature Reviews Neuroscience, 2009

29. CNS control of food intake
Homeostatic
Cognitive
Hedonic
GLP-1
GIP
Glucagon

30. Mechanisms of anti-obesity medications
⬆️ energy
expenditure
⬇️ energy
intake
⬇️ energy
absorption
Anti-Obesity
Medications
orlistat
Phentermine
Phentermine/Topiramate
Bupropion/Naltrexone
Liraglutide

31. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AGRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist
- Incretin - secreted inresponse to food intake
Hedonic
Homeo
static
⬇️ energy
absorption
⬇️ energy intake

32. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AGRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist
- Incretin - secreted inresponse to food intake
Hedonic
Homeo
static
⬇️ energy intake

33. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AGRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist
- Incretin - secreted inresponse to food intake
Hedonic

34. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AgRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist
- Incretin - secreted inresponse to food intake

35. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AGRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist
- Incretin - secreted inresponse to food intake

36. Mechanism of action: FDA-approved AOMs
Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Medication Mechanism of action to promote weight loss
Orlistat
(Xenical)
Gastric and pancreatic lipase inhibitor
- malabsorption of 30% of ingested fat
Phentermine
(Adipex, Ionamin,
Lomaira)
Sympathomimetic amine
Increases NE (and DA)
Phentermine /
Topiramate
(Qsymia)
Sympathomimetic amine (phentermine)
GABA-receptor modulation (topiramate)
- inhibitory effect of NPY/AGRP
Bupropion /
Naltrexone
(Contrave)
Reuptake inhibitor of DA and NE (bupropion)
- activates POMC neurons
Opioid antagonist (naltrexone)
- blocks the feedback inhibition of by β-endorphin
Liraglutide
(Saxenda)
GLP-1 receptor agonist - incretin - hormone secreted in
response to food intake - peripheral and central action
Hedonic
Homeo
static
⬇️ energy intake
⬇️ energy
absorption

37. Mechanism of action:
medications that promote weight loss (off-label)
Medication Indication
Mechanism of Action to
promote weight loss
Metformin
(Glucophage, Glucophage XR, Fortamet,
Glumetza, Riomet)
Type 2 diabetes
Unknown
(Decrease hepatic glucose production)
Topiramate or Zonisamide
(Topamax or Zonagran)
Seizures
GABA-receptor modulation (topiramate)
Unknown (zonisamide)
Canagliflozin or empagliflozin
or dapagliflozin
(Invokana, Jardiance, Farxiga)
Type 2 diabetes
SGLT-2 inhibitors
(calorie loss/leakage due to glucosuria)
Liraglutide or Dulaglutide or
Semaglutide or Exenatide or
Lixisenatide or Albiglutide
(Victoza or Trulicity or Ozempic or Byetta or
Bydureon or Adlyxin or Tanzeum)
Type 2 diabetes GLP-1 receptor agonists

38. GLP-1 analogues: mechanism of action

39. GLP-1
• directly activates
POMC/CART neurons
• indirectly inhibits (via
GABAergic transmission)
the NPY/AgRP neurons
• collectively results in signals
that reduce food intake
J Clin Invest DOI: 10.1172/JCI78371
AgRP/NPY
Orexigenic
increase food intake
decrease energy expenditure
POMC/CART
Anorexigenic
decrease food intake
increase energy expenditure
GLP-1 analogues mechanism of action in the brain

40. Madsbad, Diabetes, Obesity and Metabolism, 2016
GLP-1 analogues: weight loss

41. GLP-1 analogues
TBWL ⬇️ 18%

42. Anti-obesity medication in development

43. Brandt et al. J Endo, 2018
GLP-1/GIP dual-agonist
GLP-1/Glucagon dual-agonists
GLP-1/GIP/Glucagon triple-agonist
Multi-agonists in development
Multi-agonists:
The next frontier

44. Incretins-based therapy
Peptide hormones:
• GLP-1 – Glucagon-Like Peptide 1
Drucker D, J Clin Endocrinol Metab, 2016; Brandt et al. J Endo, 2018.
GLP-1/GIP dual-agonist

