Updated as on 01-02-2016

1. PHARMACOTHERAPY & RECENT
ADVANCES IN OBESITY
Dr. Jeffrey Pradeep Raj
Post-Graduate Demonstrator
Dept. of Pharmacology – SJMC
01-02-2016

2. OUTLINE
• Introduction
• Burden
• Physiology of feeding & energy expenditure
• Pharmacotherapy for obesity management
• ACC/AHA Clinical guidelines 2013
• Recent advances & Future prospects
• Summary
• References

3. INTRODUCTION TO
OVERWEIGHT / OBESITY

4. DEFINITION
• Abnormal or excessive fat accumulation that presents a
risk to health
• Crude measure – Body Mass Index (BMI)
• Obesity: BMI ≥ 30 kg/m2
• Over weight: BMI ≥ 25 kg/m2
• Major risk factor for NCDs – Heart disease, stroke,
diabetes, some cancers (Endometrium, breast & colon)
• Non-communicable diseases in the South-East Asia region – WHO (2011). Accessed on
11/12/2015 URL: http://apps.searo.who.int/PDS_DOCS/B4793.pdf?ua=1

5. • WHO technical report series 894: Obesity: preventing and managing the global epidemic. (2000)
Accessed on 11-12-2015 from URL file:///C:/Users/Jeffrey/Downloads/WHO_TRS_894.pdf
CATEGORY BMI (kg/m2)
COMORBIDITY
RISK
Under-
weight
Severe < 16 Low (but ↑ risk
of other clinical
problems)
Moderate 16.00 – 16.99
Mild 17.00 – 18.49
Normal 18.50 – 24.99 Average
Over-
weight
Pre-obese 25.00 – 29.99 Increased
Obese I 30.00 – 34.99 Moderate
Obese II 35.00 – 39.99 Severe
Obese III ≥ 40 Very severe
WHO (1997) - NUTRITIONAL STATUS

6. WHY CLASSIFY OVERWEIGHT?
• Meaningful comparisons of weight status within
and between populations
• Identification of individuals & groups at increased
risk of morbidity / mortality
• Identification of priorities for intervention at
individual & community levels
• A firm basis for evaluating interventions.

7. DISCLAIMERS
• BMI & comorbidity risk relationship can be affected
by multiple factors (diet, ethnicity & activity level)
• Fat distribution which is equally important is not
taken into consideration

8. • The Asia Pacific Perspective: Redefining obesity and its treatment (Feb 2000) – WHO western
pacific region, International association for the study of obesity (IASO) & International Obesity task
force (IOTF). Accessed on 11-12-2015
URL:http://www.wpro.who.int/nutrition/documents/docs/Redefiningobesity.pdf
CATEGORY BMI (kg/m2) COMORBIDITY RISK
Under-
weight
< 18.50 Low (but increased
risk of other clinical
problems)
Normal 18.50 – 22.99 Average
Over-
weight
At risk 23.00 – 24.99 Increased
Obese I 25.00 – 29.99 Moderate
Obese II ≥ 30 Severe
PROPOSED CLASSIFICATION
(ASIANS)

9. FINAL RECOMMENDATIONS FOR
ASIANS (2002)
• Recommended 2 additional trigger points for public
health action
BMI ≥ 23 kg/m2 – Increased risk
BMI ≥ 27.5 kg/m2 – High risk
• Based on meta-analyses
WHO Expert Consultation. Appropriate-body mass index for Asian populations and its implications
for policy and intervention strategies. Lancet 2004;363:157-63
BMI RANGE (kg/m2) COMORBIDITY RISK
< 18.50 (Underweight) Low
18.50 – 22.99 Acceptable
23.00 – 27.49 Increased
≥ 27.50 High

10. WHY DIFFERENT CUT-OFFS?

11. RATIONALE FOR REDEFINING
OBESITY
• ↑ DM & CV risk factors in Asia when BMI < 25
kg/m2
• Association b/wn BMI, % body fat & fat distribution
in body differs with population
• Low S, Chin MC, Ma S et al. Rationale for redefining obesity in Asians. Ann Acad
Med Singapore. 2009 Jan;38(1):66-9.

