Antiobesity Drugs

1. Pharmacotherapy
of obesity
Dr. Sachin R. Choudhari
JR-1, Dept. of pharmacology
SVNGMC, Yavatmal

2. Scope of presentation
What is obesity ?
Epidemic of obesity
Problems related to obesity
Why to treat obesity?
Energy homeostasis
Treatment options for obesity
Currently available drugs for obesity
Conclusion

3. Obesity :
It is defined as abnormal growth of the adipose tissue due to
enlargement of fat cell size (hypertrophic obesity) or an
increase in fat cell number (hyperplastic obesity) or a
combination of both

4. EPIDEMICS in obesity :
 It is prevalent in both developed and developing countries , and
affecting children as well as adults
 Obesity is the fifth leading risk of global death
 In 2014, more than 1.9 billion adults, 18 years and older, were
overweight. Of these over 600 million were obese.
 Overall, about 13% of the world’s adult population (11% of men
and 15% of women) were obese in 2014.
 In 2014, 39% of adults aged 18 years and over (38% of men
and 40% of women) were overweight.

5.  The worldwide prevalence of obesity more than doubled
between 1980 and 2014
 In 2013, 42 million children under the age of 5 were
overweight or obese.
 India is 3rd largest country contributing to obesity burden next
to United states and China
 In India , Tamilnadu, Karnataka, Andhra pradesh ,
Maharashtra, Kerala contributes more to obesity

7.  WHO classify this obesity according to individual’s BMI :

8. Why to classify ???
 Meaningful comparison of weight status within and in-
between population
 Identification of individual and group with increased risk of
morbidity / mortality
 Identification of priorities for intervention at individual and
community levels
 A firm basis for evaluating interventions

9. Problems related to obesity :

11. Why to treat obesity ???
Contributes to approximately 300,000 deaths a year,
making it 2nd only to smoking as a cause of death
Disease burden is increasing day by day
Contributes or causes to many other health problems
including:
Type 2 Diabetes Mellitus
Coronary Artery Disease
Degenerative Joint Disease
Certain Types of Cancer
Nonalcoholic Steatohepatitis

13. Available treatment options for
obesity :
Diet and exercise
Pharmacotherapy
Surgical option

14. Indications for use of obesity drugs
 BMI of 30 kg/m² or more or a BMI of 27 kg/m² or more with comorbid
condition
 Understand that drug therapy is adjunctive to lifestyle intervention
 Have realistic expectations about weight loss goals and outcomes
 Are unable to lose/maintain weight with lifestyle change alone
 Comply with medication use
 Have no medical or psychiatric contraindications

15. Energy Homeostasis :

18. Pharmacotherapy :
Peripherally acting agents reducing the efficiency
of digestion:
Modulation of appetite and energy expenditure :
Centrally acting agents affecting the hedonic
control of food intake :
Combination approach to obesity treatment :
Peripherally acting agents :

19. Peripherally acting agents
reducing the efficiency of digestion:
“ ORLISTAT ”
 Stable analogue of lipstatin (a naturally occurring lipase inhibitor produced by streptomyces
toxytricini )
 Indicated for the treatment of obesity in conjunction with a reduced calorie intake
 MOA : Acts locally to potently inhibit pancreatic and gastric lipase and thus
hydrolysis of TG
approx. only two third of dietary TG intake is absorbed by small
intestine
 Dose : 120mg three times daily
 FDA Approved on 2007

20.  Effect : It induces weight loss of approx. 2-4 Kg more than diet and
exercise alone.
 ADRs :
1. Deficiency of fat soluble vitamins
2. Diarrhea, flatulence, bloating, abdominal pain , dyspepsia
 Recently it comes with additional warning of possible severe liver injury
It is contraindicated in patients with malabsorption of fats or cholesterol

21. Centrally acting agents affecting the homeostatic
regulation of food intake :
Meal induced hormonal & neuronal signal travels GIT to area postrema and
NTS in brainstem
Sensory inputs from there transmitted to others centers (amygdala and
nucleus accumbence). Dopaminergic , opioid and endocannabinoid signaling
assign reward value to consumed food
Inputs from these pathway integrates with circulating signals of nutritional
state i.e. fatty acid and LEPTIN which are detected in Arcuate nucleus
Activates Activates
neurons expressing neuron expressing
Pro-opiomelanocortin (POMC) Neuropeptide Y (NPY)
Stimulate release of α MSH Activation of NPY-Y1 and Y5
Activating the melanocortin receptor 4 increase food intake and reduction
in energy expenditure
Reduction in food intake & increase
in energy expenditure