45. Incretins-based therapy
Peptide hormones:
• GLP-1 – Glucagon-Like Peptide 1
• GIP – Glucose-dependent Insulinotropic Polypeptide
Food
ingested
account for 50-70%
of total insulin
secretion after meal
Drucker D, J Clin Endocrinol Metab, 2016; Brandt et al. J Endo, 2018.
GIP
GLP-1
glucose dependent
insulin secretion
from beta cells
GLP-1/GIP dual-agonist

46. Incretins based therapy
Enteroendocrine (peptide) hormones:
• GLP-1 – Glucagon-Like Peptide 1
• GIP – Glucose-dependent Insulinotropic Polypeptide
Drucker D, J Clin Endocrinol Metab, 2016; Brandt et al. J Endo, 2018.
GLP-1/GIP dual-agonist

47. Frias JP et al. DM Obesity Metab, 2020
Average A1c
reduction:
1.7-2.0%
N=111, T2DM, avg A1c 8.4%, avg BMI 32, Age 57
Dual-agonist (GLP-1/GIP): tirzepatide
Average
weight loss:
11.5-12.5 lbs
12 weeks
Weight
HbA1c

48. Multi-agonists:
The next frontier
Brandt et al. J Endo, 2018
GLP-1/Glucagon dual-agonists
GLP-1/GIP/Glucagon triple-agonist
Multi-agonists
GLP-1/GIP dual-agonist

49. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Obesity is a
disease
Heterogeneous
Chronic
Complex

50. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Heterogeneous
Chronic
Complex
Heterogeneous
Wide variability of responses
to anti-obesity medications
Obesity is a
disease

51. Variable response to anti-obesity medications
Inadequate response
(replace)
Highly effective
Partially effective (add
new drug)
Number
of
patients
Weight Loss
10-20%
TBWL
0
5%
TBWL
Figure adapted from Blackburn 2018.

52. 0
10
20
30
40
50
<0 0 5 10 15 20 25
Percent Weight Loss
0
10
20
30
40
50
<0 0 5 10 15 20 25
Subjects
(%)
Percent Weight Loss
0
10
20
30
40
50
-10 -5 0 5 10 15 20 25
Subjects
(%)
Percent Weight Loss
Medication 1
Medication 3
Medication 2
Slides: Lee Kaplan, MD, PhD, Sriram Machineni, MD
Variability of response to anti-obesity medications
0
10
20
30
40
50
<0 0 5 10 15
Percent Weight Loss
Medication 4

53. Variability of response
Kelly A, Auerbach P, et al, NEJM, 2020
RCT (N=251)
12-17 yo
BMIavg 35 kg/m2
A1cavg 5.3%

54. Variability of response
Kelly A, Auerbach P, et al, NEJM, 2020
Why are these
patients
responding?
RCT (N=251)
12-17 yo
BMIavg 35 kg/m2
A1cavg 5.3%
Obesity is a
heterogeneous
disease

55. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Heterogeneous
Chronic
Complex
Obesity is a
disease

56. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Heterogeneous
Chronic
Complex
No cure for obesity (yet)
necessitating lifelong treatment
Obesity is a
disease

57. Kelly A, Auerbach P, et al, NEJM, 2020
Long-term therapy is needed for the treatment of obesity

58. Long-term, on-going therapy is needed for…
Schultes, Visc Med, 2016, figure adapted Ania Jastreboff, MD, PhD.
Blood
Pressure
(BP)
Months
12
6 24 36
Life intervention effect
Drug effect
Drug continued
Drug stopped
medication
stopped
blood
pressure
increases
Hypertension

59. Long-term, on-going therapy is needed for…
Schultes, Visc Med, 2016, figure adapted Ania Jastreboff, MD, PhD.
Weight
(kg)
Months
12
6 24 36
Life intervention effect
Drug effect
Drug continued
Drug stopped
medication
stopped
weight
regain
Obesity
Metabolic
adaptation?
Disease
progression?
Obesity is a
chronic disease

60. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Heterogeneous
Chronic
Complex
Obesity is a
disease

61. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Heterogeneous
Chronic
Complex
Combination therapy is
often needed
Obesity is a
disease

62. Time (months)
Rx 1
Rx 3
Rx 1
effect
Rx 3
effect
Hemoglobin
A1c
Rx 2
0 6 12 18 24
Rx 2
Rx 1
Rx 3
X
Type 2 Diabetes
Combination therapy is needed for the treatment of…

63. Combination therapy is needed for the treatment of…
Time (months)
Rx 1
Rx 3
Rx 1
effect
Rx 3
effect
Weight
(lbs.)
Rx 2
0 6 12 18 24
Rx 2
Rx 1
Rx 3
Blackburn, L. Kaplan
X
Obesity
Obesity is a
complex disease

64. Key clinical concepts in treating obesity
with anti-obesity pharmacotherapy
Obesity is a
disease
Heterogeneous
Chronic
Complex
Wide variability of responses
to anti-obesity medications
No cure for obesity (yet)
necessitating lifelong treatment
Combination therapy is
often needed

65. Our patients…
62 yo firefighter
BMI 47kg/m2
Pmhx:
T2DM (A1c 8.5%)
hypertension
hyperlipidemia
Medications:
pioglitazone, sitagliptin
lisinopril, atorvastatin, aspirin
Fmhx: CVD/CAD
25 yo preschool teacher
BMI 57kg/m2
Pmhx:
PreDM (A1c 5.9%)
Medications:
OCP
Fmhx:
Strong family h/o T2DM
Both parents have T2DM

66. Our patients…
62 yo firefighter
25
30
35
40
45
50
10/1/14 10/1/15 10/1/16 10/1/17 10/1/18 10/1/19
metformin
Liraglutide 1.8
Liraglutide 3.0 Naltrexone/bupropion
semaglutide
Lost 78 lbs
25% TBWL
empagliflozin
BMI 34.7
A1c 6.4%
BMI 47.5
A1c 8.5%
25 yo preschool teacher
BMI 57kg/m2
Pmhx:
PreDM (A1c 5.9%)
Medications:
OCP
Fmhx:
Strong family h/o T2DM
Both parents have T2DM

67. Our patients…
62 yo firefighter 25 yo preschool teacher
25
30
35
40
45
50
10/1/14 10/1/15 10/1/16 10/1/17 10/1/18 10/1/19
metformin
Liraglutide 1.8
Liraglutide 3.0 Naltrexone/bupropion
semaglutide
Lost 78 lbs
25% TBWL
25
30
35
40
45
50
55
60
10/18/17 10/18/18 10/18/19
metformin
liraglutide
Naltrexone
bupropion
Lost 129 lbs
41% TBWL
BMI 57
A1c 5.9%
empagliflozin
BMI 33.5
A1c 5.3%
BMI 34.7
A1c 6.4%
BMI 47.5
A1c 8.5%

68. neural
circuitry
neural
response
weight
gain
• Leptin & ghrelin
• Glucose levels
• Insulin
• Cortisol
• GLP-1 & GIP
Concluding thoughts:
Moving forward development of anti-obesity medications
altered altered
eating
behavior
& insulin resistance
Hormones/metabolic factors
Figure adapted: Jastreboff, Doctoral Thesis, 2011; ref: Jastreboff, Diabetes 2016; Page, JAMA, 2011; Jastreboff, Diabetes Care, 2014.
Obesity
Therapeutic implications  targeting central mechanisms
Cognitive/
Executive Hedonic/
Salience
Homeostatic
Anti-obesity
medications
weight
loss
treat

69. Thank you
Questions?

70. Thank you for participating!
Ania Jastreboff, MD, PhD
Associate Professor of Medicine
(Endocrinology & Metabolism) and
Pediatrics (Pediatric Endocrinology),
Yale University School of Medicine
CLICK HERE to learn more
and watch the webinar