pharmacotherapy in obesity

1. Pharmacotherapy of obesity
1
‫دهنده‬ ‫ائه‬‫ر‬‫ا‬:‫مکی‬‫ر‬‫نا‬ ‫الهام‬
‫تغذیه‬ ‫علوم‬ ‫ی‬ ‫تخصص‬ ‫ای‬‫ر‬‫دکت‬ ‫ی‬‫دانشجو‬
‫اهنما‬‫ر‬ ‫استاد‬:‫دکتر‬‫ر‬‫پو‬ ‫سعید‬ ‫آتوسا‬
‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬‫بهشتی‬ ‫شهید‬

2. OUTLINE
• INTRODUCTION
• HOMEOSTATIC MECHANISMS CONTROLLING ENERGY BALANCE
• DEFINITION AND MEASUREMENT
• TREATMENT OF OBESITY
• PHARMACOTHERAPY OF OBESITY
• HISTORICAL ASPECTS
• CONTEMPORARY ANTI-OBESITY DRUGS
• FUTURE DEVELOPMENTS
• CONCLUSION 2

3. INTRODUCTION
• “Globesity” on the rise.
• According to WHO, obesity is one of the most common public
health problems including cardiovascular disease, type 2
diabetes, cancer in both developed and developing countries
• According to the WHO Report 2012, globally one in six adults
is obese and nearly 2.8 million individuals die each year due
to overweight or obesity
3

4. INTRODUCTION
• The impact of obesity on morbidity, mortality, and health care
costs is profound.
• Obesity is estimated to add $3,559 annually to per-patient
medical expenditures compared with patients who do not
have obesity
4

5. ‫ان‬‫ر‬‫ای‬‫گساالن‬‫ر‬‫بز‬ ‫در‬‫چاقی‬ ‫و‬ ‫ن‬‫ز‬‫و‬‫اضافه‬‫شیوع‬ ‫ملی‬‫مطالعه‬
89,404 men and women 15 to 65 years of age
Janghorbani M, Obesity (Silver Spring). 2007
Men Women
Underweight
6.3%
Overweight
42.8%
Obese
11.1%
Normal weight
39.2%
Underweight
5.2%
Overweight
57%
Obese
25.2%
Normal weight
12.6%
5

6. Rank Country Male % Female %
1 Papua New Guinea 74.8 79.5
7 Egypt - 46.6
9 Qatar 34.6 45.3
18 USA 32.2 35.5
22 UAE 17.1 31.4
25 Kuwait 27.5 29.9
26 Turkey 16.5 29.4
38 England 24.1 24.9
66 Iran 9.1 19.2
89 Finland 14.9 13.5
91 Brazil 8.9 13.1
107 Italy 10.5 9.1
136 China 2.4 3.4
137 Japan 2.3 3.4
‫در‬ ‫چاقی‬ ‫جهانی‬ ‫شیوع‬‫گساالن‬‫ر‬‫بز‬‫سال‬‫در‬2010
Source: International Obesity Task force
6

7. HOMEOSTATIC MECHANISMS
CONTROLLING ENERGY BALANCE
• Arcuate Nucleus (ARC) located in Hypothalamus
• primary regulators of energy homeostasis
• Arcuate nucleus neurons are called „first order‟ neurons since
peripheral factors transported actively across the blood brain
barrier and bind to respective receptors on(ARC)
7

8. Arcuate nucleus
Orexigenic and anorexigenic systems
8
Lateral hypothalamus express Orexigenic neuropeptides
Paraventricular nucleus express Anorexigenic neuropeptides

9. • Second order neurons project to the nucleus tractus solitarius
(NTS) in the brainstem that is considered an integral part of the
brain stem that receives inputs and processes peripherally-derived
energy-status signals such as leptin, ghrelin, and glucose as well as
signals from hypothalamic neurons (paraventricular nucleus, lateral
hypothalamus and arcuate nucleus)
• Monoamine neurotransmitters, norepinephrine (NE) and serotonin
(5-HT), are synthesized in brain stem and regulate food intake
9