22. Serotonin reuptake inhibitors :
SIBUTRAMINE
 Approved by FDA in 1997 as 5HT and NE reuptake inhibitor (presynaptic)
 Potentiate anorexic effect of these two neurotransmitters in the CNS
 Act at hypothalamic site that regulates food intake
 Reduces food intake and causes dose dependent weight loss with reduction in
visceral fat
 In addition , it also decreases plasma TGs , LDL , VLDL but increases HDL
 Also, stimulates thermogenesis by activating β3 receptors in adipose tissue
 Dose : 10-15 mg once daily

23.  Weight loss is between 5-10%
 ADRs :
1. Increase in HR and BP
2. Dry mouth , constipation , insomnia
 Contraindicated in cardiovascular diseases
 SCOUT trial showed that , there is higher risk of cardiovascular events in
patient taking sibutramine as compared to placebo
 Based on these findings it has undergone a revision process and was
finally withdrawn from European and US market in 2010

24. TESOFENSINE (NS2330)
 Described in clinical trial as an inhibitor of the reuptake of nor adrenaline ,
dopamine and 5 HT
 It initially developed in the treatment of Alzheimer’s and Parkinson’s disease
 Reported to cause some weight loss in obese patients being treated for these
two conditions
 It induced promising weight reduction of 2.1% (0.125mg dose), 8.2 % (0.25mg),
14.1 % (0.5mg), 20.9 % (1mg ) after 14 weeks of therapy
 Phase 2 trial cleared
 Now in phase 3 trial

25. Serotonin receptor agonist and antagonist :
LORCASERIN
 Selective 5 HT2c receptor agonist
 Phase 3 trial successful with avrg. Weight loss of 5.8 kg compared to placebo
after 1 year
 Recently approved (2013-14 ) as anti obesity drug
 No serotonin related valvulopathy / neuropsychiatry issue
 ADRs : Headache , nausea, URI
 Dose : 10 mg BD

26.  If weight reduction is < 5 % after 12 weeks stop the drug
 Contraindicated in renal failure (GFR : < 30ml / min )
 Decreases systolic and diastolic BP , HR, total and LDL-c

27. FENFLURAMINE , DEXFENFLURAMINE
 Induce weight loss via formation of active metabolite D- norfenfluramine , a
potent 5-HT2C agonist
 used in 1980 and 1990s
 But soon escape from their effect and landed with rare but serious adverse
effect i.e. Pulmonary hypertension
 Use declines
PHENTERMINE
 Amphetamine like compound which acts by releasing noradrenaline from
presynaptic vesicles in lateral hypothalamus
 It is used along with dexfenfluramine as combination therapy in 1990s but
withdrawn from market in 1997 after dexfenfluramine shown to be associated
with valvulopathy and PH

28. Melanocortin 4 receptor agonist :
MK- 0493
 Melanocortin 4 receptor (MC4R) is crucial regulation of appetite
 MC4R deficiency is the most common monogenetic cause of obesity in
human
 its an orally active , selective MC4R agonist
 No significant weight reduction results in phase 2 trial
 But peptide of MC4R shows promising results in rodents and will soon
enter in phase 1 trial

29. NPY receptor ligands :
 Neuropeptide NPY is thought to stimulate appetite by activation of the Y1
and Y5 receptors
 So antagonist at this level have been produce with the aim of blocking these
orexigenic effect
MK- 0557
 A 52 week multicenter , double blind RCT showed only 1.6 kg reduction in weight
among humans
 Various other drugs been developed and under trial :
BMS- 193885 ( only animal study no human trial yet )
PYY3-36 ( phase 2 )
RG7089 ( phase 1 )
Pegylated PYY3-36 plus metformin ( phase 1 )
 Nausea if frequent side effect of all these drugs

30. Glucagon like peptide 1 receptor agonist :
 GLP-1 receptor is expressed in paraventricular, arcuate and dorsomedial
nuclei in the hypothalamus and NTS , area postrema and parabrachial
nucleus in brainstem
 It has been shown to inhibit food intake when administered peripherally
and centrally
 It acts as incretin, increasing glucose stimulated insulin release and inhibit
glucagon release and gastric emptying
 Chronis subcutaneous infusion of GLP to patients with type 2 DM can
induced weight loss and improved glucose homeostasis

31. EXENATIDE AND LIRAGLUTIDE
 Approved for treatment of DM2 but not licensed to treat
obesity
 Exenatide shows increased risk of benign C cell adenomas
TAPSOGLUTIDE
 Another product shows promising results in pre clinical and animal study but
stop in phase 3 due to diverse GI events and hypersensitivity issues