12. BURDEN OF
OVERWEIGHT / OBESITY

14. GLOBAL STATUS (2014)
• 1.9 billion adults (39%) – over weight
• 600 million (13%) – obese
• Majority population live in nations where
overweight/obesity kills more people than underweight
• 42 million children under 5 – overweight in 2013
• Obesity and overweight fact sheet. WHO. Accessed on 21/12/2015 from
http://www.who.int/mediacentre/factsheets/fs311/en/

15. PREVALENCE IN INDIA – NFHS3
• National family Health survey 3 (2005-2006)
• Large-scale, multi-round survey in representative
sample of households through out India
• International Institute of population services (IIPS,
Mumbai) – nodal centre appointed by MOFHW, Ind
• The overall prevalence : 13.45%
Among women: 14.8%
Among Men: 12.1%
In Urban areas: 25.55%
In rural areas: 7.95%
• NFHS-3 data (2005-2006). Accessed on 21/12/2015 from URL
http://rchiips.org/nfhs/pdf/India.pdf

16. OBESITY IN S.INDIA – NFHS 4
30.9
23.3
33.2
20.9
15.3
17.7
34
28.2
22.1
33.5
14.5
10.9
17.6
24.3
0
5
10
15
20
25
30
35
40
Tamil Nadu Karnataka Andhra Pradesh Kerala*
Women NFHS3-W Men NFHS3-M
All values in %
* Data not yet available. Accessed on 27/01/16 from URL http://rchiips.org/nfhs/factsheet_NFHS-4.shtml

17. PHYSIOLOGY OF
FEEDING & ENERGY
EXPENDITURE

18. MEDIATORS OF FEEDING

19. SIGNALLING OF FEEDING
• Hypothalamus – arcuate nucleus
Orexigenic neurons – PYY, AgRP
Anorexigenic neurons – POMC, CART
• Signals from
Neurons (orexin, 5HT)
Adipose tissue (Leptin)
GI via blood stream (All others)
• Afferents: vagal afferents via NTS or directly in Arc.
nuc

20. EFFECTS OF VARIOUS PEPTIDES
HORMONE SOURCE EFFECT
CCK GI tract Limits size of
mealAmylin, Insulin,
glucagon
Pancreas
PYY* Ileum/colon Postpones need
for next mealGLP-1 Stomach
Oxcyntomodulin* Stomach
Leptin* Adipose tissue Long term reg.
Ghrelin Stomach ↑ food intake
* In Phase II trials

21. EFFECT of rLEPTIN
• Translated
from Ob gene
• Pulsatile
production
• High bwn mid
night & early
morning

22. PHARMACOTHERAPY
FOR OBESITY
MANAGEMENT

23. HISTORICAL LANDMARKS IN ANTI-
OBESITY PHARMACOTHERAPY
• 1920: synthetic thyroid hormone – exophthalmos,
hyperthermia & palpitations
• 1930s: Mitochondrial ATP production blockers – 2,4
dinitrohenol (DNP) – hyperthermia, sweating, cataract
& premature death (withdrawn 1938)
• 1950-60s: CNS stimulants popular – some still in use;
many withdrawn
• 70s-80s: era of fenfluramine / dexfen & cardiac
valvulopathy
• Early 90s: Fen-Phen. No relief from valvulopathy –
withdrawn in 1997
• 1999 – pancreatic lipase inhibitors

24. DRUG CLASSIFICATION (1/2)
CLASS OF DRUG EXAMPLE
Centrally acting
sympatho-
mimetic
(Amphetamine
derivatives)
NE release / NE reuptake inhibitor:
phentermine, diethylpropion,
phendimetrazine, desoxyephedrine
NE & 5HT reuptake inhibitor:
Sibutramine
Serotonergic
agents
Non selective: Fenfluramine,
Dexfenfluramine. Selective: Lorcaserin
CB1 receptor
antagonist
Rimonobant, taranabant, otenabant,
surnibant, ibipinabant
Lipase inhibitors Orlistat, cetilistat

