PHARMACOTHERAPY & RECENT ADVANCES IN

OBESITY

Dr. Jeffrey Pradeep RajPost-Graduate Demonstrator

Dept. of Pharmacology – SJMC01-02-2016

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

INTRODUCTION TO OVERWEIGHT /

OBESITY

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

• 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 – 16.99Mild 17.00 – 18.49

Normal 18.50 – 24.99 AverageOver-weight

Pre-obese 25.00 – 29.99 IncreasedObese I 30.00 – 34.99 ModerateObese II 35.00 – 39.99 SevereObese III ≥ 40 Very severe

WHO (1997) - NUTRITIONAL STATUS

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.

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

• 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 RISKUnder-weight

< 18.50 Low (but increased risk of other clinical problems)

Normal 18.50 – 22.99 AverageOver-weight

At risk 23.00 – 24.99 IncreasedObese I 25.00 – 29.99 ModerateObese II ≥ 30 Severe

PROPOSED CLASSIFICATION (ASIANS)

FINAL RECOMMENDATIONS FOR ASIANS (2002)

• Recommended 2 additional trigger points for public health actionBMI ≥ 23 kg/m2 – Increased riskBMI ≥ 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 Acceptable23.00 – 27.49 Increased≥ 27.50 High

WHY DIFFERENT CUT-OFFS?

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.

BURDEN OF OVERWEIGHT /

OBESITY

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/

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

OBESITY IN S.INDIA – NFHS 4

Tamil Nadu Karnataka Andhra Pradesh

Kerala*05

10152025303540

30.9

23.3

33.2

20.9

15.317.7

34

28.2

22.1

33.5

14.510.9

17.6

24.3

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

PHYSIOLOGY OF FEEDING & ENERGY

EXPENDITURE

MEDIATORS OF FEEDING

SIGNALLING OF FEEDING• Hypothalamus – arcuate nucleus

Orexigenic neurons – PYY, AgRPAnorexigenic neurons – POMC, CART

• Signals fromNeurons (orexin, 5HT)Adipose tissue (Leptin)GI via blood stream (All others)

• Afferents: vagal afferents via NTS or directly in Arc. nuc

EFFECTS OF VARIOUS PEPTIDES

HORMONE SOURCE EFFECTCCK GI tract Limits size of

mealAmylin, Insulin, glucagon

Pancreas

PYY* Ileum/colon Postpones need for next mealGLP-1 Stomach

Oxcyntomodulin* StomachLeptin* Adipose tissue Long term reg.Ghrelin Stomach ↑ food intake

* In Phase II trials

EFFECT of rLEPTIN• Translated

from Ob gene• Pulsatile

production • High bwn mid

night & early morning

PHARMACOTHERAPY FOR OBESITY MANAGEMENT

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

DRUG CLASSIFICATION (1/2)

CLASS OF DRUG EXAMPLECentrally acting sympatho-mimetic (Amphetamine derivatives)

NE release / NE reuptake inhibitor: phentermine, diethylpropion, phendimetrazine, desoxyephedrineNE & 5HT reuptake inhibitor: Sibutramine

Serotonergic agents

Non selective: Fenfluramine, Dexfenfluramine. Selective: Lorcaserin

CB1 receptor antagonist

Rimonobant, taranabant, otenabant, surnibant, ibipinabant

Lipase inhibitors Orlistat, cetilistat

DRUG CLASSIFICATION (2/2)

CLASS OF DRUG EXAMPLEAnti DM drugs Exenetide, Liraglutide (GLP1

analogs), Metformin (Biguanide), Pramlinitide (Islet amyloid peptide)

Antidepressant BupropionAnti-epileptic drugs Topiramate, ZonisamideCombination drugs Phentermine – Topiramate

Naltrexone – BupropionExperimental peptides

Leptin, peptide YY, Oxyntomodulin, melanocortin 4 Receptor agonist

DRUGS WITHDRAWNCLASS OF DRUG DRUG REASONSympatho-mimetics

Desoxyephedrine CVDPhenylpropanolamine Haemorrhagic

stroke in womenSibutramine CVS/CNS events

Serotonergic agents

Fenfluramine, Dexfenfluramine

Cardiac valvular defects

Cannabinoids CB1 receptor antagonist

Rimonobant Neuropsychiatric problems

SYMPATHOMIMETIC DRUGSMOA Early satiety. ↑ BMR & thermogenesisPharmacology

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

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

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

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

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

ORLISTATMOA Pancreatic lipase inhibitor – alters fat digestion

Dose dependant increase in faecal fat excretionPharmacology

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

XENDOS TRIAL (1/2)Randomized, placebo controlled, double-blinded RCTParticipants 3305 patients BMI ≥ 30 kg/m2 & normal (79%) or

impaired (21%) glucose tolerance (IGT)Intervention Lifestyle changes + orlistat 120 mg/placebo TIDEnd point Time to onset of type 2 diabetes & change in body

weightResults 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

XENDOS TRIAL (2/2)

ORLISTAT ON S.INSULIN

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

ORLISTAT ON LDL-C & TOT-C

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

LORCASERIN MOA Serotonin 2C receptor agonist – reduces

appetiteP.kinetics CYP2D6 metabolism; renal excretionADR 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

BLOSSOM TRIALRandomized, placebo-controlled, double-blind, parallel arm trial – 97 USA CENTRESParticipants 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 yrResults 5% wt loss: 47.2, 40.2 & 25.0% resp. P<0.001 vs.