10. HOMEOSTATIC MECHANISMS
CONTROLLING ENERGY BALANCE
10

11. 11

12. Energy Expenditure
• Symp. Nerv. Sys. (sometimes with thyroid hormone) in regulation of
energy expenditure.
• Both ‘white’ and ‘brown’ fat cells have a major role in
thermogenesis.
• Mitochondrial uncoupling proteins (UCP).
• Noradrenaline (β3), increases PPAR-γ.
12

13. DEFINITION AND MEASUREMENT
• It is defined as abnormal growth of the adipose tissue due to
enlargement of fat cell size (hyper trophic obesity) or an increase
in fat cell number (hyperplastic obesity) or a combination of
both.
13

14. 14

15. 15

16. Diet and life-style modification
 Diet and life-style modification represent the first-line
treatment in the management of obesity.
 Pharmaceutical intervention may be necessary for the
achievement of long-term, clinically relevant weight loss.
16
These often fail to provide sustainable weight loss

17. 17
There is a need for adjunctive therapies that can
help patients who are not able to lose or sustain
sufficient weight loss to improve health with
lifestyle interventions alone.

18. Medication to treat obesity
 Trials conducted in academic medical centers have shown
that adding weight loss medication to lifestyle counseling
increases weight loss, compared with counseling alone.
 Medication is thought to facilitate adherence to diet and
calorie recommendations by reducing hunger and
increasing satiation .
18

19. Indication for Pharmacotherapy
• BMI ≥ 30 kg/m².
OR
• BMI ≥ 27 kg/m²- For patients who have concomitant
• obesity-related diseases and for whom dietary and
physical activity therapy has not been successful.
• Drug therapy is adjunctive to lifestyle intervention.
19

20. PHARMACOTHERAPY: HISTORICAL ASPECTS
• Soranus of Ephesus a Greek physician in the second century
He prescribed elixirs of laxatives , as well as heat, massage, and
exercise. This remained the mainstay of treatment for well over a
thousand years.
20

21. PHARMACOTHERAPY: HISTORICAL ASPECTS
• 1920s - Thyroid hormone
• thyroid hormones were used as weight loss agents in obese
euthyroid people.
• The treatment had modest effect on weight and produced
unfavourable thyrotoxic symptoms, such as palpitations,
tremor and restlessness
21

22. PHARMACOTHERAPY: HISTORICAL ASPECTS
• 1933 - 2,4-Dinitrophenol (DNP)
• worked by uncoupling the respiratory chain, favouring
mitochondrial production of heat instead of energy.
• Common side effects were sensation of body warmth
associated with sweating, and overdose lead to rising body
temperature, ultimately with the risk of fatal hyperthermia
22

23. PHARMACOTHERAPY: HISTORICAL ASPECTS
• Late 1930s – Amphetamine (Benzedrine)
• amphetamines became a popular approach to produce short
term weight loss, which resulted from enhanced
norepinephrine/dopamine stimulation of CNS regions POMC
neurons and reward pathways .
• the potential of abuse and risk of psychosis, cardiovascular
toxicity and associated deaths ultimately led to a ban from the
market
23

24. PHARMACOTHERAPY: HISTORICAL ASPECTS
• Phentermine (Adipex-P®) ( 1959)
• A drug with similar pharmacology to amphetamine is a
sympathomimetic amine.
• Despite a long history of use, limited information is available with
respect to controlled trials demonstrating efficacy of phentermine
monotherapy for a year or more or regarding risk for cardiovascular
disease.
24

25. • The longest (36 wk) placebo-controlled trial(1999) evaluating 108
obese women treated with phentermine 30 mg/day administered
either continuously or intermittently (alternating months)reported
a mean weight loss of 12.2 and 13.0 kg, respectively, compared
with 4.8 kg given placebo. But only 59% of participants completed
the trial, underscoring the need for controlled long-term studies to
demonstrate safety and efficacy
25

26. • Physicians typically prescribe the generic 37.5 mg tablet and
advise patients to administer a half tablet (18.75 mg) mid
morning, once daily
• Adverse effects
• dry mouth , insomnia , palpitations, tachycardia and
hypertension
• phentermine alone is still approved by the FDA for short-
term weight management
26

27. PHARMACOTHERAPY: HISTORICAL ASPECTS
• fenfluramine (1973)
• works by releasing serotonin and partially blocking its reuptake
into nerve endings
Adverse effects
headache, diarrhea, dizziness, dry mouth, erectile dysfunction,
anxiety, insomnia, irritability.
27