25. DRUG CLASSIFICATION (2/2)
CLASS OF DRUG EXAMPLE
Anti DM drugs Exenetide, Liraglutide (GLP1
analogs), Metformin (Biguanide),
Pramlinitide (Islet amyloid peptide)
Antidepressant Bupropion
Anti-epileptic drugs Topiramate, Zonisamide
Combination drugs Phentermine – Topiramate
Naltrexone – Bupropion
Experimental
peptides
Leptin, peptide YY, Oxyntomodulin,
melanocortin 4 Receptor agonist

26. DRUGS WITHDRAWN
CLASS OF DRUG DRUG REASON
Sympatho-
mimetics
Desoxyephedrine CVD
Phenylpropanolamine Haemorrhagic
stroke in women
Sibutramine CVS/CNS events
Serotonergic
agents
Fenfluramine,
Dexfenfluramine
Cardiac valvular
defects
Cannabinoids
CB1 receptor
antagonist
Rimonobant Neuropsychiatric
problems

27. SYMPATHOMIMETIC DRUGS
MOA Early satiety. ↑ BMR & thermogenesis
Pharma
cology
Rapid oral absorption; short t1/2 (except
sibutramine); metabolized in liver & renal
excretion
ADR ↑ HR, ↑BP, insomnia, dry mouth, constipation,
nervousness
Salient
features
Short term use (upto 12 weeks)
Contraindicated in IHD, hypertension,
hyperthyroid & drug abusers

28. TALE OF SIBUTRAMINE
• Centrally acting SNRI – serotonin NE reuptake inh.
• Prodrug - Well absorbed orally with 77% BA
• Approved by US FDA in 1997 for obesity Rx
• Efficacy : mean change in wt -6.8kg
• RCT with 10,000 pts, non fatal MI (4.1% vs 3.2, HR
1.28 [95CI 1.04 – 1.57; non fatal stroke 2.6% vs 1.9
HR 1.36 [95CI 1.04-1.77)
• Withdrawn in January 2010

29. DIETHYLPROPION
• Structure similar to Bupropion
• Taken 25mg Q8H or 75mg ER 1 hour before meal
PHENDIMETRAZINE
• Avg weight loss 3.6kg
• May cause changes in libido & blurry vision

30. EFFECT OF PHENTERMINE
Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent
anorectic therapy in obesity. Br Med J 1968; 1:352
• Commonest drug prescribed as monotherapy

31. CANNABINOID CB1 RECEPTOR
BLOCKER
• Developed in mid 1990s. Protype: Rimonobant
• 4 major RCTs between years 2005-06; mean weight
change of -4 to -5kg
• Never approved in USA, but licensed in Europe
• Serious neuropsychiatric problems – anxiety,
depression & suicide
• Withdrawn in 2008
• Trials on taranabant, otenabant, surinabant &
ibipinabant terminated rapidly

32. ORLISTAT
MOA Pancreatic lipase inhibitor – alters fat digestion
Dose dependant increase in faecal fat excretion
Pharma
cology
Does not affect lipophilic drugs like digoxin,
phenytoin etc except cyclosporin
↓ absorption of fat soluble vitamins (↓ Warfarin
as vit K is def)
ADR Abdominal bloating, flatus, fecal incontinence.
Rarely liver injury & calcium oxalate renal injury
No renal/ gall stones. No CVS/CNS events
Salient
features
↓ systolic & diastolic BP in hypertensives; ↓
Total & LDL-C