Lorcaserin BD10% 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

BUPROPION: ANTI-DEPRESSANT

MOA NE & dopamine reuptake inhibitorP.kinetics CYP2B6 metabolism; renal excretion. ER dosage

form preferredADR Suicidal tendency, ↓ seizure thresholdSalient 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.

TOPIRAMATE: ANTI-EPILEPTIC

MOA Carbonic anhydrase inhibitor, prolongation of Na channel inactivation, GABA potentiation , glutamate antagonism

P.kinetics CYP3A4 induces; CYP2C19 inhibits. t ½ = 21hrsADR Sedation, poor memory, ataxia, word finding

difficulty, weight loss, paraesthesia, renal stonesUses GTCS & partial seizures, MigraineEBM 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.

ZONISAMIDE: ANTI-EPILEPTIC

MOA Carbonic anhydrase inhibitor, prolonged Na channel inactivation, T-type CA2+ inhibitor

P.kinetics Excreted unchanged in urine. t ½ = 60 hrsADR Sedation, headache & irritability. Rarely metabolic

acidosis & renal stones.Uses Refractory partial seizuresEBM 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 adults: a 1 year randomized controlled trial. Arch Intern Med 2012; 172:1557

EXENATIDE: ANTI-DMMOA Glucagon like polypeptide-1 receptor agonistP.kinetics Poor Oral bioavailability: S/c inj, proteolytic

degradation after glomerular filtrationADR Injection site reactions/nodules, NVD. Rarely

alopecia, allergy, thyroid C cell tumoursMeta 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.

LIRAGLUTIDE: ANTI-DMMOA GLP 1 agonistP.kinetics 98% protein bound. No specific metab organ. S/c

inj. 5-6% excreted in urine / faeces ADR NVD, hypoglycaemia, injection site reactionsSCALE 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 weightin patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review andmeta analysis. Diabetes Obes Metab 2011; 13:169

METFORMIN: ANTI-DMMOA ↓ hepatic glucose production & GI absorption, ↑

peripheral insulin sensitivityP.kinetics Not metabolized, excreted in urineADR Lactic acidosis (rare). Other infrequent ADRs

include diarrhoea, heartburn & dyspepsiaBIGPRO 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.

PRAMLINTIDE: ANTI-DMMOA Amylin analogue; amylin – produced by β cells to

nutrient stimuli. Slows gastric emptyingP.kinetics Oral bioavailability: 30-40%. S/c injADR Severe hypoglycaemia, vomiting, headacheMeta-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 and weightin patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review andmeta analysis. Diabetes Obes Metab 2011; 13:169

PHENTERMINE - TOPIRAMATE

CONQUER trial: randomised, placebo-controlled trial – 93 US centresParticipants 2487 patients aged 18-70 yrs BMI 27-45 kg/m2 & 2 or

more obesity related co-morbiditiesIntervention 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

NALTREXONE - BUPROPIONCOR-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/HTNIntervention (Nal SR 32mg + Bup SR 360mg), (Nal SR 16mg + Bup SR

360mg) or placebo BD in ratio 1:1:1Results 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

SUMMARY OF EFFICACY OF CURRENT ANTI-OBESITY

DRUGSDRUG LENGTH OF RCT WT LOSS (kg)Phent/Topiramate ≥ 1 year -10.2Bupropion 24 weeks -8.0Diethylpropion 18 weeks -6.5Phentermine 13 weeks -6.4Buprop/Naltrex ≥ 1 year -6.1Lorcaserin ≥ 1 year -5.8Orlistat ≥ 1 year -5.3Exenatide 24 weeks -2.9Liraglutide 24 weeks -2.8Metformin 1 year -2.8

ACC/AHA GUIDELINES ON

MANAGAEMENT OF OBESITY - 2013

ACC/AHA GUIDELINE 2013 (1/5)

ACC/AHA GUIDELINE 2013 (2/5)

ACC/AHA GUIDELINE 2013 (3/5)

ACC/AHA GUIDELINE 2013 (4/5)

ACC/AHA GUIDELINE 2013 (5/5)

RECENT ADVANCES & FUTURE

PROSPECTS

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

DRUGS IN THE PIPELINE (1/2)

DRUG NAME CLASS STATUS Cetilistat Pancreatic lipase inhibitor Phase IIIBeloranib 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)

Remogliflozin etabonate

SGLT-2 Inh. (↑ urinary excretion of glucose)

Phase II (DM)Phase I (obes)

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 IBuproprion Zonisamide

FDC Suspended

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

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)

CANNABINOID CB1 – R BLOCKERS

• Rimonobant – posses inverse agonist activity. Not neutral antagonistNeutral 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 effectsCB1-R blockers that do not cross BBB to produce wt

loss• Other possibilities – partial agonists, allosteric

modulators, FDCs (low dose CN1RB & other anorectics)

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!

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

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

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.

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)

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