28. PHARMACOTHERAPY: HISTORICAL ASPECTS
• Fenfluramine/phentermine (1992)
• induced sustained weight loss of 10% for 2 years.
• The fen/phen combination soon became an intensively marketed
diet pill, but increasing evidence pointed towards a causal link to
valvular heart disease and pulmonary hypertension, leading to its
withdrawal from the market in 1997
28

29. PHARMACOTHERAPY: HISTORICAL ASPECTS
• Sibutramine (1997)
• serotonin-norepinephrine reuptake inhibitor
• Sibutramine is rapidly metabolised generating two active
substances affecting both food intake and energy expenditure
• The use was terminated in 2010 on the basis of a post-marketing
cardiovascular outcome trial (SCOUT) showing a 16% increased
risk of non-fatal myocardial infarction and stroke in patients with
prior cardiovascular disease.
29

30. ANTI-OBESITY DRUGS
• 1) medications that act peripherally to impair dietary fat
absorption
• 2) medications that act centrally to decrease food intake
• 3) medications that facilitate energy expenditure.
30

31. ANTI-OBESITY DRUGS
• Orlistat (2000)
• Lorcaserin (2012)
• Phentermine-Topiramate - Qsymia (2012)
• Naltrexone-Bupropion – Contrave (2014)
• Liraglutide (2014)
31

32. 32

33. Drugs That Modify Fat Absorption
Orlistat (Xenical)
• Initially approved by FDA in 2000 and has since been
approved for long-term treatment of obesity in most
countries by prescription (120mg), and in some countries, it is
approved for sale in pharmacies without a prescription
(60mg).
33

34. Orlistat
Clinical Pharmacology
• Orlistat (tetrahydrolipstatin) was isolated from the bacterium
Streptomyces toxytricini
• is a potent and selective inhibitor of pancreatic and other lipases,
reducing the intestinal digestion of fat.
34

35. Orlistat
Clinical Pharmacology
• drug produces dose-dependent increase in fecal fat that peaks at
approximately 30% of dietary fat intake .
• Orlistat inhibits lipases by binding to the active center of the
enzyme and reducing the accessibility of this site for cleaving TG.
35

36. 36

37. Author/Year
Orlistat/
Placebo (n) Study Design
W/L
Orlistate(Kg)
W/L
Placebo(Kg)
Davidson et al.
(1999)
657/223 1 year wt loss + 1 year maintenance;
orlistat 120 mg tid; 600–700 kcal/day deficit diet
8.76 5.81
Finer et al
(2000)
110/108 1 year wt loss trial; orlistat 120 mg tid; 600–800
kcal/day deficit diet
3.29 1.31
Hauptman et
al.(2001)
210/213/212 1 year + 1 year maintenance; orlistat 120 or 60 mg
tid; 1000 MJ/day deficit + food diary + exercise +
video education
7.94 4.14
Krempf et al.
(2003)
242/239/237 18-month trial; orlistat 120 mg tid; 20% energy
reduced diet; food diary
7.3 4.4
Rossner et al
(2009)
242/239/237 1 year wt loss + 1 year maintenance; orlistat 120
mg tid; 600 kcal/day energy deficit
9.4 6.4
Sjostrom et al.
(2005)
343/340 1 year + rerandomized for the second year of
maintenance; orlistat 120 mg tid
10.3 6.1
Torgerson et
al.(2005)
1640/1637 4-year, double-blind, prospective study
used; orlistat 120 mg tid; 21% had
impaired glucose tolerance
10.6 6.2
37
Clinical Trials on over weight and obese patient