33. XENDOS TRIAL (1/2)
Randomized, placebo controlled, double-blinded RCT
Participants 3305 patients BMI ≥ 30 kg/m2 & normal (79%) or
impaired (21%) glucose tolerance (IGT)
Intervention Lifestyle changes + orlistat 120 mg/placebo TID
End point Time to onset of type 2 diabetes & change in body
weight
Results Cumulative incidence of DM: 9.0% with placebo &
6.2% with orlistat ~ a risk reduction of 37.3% (P =
0.0032). Mean weight loss after 4 years 5.8 vs. 3.0 kg
with placebo; P<0.001
Torgeson JS, Haumptman J, Boldrin MN, Sjostrom L. XENical in the prevention of
diabetes subjects (XENDOS) study: a randomized study of orlistat as an adjunct to
lifestyle changes in prevention of type 2 diabetes in obese patients. Diabetes Care
2004; 27:155

34. XENDOS TRIAL (2/2)

35. ORLISTAT ON S.INSULIN
Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obe
se subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281:235.

36. ORLISTAT ON LDL-C & TOT-C
Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obe
se subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281:235.

37. LORCASERIN
MOA Serotonin 2C receptor agonist – reduces
appetite
P.kinetics CYP2D6 metabolism; renal excretion
ADR Headache, URI, nausea. No serotonin associated
valvulopathy/neuropsychiatry issues
Salient
features
• 10 mg BD. If ↓ wt < 5% at week 12 – stop
• Contraindicated in renal failure (eGFR
<30ml/min), pregnancy & other 5HT drugs
• ↓ systolic & diastolic BP, HR, Total & LDL-C,
CRP, fibrinogen, fasting glucose & insulin

38. BLOSSOM TRIAL
Randomized, placebo-controlled, double-blind, parallel arm trial –
97 USA CENTRES
Participants 4008 patients, aged 18-65 yr, with BMI 30 - 45 kg/m2 or
27 - 29.9 kg/m2 with related comorbid condition.
Intervention 2:1:2 ratio – 10mg BD, 10mg OD, placebo. Diet + exer
End point 5% ↓ wt & 10% ↓ wt at 1 yr
Results 5% wt loss: 47.2, 40.2 & 25.0% resp. P<0.001 vs.
Lorcaserin BD
10% wt loss: 22.6, 17.4 & 4.7% resp. P<0.001 vs.
lorcaserin BD
Fidler MC, Sanchez M, Raether B et al. A one-year randomized trial of lorcaserin for
weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol
Metab. 2011 Oct;96(10):3067-77

39. BUPROPION: ANTI-DEPRESSANT
MOA NE & dopamine reuptake inhibitor
P.kinetics CYP2B6 metabolism; renal excretion. ER dosage
form preferred
ADR Suicidal tendency, ↓ seizure threshold
Salient
features
• Mainly anti-depressant
• Used in smoking cessation & neuropathy pain
EBM 300mg SR vs 400mg SR vs placebo OD – 6 month
trial 7.2, 10.1 & 5 % loss of weight from baseline
& maintained next 6 months
Anderson JW, Greenway FL, Fujioka K, et al. Bupropion SR enhances weight loss: a 48-
week double blind, placebo controlled trial. Obes Res 2002; 10:633.

40. TOPIRAMATE: ANTI-EPILEPTIC
MOA Carbonic anhydrase inhibitor, prolongation of
Na channel inactivation, GABA potentiation ,
glutamate antagonism
P.kinetics CYP3A4 induces; CYP2C19 inhibits. t ½ = 21hrs
ADR Sedation, poor memory, ataxia, word finding
difficulty, weight loss, paraesthesia, renal stones
Uses GTCS & partial seizures, Migraine
EBM MA of 9 RCT – pooled weight loss at 6 months -
6.5% (CI, 4.8% - 8.3%) pre – Rx wt.
Li Z, Maglione M, Tu W, et al. Meta-
analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142:532.