32. OXYNTOMODULIN ( phase 1 )
 Endogenous GLP – receptor agonist
 It reduces food intake in rats when administered centrally or peripherally but
unlikely GLP -1 oxyntomodulin also increases energy expenditure
 In humans iv infusion of oxyntomodulin reduces food intake
 While repeated sc injections increases energy expenditure and causes weight
loss in obese volunteers
 Pegyaated form of it named PF- 05212389 also in phase 1 trial

33. Centrally acting agents affecting
the hedonic control of food intake :
 Here, target is the brain’s reward pathways
 The reward system is activated in response to the intake of high calorie
palatable foods and thought to stimulate intake of these foods even in the
absence of nutrients deficit and weight loss
Cannabinoid receptor (CB1) antagonists :
 Endogenous lipid derived from arachidonic acid , which activates G- protein
coupled receptors
 Administration of an endocannabinoid into ventromedial hypothalamus ond
nucleus accumbens of rats causes increased food intake and effect blocked by
receptor antagonist

34. RIMONABANT
 Selective CB1 receptor antagonist
 It is thought to control food intake by reinforcing motivation to consume food
 First approved product to treat obesity in this class
 Weight loss appr. 7% achieved over a 1 year period in patients treated with this
drug
 Significant decrease in co-morbidities also noted
 Never approved in USA but licensed in Europe
 Suicidal thoughts and depression are major side effects and for the same it has
been banned in Europe 2009 but still used in India
 Trials on some other drug such as TARANABANT , OTENABANT terminated
rapidly

35. Combination approaches :
PHENTERMINE – TOPIRAMATE ( QNEXA )
 Its an combination of two approved drug
 Phentermine : Amphetamine derivative
 Topiramate : Anti convulsant drug
 Combination is approved in Dec 2012
 They demonstrated biphasic dopaminergic and serotonergic activity
 In combination with a balance diet and exercise lost 10% to 11% of their body
weight compared to 1% to 2% for those who received placebo
 ADRs : paraesthesia (tingling in fingers/toes), dizziness, dysgeusia (altered
taste), insomnia, constipation, and dry mouth

36. BUPRIPION – NALTREXONE ( CONTRAVE)
 Its an combination of centrally active opioid receptor antagonist
 Approved in Sept. 2014 as anti obesity drug
 Both these stimulates firing of anorexigenic POMC neurons
 Naltrexone is hypothesized to block opioid mediated negative feedback that
suppresses POMC firing
 Weight loss of 4.2% is seen in clinical trials
 ADRs : nausea, headache, constipation, dizziness, vomiting, dry mouth, risk of
major cardiovascular events in obese patients

37. BUPRIPION – ZONISAMIDE ( EMPATIC)
 Another combination which in phase 2 trial showed significant weight reduction in
obese patients with or without depression compared with placebo
 Zonisamide induced bodyweight loss has not been fully characterized ; however it
has been shown to have dopaminergic and serotoninergic activity and likely to
work through these pathways
 Weight loss is around 7.2 % as compared to 2.9 % with placebo
 ADRs : Increased cardiovascular events , mood disorders
 Currently in phase III trial

38. Peripherally acting agents :
 Several anorectic peptides are released from gut postprandially and there
has been interest in developing therapeutics to mimic this effect
CB1 antagonist
 New antagonist have been designed to antagonize peripherally expressed
CB1 receptors but not to penetrate blood brain barrier and thus avoids
behavioral effects
 They induce weight loss and also have beneficial effect on energy
expenditure
 Two products are now in clinical trial :
1. TM38837 ( cleared phase 1 trial now in phase 2 )
2. AM6545 ( in preclinical studies )

39. Gut related peptide to treat obesity &metabolic
syndrome :
 Similar to GLP -1R agonist , other new agents , which not only affect
weight control but also improve metabolic and cardiovascular disorders
PRAMLINTIDE
 An analog of pancreatic hormone amylin
 Approved as an adjunct to mealtime insulin in patients with type 1 &2 DM
 But it also associated with reduction in appetite and food intake through a delayed
gastrointestinal motility
 In clinical trial, with the dose 120, 240, 360 μg it shows progressive weight
reduction at 12 months i.e. from 6.1 kg to 7.2 kg

40.  Two another amylin analog undergoing development for obesity
treatment
1. DAVALINTIDE
2. PRAMLINTIDE – METRELEPTIN
( RECOMBINANT HUMAN LEPTIN )
 Hypoglycemia , nausea, vomiting are side effects

41. AMP activated protein kinase & peroxisome proliferator
activated receptor modulator :
 Its an key enzyme in the regulation of energy metabolism that has pleiotropic
effects in multiple tissue
 Experimental study activation of AMPK in the periphery maybe beneficial to obese
patients by increasing energy expenditure
 In brain, its suppression would be desirable to inhibit appetite
 Similar effects are seen with PPAR-y antagonism
 Products in clinical trial are :
1. GW0072
2. LG100641