38. 38

39. Trials in Diabetic Patients
39Hd: hypocaleric Diet Pa: physical Activity rf: reduced fat diet

40. Trials in Hypertensive or Dyslipidemic Patients
Author/Year Intervention
1-year trial
Difference (primary and end point)
Weight
(Kg)
DBP
(mmHg)
SBP
(mmHg)
FBS
(mmol/l)
TC% LDL%
Bakris/
2002
orlistat 120 mg tid; - 600
kcal/day energy education
- 2.7 -2.4 -4 -1.84 -6.1 -6.5
Broom/
2002
orlistat 120 mg tid; 2.5 to
3.8 MJ/day energy , food
diary
-3.5 -2.5 -5 -2 -5.5 -7
Derosa/
2006
orlistat 120 mg tid; - 600
kcal/day
-1 -3 -3 -3 -2.4 -5.3
Swinburn/
2005
orlistat 120 mg tid; diet and
exercise counseling
-3.8 -2.7 -3.5 -2.3 -5
Orlistat weight loss is associated with improvements in
cardiovascular co-morbidities, and hence cardiovascular risk
40

41. Orlistate and Prevention of Weight Regain
41
Effect of orlistat on weight regain and
cardiovascular risk factors following a very-low
energy diet in abdominally obese patients: A 3-
year randomized, placebo- controlled study.

42. • patients received a very-low-energy diet for 8 weeks and
those who lost a minimum of 5% of their body weight
were randomized to lifestyle or lifestyle plus orlistat.
Weight loss continued to decline for 3 months and
remained below randomization levels at 12 months in
the orlistat group but had risen above randomization
level by 6 months in the lifestyle controls. At the end of
3 years, patients on orlistat were still −2.4 kg lighter
than the controls.
42

43. Adverse Effect
• Malabsorption of dietary fat
• flatus with discharge
• fecal urgency
• fatty/oily stool
• decreases in fat-soluble vitamins(routinely take of
multivitamin before bedtime)
• increased oxalate absorption and renal oxalate stones
• Interaction with cyclosporine and warfarin
43

44. 44

45. KEY ROLE FOR THE 5-HT R IN BODY WEIGHT
REGULATION
• 5-Hydroxy tryptophan (serotonin) is neurotransmitter/
hormone .
• Most of theme are G-protein-coupled receptors (GPCRs)
• 5-HTR that involved in the regulation of food intake and
body weight are: 5-HT1BR, 5-HT2CR
45

46. Lorcaserin (Belviq®)
• In 2012, the FDA approved lorcaserin
• exhibits high selectivity for 5-HT2C receptors and is devoid of
adverse effects associated with 5-HT2B receptor activation
46

47. Mechanism of action of lorcaserin
• activates the Gq-coupled 5-HT2C receptor in the arcuate
nucleus This causes the release of (α-MSH) at the
melanocortin-4 receptor (MC4R) reduces food intake.
• Serotonin also reduces the activity of AgRP-releasing neurons
via 5-HT1BR and reduces food intake
47

48. Lorcaserin (Belviq®)
• The FDA approved lorcaserin at a dose of 10 mg twice daily
when supplemented by a reduced calorie diet and increased
physical activity .
• The approved labeling indicates that at wk 12, if body weight
is not decreased by 5% or more, lorcaserin treatment should
be discontinued
48

49. 49

50. Behavioral Modification and Lorcaserin for
Overweight and Obesity Management [BLOOM]
• In a 2-year, double-blind, placebo-controlled study in 2010, 3,182
obese and overweight patients who were treated with placebo or
lorcaserin 10 mg/kg twice daily, obese patients lost 3.6 kg more than
controls at the end of the first year.
• the weight reduction was maintained in more patients who continued to
receive lorcaserin during year 2 (67.9%) than in patients who received a
placebo (50.3%)
• No difference in the development of valvulo pathy between drug-
treated and placebo-treated participants at 2 year
50

51. (Behavioral Modification and Lorcaserin for
Overweight and Obesity Management [BLOOM]
51

52. A One-Year RCT of Lorcaserin in Obese and
Overweight Adults: The BLOSSOM Trial(2011)
• 4,008 patients were treated with lorcaserin 10 mg BID/QD
for 2 year ,administered in conjunction with a nutritional and
physical exercise
• The participants who took lorcaserin 10 mg BID /QD/Placebo
achieved weight loss of 5.9% - 4.8% and 2.8% of their body
weight respectively at the end of 1 year.
52

53. Behavioral Modification and Lorcaserin for Obesity
Management in Diabetes Mellitus (BLOOM-DM) 2012
• In he BLOOM-DM study 604 patients with type 2 diabetes
were treated with lorcaserin 10 mg BID/placebo .
• At week 52, 37.5% of patients Drug group achieved at least
5% weight loss Vs. 16.1% of placebo group.
• Drug group achieved a mean weight loss of (4.7 kg),
compared to (1.6 kg) with the placebo.
53