41. ZONISAMIDE: ANTI-EPILEPTIC
MOA Carbonic anhydrase inhibitor, prolonged Na
channel inactivation, T-type CA2+ inhibitor
P.kinetics Excreted unchanged in urine. t ½ = 60 hrs
ADR Sedation, headache & irritability. Rarely
metabolic acidosis & renal stones.
Uses Refractory partial seizures
EBM 1 year RCT – 225 pts. Placebo vs 200mg vs 400mg
≥ 10% wt loss = 8.1%, 22.4%(p=.02) & 32.0%
(p<.001) resp.
Gadde KM, Kopping MF, Wagner HR 2nd, et al. Zonisamide for weight reduction in obese adu
lts: a 1year randomized controlled trial. Arch Intern Med 2012; 172:1557

42. EXENATIDE: ANTI-DM
MOA Glucagon like polypeptide-1 receptor agonist
P.kinetics Poor Oral bioavailability: S/c inj, proteolytic
degradation after glomerular filtration
ADR Injection site reactions/nodules, NVD. Rarely
alopecia, allergy, thyroid C cell tumours
Meta
analysis
Pooled weight change: -1.38kg with 10mcg BD.
No substantial ↓ with 5mcg BD or 2mg Q2weekly
Sun F, Chai S, Li L, et al. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss
in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis. Journal of
Diabetes Research. 2015;2015:157201. doi:10.1155/2015/157201.

43. LIRAGLUTIDE: ANTI-DM
MOA GLP 1 agonist
P.kinetics 98% protein bound. No specific metab organ. S/c
inj. 5-6% excreted in urine / faeces
ADR NVD, hypoglycaemia, injection site reactions
SCALE
diabetes
RCT
56w RCT; n=846 in Ty II DM BMI ≥ 27 kg/m2.
3mg vs 1.8mg vs placebo OD. Weight loss
6.0%,4.7% & 2.0% resp. ≥ 10% wt loss in 25.2%,
15.9% & 6.7% resp. P <0.001
SinghFranco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control and weight
in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and
metaanalysis. Diabetes Obes Metab 2011; 13:169

44. METFORMIN: ANTI-DM
MOA ↓ hepatic glucose production & GI absorption, ↑
peripheral insulin sensitivity
P.kinetics Not metabolized, excreted in urine
ADR Lactic acidosis (rare). Other infrequent ADRs
include diarrhoea, heartburn & dyspepsia
BIGPRO
trial
324 middle aged patients with Insulin resistance
syndrome & high waist-hip ratio; metformin vs
placebo. Mean weight change approx 2kg (<5%
wt loss)
Fontbonne A, Charles MA, Juhan-Vague I et al. The effect of metformin on the metabolic
abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes
Care. 1996;19(9):920.

45. PRAMLINTIDE: ANTI-DM
MOA Amylin analogue; amylin – produced by β cells to
nutrient stimuli. Slows gastric emptying
P.kinetics Oral bioavailability: 30-40%. S/c inj
ADR Severe hypoglycaemia, vomiting, headache
Meta-
analysis
Pooled from 8 RCT: ↓HbA1c -0.33% [95% CI -
0.51, -0.14], p = 0.004) & ↓wt (-2.57 kg, [95% CI -
3.44, -1.70], p<0.00001)
SinghFranco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control a
nd weightin patients with type 2 diabetes mellitus and in obese patients without diabetes: a
systematic review andmetaanalysis. Diabetes Obes Metab 2011; 13:169

46. PHENTERMINE - TOPIRAMATE
CONQUER trial: randomised, placebo-controlled trial – 93 US centres
Participants 2487 patients aged 18-70 yrs BMI 27-45 kg/m2 & 2 or
more obesity related co-morbidities
Intervention 2:1:2 ratio = placebo: (7.5mg P + 46mg T) : (15mg P +
92mg T)
Results At 56 w, change in body wt -1.4kg, -8.1kg, -10.2kg resp,
P <0.0001. ≥10% weight loss 7%, 37% & 48% resp.
p<0·0001. ADRs include dry mouth, paraesthesia,
constipation, insomnia dizziness & dysgeusia
Conclusion Rx of obesity at family doctor level with life-style Mx
Gadde KM, Allison DB, Ryan DH et al. Effects of low-dose, controlled-release,
phentermine plus topiramate combination on weight and associated comorbidities in
overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3
trial. Lancet. 2011;377(9774):1341