42. G- protein coupled receptor 119 :
 Glucose dependent insulinotropic receptors are predominantly expressed
in islets β cells and GI tract
 These receptors are attractive target for the treating type 2 DM as they
have been shown to play crucial role in glucose homeostasis through
modulation of insulin secretion
 They also seems to have major beneficial effect on bodyweight

43. Sodium – glucose transporter 2 inhibitors :
Selective inhibitors of SGLT2 reduce glucose reabsorption
Leads to excessive glucose to be eliminated from urine
Decrease in plasma glucose level
This glucosuria is a/w weight loss and reduce blood pressure
 Available drugs : 1. DAPAGLIFLOZIN
2. CANAGLIFLOZIN
3. BL 10733
 Currently all drugs are in clinical development

44. Leptin :
• Naturally occurring hormone that plays a role in satiety and weight
maintenance.
• Produced in adipocytes
• Its role in weight regulation is related to its effects on the hypothalamus,
where it leads to:
• satiety
• decreased food intake
• increased energy expenditure in the periphery

46.  Initial human trials with recombinant leptin were modestly
successful
 Most subjects in the initial trial developed local reactions at
the injection site
 Weight loss was relatively modest
 However, the hormone needs to be given subcutaneously
and has a short half-life
 Thus a modified recombinant human leptin (m-leptin) was
created that has a longer half-life

47. Efficacy of current anti obesity drugs :
DRUG LENGTH OF RCT WT LOSS (KG)
Phen / Topiramate > 1 year - 10.2
Bupropion 24 weeks - 8.0
Diethylpropion 18 weeks - 6.5
Phentermine 13 weeks - 6.4
Bupro / Naltrex > 1 year - 6.1
Lorcaserine > 1 year - 5.8
Orlistat > 1 year - 5.3
Exenatide 24 weeks - 2.9
Liraglutide 24 weeks - 2.8
Metformin 1 year - 2.8

48. Need of new drugs :
 Efficacy of available drug is not satisfactory
 No sustained weight loss
 High side effect profile
 Different mechanism of action not fully explore
 Current drug increases energy expenditure : no drug yet that
alter signals of hunger & satiety
 Very few drug options are available currently

49. Pipeline drugs :
Drug name class status
GT 389-225 Conjugate of
pancreatic lipase
inhibitor & fat binding
hydrogel polymer
Phase I
BVT 74316,
PRX 07034
5 HT-6-R antagonist Phase I
TKS 1225 GLP-1 –R agonist Phase I
Bupropion -
zonisamide
FDC suspended

50. Drug name class Status
Cetilistat Pancreatic lipase
inhibitor
Phase III
Beoranib Methionine
aminopeptidase II
inhibitor . Decreases
hepatic FA &
promotes fat break
down
Suspended
( Prader wili )
Phase II
Semaglutide GLP-1-R agonist Phase III(DM)
Phase II (obesity)
Remogliflozin
etabonate
SGLT -2 inhibitor
(increase urinary
secretion of
glucose)
Phase II (DM)
Phase I (obesity)

51. Conclusion ???
 Obesity – abnormal excessive fat accumulation that harms
 WHO cut off points BMI > 25kg/m2 and > 30 kg/m2 for
obesity and overweight
 Obesity impacts the whole world through its harmful effects
and comorbid conditions
 Current drugs are not satisfactory as far weight reduction
results are concern
 Lifestyle management , diet control and exercise precedes
drug therapy

52. Take home message :
Think healthy
Behave healthy
Eat healthy
Be happy

54. References :
 Katzung BG, Trevor AJ. Basics and clinical pharmacology.
13th ed.McGraw Hill education:2015;p664-5
 Bruton Chabner B, Knollman B. Goodman & Gilman’s The
Pharmacological basis of therapeutics. 12th ed. McGraw Hill
medical: 2011;p881,91
 HL sharma, KK sharma. Principles of Pharmacology. 2nd
ed.2011;p 901
 Rodgers RJ, Tschop MH, Wilding JPH. Antiobesity drugs:
past,present and future. Dis model mech. 2012
Sept;5(5):621-626

55.  Fenske W, Parker J, Bloom S. Pharmacotherapy of obesity.
Expert Review of endocrinology and
metabolism.2011;6(4):563-577
 Bray GA. Obesity in adults: Drug therapy. Accessed on
06/12/2015 from URL
http://www.uptodate.com/contents/obesity-in-adults-drug-
therapy?source=search_result&search=obesity&selectedTitle
=~150
 For pipeline drug status
( http://adisinsight.springer.com/drugs )
 For various trial details ( https://clinicaltrials.gov )