54. 54

55. • Within the glycemic, lipid and blood pressure families, lorcaserin
patients achieved statistically significant improvements relative
to placebo.
• Lorcaserin was associated with significant weight loss and
improvement in glycemic control in patients with type 2 diabetes
55

56. adverse effects
• Lorcaserin was generally well tolerated.
• headache, nausea, and dizziness. These were mild in severity,
occurred early during treatment, and trended downward with
continued dosing.
56

57. • The majority of drugs launched for the treatment of obesity over
the last two decades withdrawn due to safety issues associated
with increased risk of cardiovascular and psychiatric complications.
• The failure of these medications is attributed to the multifactorial
pathogenesis and the complex neuro-hormonal regulation of
energy balance
• a disease with multiple etiologies, requires a multi-target approach
57

58. 58

59. PHENTERMINE-TOPIRAMATE (Qsymia®)
• In 2012, the FDA approved Qsymia as a combination therapy
for use with a reduced-calorie diet and increased exercise to
achieve effective weight loss
• Qsymia is a fixed dose, controlled-release containing
immediate-release phentermine hydrochloride and extended-
release topiramate
59

60. Mechanism Of Action Qsymia
• Appetite suppressant effect of phentermine, a potent inhibitor of
the NE transporter, mediated by activation of POMC arcuate
nucleus neurons
60

61. • Topiramate a GABA agonist, was approved for the treatment of
epilepsy (exhibited decreased calorie intake and weight loss)
• Topiramate appetite suppression due to modulation of voltage-
gated ion channels, increased activity at GABA-A receptors
and/or inhibition of AMPA/kainite glutamate receptors
61

62. • Clinical studies demonstrate topiramate's ability to inhibit
compulsive food cravings and addictive behavior.
• Patients with a binge eating disorder receiving topiramate (starting
dose of 25 mg/day, titrated over 8-wks to 400 mg/day)
experienced reductions in binge eating days and episode
frequency and body weight compared to placebo.
• Qsymia® is the first combination therapy approved for the
treatment of obesity that targets both homeostatic (phentermine)
and non-homeostatic (topiramate) mechanisms.
62

63. 63

64. • clinical development began with a 24-week proof-of-concept
RCT that utilized a factorial design to compare the individual
components and the combination against placebo.
Subsequently, three phase 3 trials were conducted
• OB-301 for 28 weeks
• two1-year trials,OB-302 and OB-303
• diet and lifestyle counseling were provided for patients in all
trials
64

65. Proof-of-Concept Trial ( 2006)
• In this 24-week RCT conducted at the Duke University North Carolina,
by Gadde et al, 200 obese patients without diabetes were randomized
to receive phentermine 15 mg, topiramate 100 mg, combination
(PHEN/TPM), or placebo, with 50 patients assigned to each treatment
arm.
• changes in weight were −2.2 kg for placebo, −5.3 kg for phentermine,
−6.6 kg for topiramate, and −11.4 kg for PHEN/TPM. Percentages of
patients with 10% or more weight loss were 8% with placebo, 14% with
phentermine, 16% with topiramate, and 50% with PHEN/TPM.
65

66. 66
(2011)
(2012)
(2013)

67. PRESCRIBING INFORMATION FOR (QSYMIA)
• Available doses: Capsules of PHEN/TPM 3.75/23, 7.5/46,
11.25/69, and 15/92
• Patients with renal or hepatic impairment: Do not exceed 7.5/46
• Contraindications: Pregnancy, glaucoma, hyperthyroidism,
monoamine oxidase inhibitors.
• Advers Effects:
• Paresthesia, dizziness, dysguesia, insomnia, constipation, and
dry mouth.
67

68. 68

69. Bupropion plus Naltrexone (Contrave)
• Contrave is a fixed-dose combination of naltrexone sustained-
release (SR) and bupropion SR was approved by the FDA in 2014.
• Bupropion, a DA ans NE reuptake inhibitor was approved for
depression and smoking cessation and showed modest weight
loss.
69