47. NALTREXONE - BUPROPION
COR-I trial: randomised, double blind placebo-controlled trial
Participants 1742 adults :18-65 yrs with BMI 30-45 kg/m2 or BMI
27-45kg/m2 with dyslipidemia/HTN
Intervention (Nal SR 32mg + Bup SR 360mg), (Nal SR 16mg + Bup SR
360mg) or placebo BD in ratio 1:1:1
Results Mean change in body wt: -6.1%, -5.0% & -1.3% resp.
≥5% weight loss: 48%, 39% & 16% resp. P <0.0001.
ADRs: nausea, headache, constipation, dizziness,
vomiting, dry mouth, depression & suicidality
Conclusion FDC of SR naltrexone + Bupropion useful
Greenway FL, Fujioka K, Plodkowski RA et al. Effect of naltrexone plus bupropion on
weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595

48. SUMMARY OF EFFICACY OF
CURRENT ANTI-OBESITY DRUGS
DRUG LENGTH OF RCT WT LOSS (kg)
Phent/Topiramate ≥ 1 year -10.2
Bupropion 24 weeks -8.0
Diethylpropion 18 weeks -6.5
Phentermine 13 weeks -6.4
Buprop/Naltrex ≥ 1 year -6.1
Lorcaserin ≥ 1 year -5.8
Orlistat ≥ 1 year -5.3
Exenatide 24 weeks -2.9
Liraglutide 24 weeks -2.8
Metformin 1 year -2.8

49. ACC/AHA GUIDELINES
ON MANAGAEMENT OF
OBESITY - 2013

50. ACC/AHA GUIDELINE 2013 (1/5)

51. ACC/AHA GUIDELINE 2013 (2/5)

52. ACC/AHA GUIDELINE 2013 (3/5)

53. ACC/AHA GUIDELINE 2013 (4/5)

54. ACC/AHA GUIDELINE 2013 (5/5)

55. RECENT ADVANCES &
FUTURE PROSPECTS

56. NEED FOR NEW DRUGS
• Efficacy of available drugs not satisfactory
• No sustained weight loss
• High side effect profile
• Different mechanisms of action not fully explored
• Current drugs ↑ energy expenditure - No drugs yet
that alter signals of hunger & satiety
• Very few drug options currently available

57. DRUGS IN THE PIPELINE (1/2)
DRUG NAME CLASS STATUS
Cetilistat Pancreatic lipase inhibitor Phase III
Beloranib Methionine aminopeptidase
II inh. ↓ hepatic FA &
promotes fat break down
Suspended
(Prader willi)
Phase II (obes)
Semaglutide GLP-1-R agonist Phase III (DM)
Phase II (obes)
Remogliflozi
n etabonate
SGLT-2 Inh. (↑ urinary
excretion of glucose)
Phase II (DM)
Phase I (obes)

58. DRUGS IN THE PIPELINE (2/2)
DRUG NAME
(Primary use)
CLASS STATUS
GT389-225 conjugate of pancreatic
lipase inhibitor & fat-
binding hydrogel polymer
Phase I
BVT 74316,
PRX 07034
5HT-6-R antagonist Phase I
TKS1225 GLP-1-R agonist Phase I
Buproprion
Zonisamide
FDC Suspended

59. HYDROGEL POLYMERS (PHASE II)
• Capsule containing salt like granules swallowed 20
mins before meal
• In stomach, absorb water 100 times its dry weight
• After several hours – particles shrink releasing
water
• In small intestine rehydrate & elasticity / viscosity
• In Large intestine, enzymes cleave cross-linkers of
hydrogel & release water for reabsorption
• Particles become small & excreted
• EG: Gelesis 100 & GT389-225

