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
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
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.
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
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
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
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
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)