70. Bupropion plus Naltrexone (Contrave)
• Naltrexone, approved for the treatment of opioid addiction
and alcoholism, is not associated with weight reduction.
• However, the combination with bupropion and naltrexone
leads to a synergistic effect on weight control, although the
mechanism by which the naltrexone/bupropion combination
induces weight loss is not entirely understood
70

71. MECHANISM OF ACTION
• The hypothalamus( arcuate nucleus) is thought to be an
important regulatory center for food intake and energy
expenditure regulation
• Bupropion has shown to stimulate (POMC) neurons that
release (α-MSH) which, in turn, binds to (MC4) receptors.
• The binding of α-MSH to MC4 receptors initiates a cascade of
actions that results in weight loss via reduced energy intake
71

72. MECHANISM OF ACTION
• When α-MSH is released, POMC neurons release β-
endorphin, an endogenous agonist of the mu-opioid receptor
that mediates a negative feedback loop on POMC neurons,
leading to a decrease in the release of α-MSH . Blocking this
inhibitory feedback loop is action of naltrexon
72

73. 73

74. TITLES/Year Number /
Duratin
IINTERVENTION RESULTS LIMITATION
(COR-I)
(2010)
1742/56 w (NB16)
16mg- 360mg/day
(NB32)
32mg-360mg/day
- Placebo
- NB16: -5%
NB32: -6.14%
Placebo: -1.33%
- subjects were generally
healthy middle-aged white
women with completion rate of 50%
in all groups
- excluded individuals with
diabetes or activecardiovascular
disease
- only compared with placebo
(in all 4 studies)
(COR-II) –
(2011)
1300/28w - NB32
- Placebo
- NB32: -6.45%
Placebo: -1.89%
- subjects were generally
healthy middle-aged white
women with completion rate of
54% in all groups
- individuals with diabetes were
excluded
- duration of study was only 28 week
(COR-Diabetes)
(2013)
890/56w -NB32
-Placebo
- NB32: -5.03%
Placebo: -1.75%
- study excluded subjects who
were taking insulin therapy
(which can promote weight
gain) and GLP-1 (which is
asscoiated with mild weight loss)
- relatively high drop-out rate
(CORBMOD) 122
(2011)
793/56w - NB32
- Placebo
- NB32: -9.02%
Placebo: -5.08%
- lack of male participants and
participants with significant
comorbidities
74

75. • Contrave®treatment is initiated with once daily tablet of 8 mg
naltrexone and 90 mg bupropion for wk 1, and escalated to a
maintenance 2 tablets twice daily for a total daily dose of 32
mg/naltrexone and 360 mg bupropion
• Adverse Effect
Nausea, headache, dizziness, vomiting and dry mouth.
75

76. 76

77. GLUCAGON-LIKE PEPTIDE-1
• GLP-1 is coproduced and cosecreted with GLP-2 from the
preproglucagon precursor molecule in two sites in the body:
• (1) in the epithelium of the gut (from the duodenum to the colon)
• (2) a small population of neurons in the nucleus of the solitary
tract (NTS)
77

78. GLP-1
 Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted
from enterondocrine L-cells directly in response to nutrient intake.
 GLP-1 secretion is clearly meal related. In the fasting state, the
plasma concentrations are very low.
Can J, et al. International Journal of Obesity 2014. Holst J, et al. Physiol Rev. 2007 78

79. GLP-1 Functions
79
Holst J, et al. Physiol Rev. 2007

80.  GLP-1 is a potent anti hyperglycemic hormone, inducing
glucose-dependent stimulation of insulin secretion while
suppressing glucagon secretion.
 GLP-1 appears to restore the glucose sensitivity of pancreatic -
cells, with the mechanism possibly involving the increased
expression of GLUT2 and glucokinase.
When the plasma glucose concentration is in the normal fasting
range, GLP-1 no longer stimulates insulin to cause hypoglycemia.
GLP-1 and blood glucose
80

81. GLP-1 and Appetite
The ability of GLP-1 to penetrate the brain–blood barrier,
possibly through simple diffusion or via fenestrated
capillaries, which suggests a possible mechanism for
circulating GLP-1 to access central GLP-1 receptors.
81
GLP-1 promotes appetite suppression by stimulating GLP-1
receptors expressed in the hypothalamus and brainstem.
Silvia a, et al. Gut and Liver. 2012 Holst J, et al. Physiol Rev. 2007