60. β3 ADRENERGIC RECEPTORS
• Actions of the β3 receptor include:
Enhancement of lipolysis in white fat.
Thermogenesis in skeletal muscle/brown fat
• Epinephrine & NE-induced, G protein (Gs) mediated
activation of adenylate cyclase
• Agonists: Mirabegron (marketed – overactive
bladder - OAB), Solabegron (Phase II – OAB, IBS),
Amibegron, BTA243 (discontinued – Obesity)
• Selective β3 agonist - potential weight loss effects
through modulation of lipolysis (Animal studies)

61. CANNABINOID CB1 – R BLOCKERS
• Rimonobant – posses inverse agonist activity. Not
neutral antagonist
Neutral anta-agonists– weight loss but no side
effects (proved in animal studies)
• Tolerance develops to acute anorectic effects of
Rimonobant but not to wt loss effects
CB1-R blockers that do not cross BBB to
produce wt loss
• Other possibilities – partial agonists, allosteric
modulators, FDCs (low dose CN1RB & other
anorectics)

62. PHARMACOGENOMICS
• Polymorphism in CB1 receptor gene & serotonin
transporter (SLC6A4) – development of side effects
• Genetic screening can personalise choice of
medication
• Pharmacogenomics + newer highly selective drugs
– Anti-obesity Rx with greater efficacy & low side
effect profile will soon be a reality!

63. SUMMARY (1/2)
• Obesity –abnormal excessive fat accumulation that
harms
• WHO cut off points BMI >25 kg/m2 & >30 kg/m2
for obesity & overweight
• Asian Population, 2 additional trigger points 23
kg/m2 & 27.5 kg/m2
• Physiology of feeding regulated by multiple
peptides – potential drug targets
• Lifestyle management & exercise precedes drug
therapy

64. SUMMARY (2/2)
• Drug therapy indications - obesity / overweight
(BMI >27) with 1 related comorbidity
• Most widely used monotherapy –
sympathomimetics – used short term (<12 weeks)
• Newer drugs – orlistat (1st Line), lorcaserin (2nd
Line)
• FDC better efficiency than monotherapy but more
side effects than orlistat / lorcaserin
• β3 adrenergic receptors agonist, hydrogel
polymers, CB1-R neutral antagonist – potential new
drugs

65. REFERENCES (1/2)
• Rang HP, Ritter JM, Flower RJ & Henderson G. Rang & Dales
Pharmacology. 8th ed. Elsevier Ltd: 2016; p 393-401
• Katzung BG, Trevor AJ. Basic & Clinical Pharmacology. 13th ed.
McGraw Hill education: 2015; p 664-5
• Brunton L, Chabner B, Knollman B. Goodman & Gilman’s The
Pharmacological basis of Therapeutics. 12th ed. McGraw Hill
medical: 2011 p 881,91
• Rodriguez JE, Campbell KM. Past, Present, and Future of
Pharmacologic Therapy in Obesity. Prim care: clin in off prac
(Article in press)
• Rodgers RJ, Tschop MH, Wilding JPH. Anti-obesity drugs: past,
present and future. Dis Model Mech. 2012 Sep; 5(5): 621–626.

66. REFERENCES (2/2)
• Jensen MD, Ryan DH, Apovian AM et al. 2013 AHA/ACC/TOS
Guideline for the Management of Overweight and Obesity in
Adults: A Report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines and The
Obesity Society. Circulation. 2014; 129: S102-138
• 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=7~
150
• For pipeline drugs status (http://adisinsight.springer.com/drugs )
• For various trial details (https://clinicaltrials.gov)

67. DRUGS THAT INCREASE WT
• TCAs
• Monoamine oxidase inhibitors
• Paroxetine
• Escitalopram
• Lithium
• Olanzapine
• Clozapine
• Risperidone
• Carbamazepine
• Valproate
• Mirtazapine