82. GLP-1 limitation
Secreted GLP-1 is rapidly exposed to dipeptidyl peptidase-IV
(DPP-IV) mediated degradation:
 Only 10–15% enters the systemic circulation.
 Very short plasma half-life of GLP-1 (<2 min).
82
Endogenous GLP-1 does not regulate food
intake under physiological conditions.
Hansen HH, et al. European Journal of Pharmacology 2014

83. VICTOZA
Victoza Liraglutide
83
Liraglutide: A glucagon-like peptide-1 (GLP-1) analogue
Farr, O, et al. Diabetologia 2016

84. Liraglutide
 Liraglutide is a once-daily injectable derivative of the
human incretin (metabolic hormone) glucagon-like peptide-
1 (GLP-1), for the treatment of type 2 diabetes or obesity.
84Apovian CM, et al. The Journal of Clinical Endocrinology & Metabolism. 2015.

85. Liraglutide
 Liraglutide is a GLP-1 analogue with 97% amino acid sequence
identity to native human GLP-1 and an acyl sidechain attachment,
which makes it bind to albumin.
 These small structural differences prolong the half-life of the
analogue to 13 h, making it suitable for once daily administration.
85Jendle, J, et al. Diabetes, Obesity and Metabolism. 2009

86. Liraglutide approved
86

87. Liraglutide and Appetite
 GLP-1 markedly reduces gastric emptying and appetite.
 Recent studies in both humans and animals have shown that
GLP-1R agonists, such as liraglutide, that lead to
pharmacological concentrations for 24 h/day only have a
minor effect on gastric emptying; such an effect is unlikely to
have lasting effects on appetite reduction.
87
Knudsen L, et al. J Diabetes Investig, 2016

88. Liraglutide and Appetite (Mechanisms)
 Liraglutide has been shown to have direct effects in the rodent
brain
 Activating pro-opiomelanocortin neurons and increasing levels
of the cocaine- and amphetamine-stimulated transcript(CART)
neuropeptide messenger ribonucleic acid, which correlate nicely
to increase feelings of satiety.
Knudsen L, et al. J Diabetes Investig, 2016
88

89. • liraglutide also was able to prevent a hunger associated
increase in agouti-related peptide and neuropeptide Y
neuropeptide messenger ribonucleic acid, again with a strong
correlation to reduce hunger feelings in patients while taking
liraglutide.
89

90. CLINICAL TRIALS
90

91. Safety, tolerability and sustained weight
loss over 2 years with the once-daily
human GLP-1 analog, liraglutide
Astrup A, et al. International journal of Obesity. 2012
91

92. Method:
92

93. Results:
93

94. Results:
94

95. Results:
95

96. • Weight maintenance and additional
weight loss with liraglutide after low-
calorie-diet-induced weight loss: The
SCALE Maintenance randomized study
• Wadden TA, International Journal of Obesity, 2013.
96

97. Method
 RCT study
 56-week, 422 participants
 Obese/overweight participants (≥18 years, body mass
index ≥30 or ≥27 with comorbidities) who lost ≥5% of
initial weight during a low-calorie diet 1200-1400 Kcal-
day).
97
liraglutide 3.0mg per day or placebo (subcutaneous administration)
Participants were prescribed a 500 kcal/day deficit diet

98. Results
98
Weight decreased an additional
mean 6.2% with liraglutide and
0.2% with placebo (P<0.0001).
Gastrointestinal (GI) disorders
were reported more frequently
with liraglutide than placebo,
but most events were transient,
and mild or moderate.
More participants receiving liraglutide (81.4%) maintained the
≥5% run-in weight loss, compared with those receiving placebo
(48.9%) (P<0.0001), and 50.5% versus 21.8% of participants lost
≥5% of randomization weight (P<0.0001).

99. Results:
99

100. Safety and tolerability
100

101. • Adverse reactions
• nausea, hypoglycemia, diarrhea, constipation, vomiting,
headache, decreased appetite, dyspepsia, fatigue, dizziness,
abdominal pain.
• Saxenda® can raise heart rate and should be discontinued in those
with a sustained increase in resting heart rate
• Saxenda® has a boxed warning stating that thyroid gland tumors
(thyroid C-cell tumors) have been observed in rodent studies
101

102. • The FDA has required post-marketing evaluations for Saxenda®
including case registry of medullary thyroid carcinoma for at least
15 years to identify any increase in incidence, and an evaluation of
the potential risk of cancer.
102

103. Downside:
 The downside is that liraglutide is delivered subcutaneously, which
limits its use in needle-phobic people.
 The current drug costs for liraglutide 1.8 mg daily as reported by
Novo Nordisk are £3.92 per day and £1432.26 per year.
 The economic considerations of this may limit liraglutide to only
obese individuals with significant co-morbidities who are proven to
not be controlled with conventional therapy.
103Ng SYA, et al. Expert opinion on biological therapy. 2014

104. Anti-obesity drugs in clinical development
104

105. Tesofensine
• Tesofensine is an inhibitor of noradrenaline, dopamine and
serotonin reuptake that reportedly also indirectly stimulates the
cholinergic system and a sympathomimetic in the family of
sibutramine. The drug was initially developed for the treatment
of Parkinson’s disease or Alzheimer’s disease. Although its
efficacy was limited for this application, significant weight loss
was evident
105

106. • A proof of concept phase 2 study, a 24- week randomized
double-blind placebo-controlled study, showed the
proportion of patients achieving ≥5 kg was 59%, 87%, and
91% for 0.25, 0.5, and 1 mg groups, respectively, compared
with 29% of controls. However, heart rate was significantly
elevated in all tesofensine groups, and the highest dose of
tesofensine (1 mg daily) showed a significant increase in blood
pressure and the highest frequency of mood change .
106

107. Cetilistat
• Cetilistat is a gastric- and pancreatic-lipase inhibitor that is
currently undergoing Phase III clinical trials for the treatment of
obesity.
• This drug, while similar to the currently FDA-approved drug
orlistat, may have a more tolerable side-effect profile due to a
different molecular structure
• Phase 3 trials of cetilistat are currently in progress.
107

108. Beloranib
• a methionine aminopetidase 2 (MetAP2) inhibitor, is an
investigational drug candidate for the treatment of obesity
• MetAP2, is encoded by the METAP2 gene in humans, and
increased expression of this gene is associated with various
cancers
• Inhibitors of MetAP2 were developed originally as anti angiogenic
agents
108

109. Beloranib
• Interestingly, MetAP2 inhibition also reduces fat biosynthesis
and stimulates fat oxidation and lipolysis, suggesting anti-
obesity potential.
• Beloranib is suggested to act in adipose tissue to inhibit
formation of new blood vessels and stimulate apoptosis of
endothelial cells, thereby inhibiting adipose tissue expansion.
109

110. Beloranib
• Long-term studies are needed in a larger and diverse patient
population, which includes participants with obesity related
• comorbidities, to confirm the safety, efficacy and tolerability
of beloranib for weight loss and improvements in cardio-
metabolic risk factors.
110

111. Anti-obesity drugs in clinical
development
• RM-493 ( selective, MC4R peptide agonist)
• KD026 (nonsystemically available intestinal microsomal
transfer protein inhibitor)
• Remogliflozin etabonate(The bulk of the filtrated glucose in
kidney tubules)
111

112. Conclusion
• Research over the past two decades has advanced substantially
our knowledge of central and peripheral mechanisms underlying
energy balance, making these mechanisms attractive targets for
anti-obesity therapeutics
• Given that multiple central and peripheral mechanisms underlie
the development and maintenance of obesity, combination
therapies may exert greater and longer-term weight loss
compared to monotherapies.
112

113. Conclusion
• Currently two combination products have been approved by
the FDA for the treatment of obesity. There are several
potential combination therapy approaches that appear
beneficial.
• additional long-term studies are needed, especially for
centrally acting anti-obesity drugs, to evaluate potential
neuropsychiatric adverse effects and the benefit to risk ratio.
113

114. Conclusion
• Future studies focusing on not only central, but also
peripheral targets governing energy expenditure, may offer
novel treatment strategie.
114

115. 115

116. 116

117. 117

118. 118