Anti obesity drugs

1. ANTI-OBESITY DRUGS
DR. SAHIL KUMAR

2. OUTLINE
• INTRODUCTION
• DEFINITION AND MEASUREMENT
• HOMEOSTATIC MECHANISMS CONTROLLING ENERGY BALANCE
• ETIO-PATHOGENESIS OF OBESITY
• TREATMENT OF OBESITY
• PHARMACOTHERAPY OF OBESITY
• HISTORICAL ASPECTS
• CONTEMPORARY ANTI-OBESITY DRUGS
• FUTURE DEVELOPMENTS
• CONCLUSION
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3. INTRODUCTION
• Survival is continuous; Food is intermittent.
• “Globesity” on the rise.
• 2.1 billion people – nearly 30% of the world’s
population – either obese or overweight.
(Lancet. 2014 Aug 30;384(9945):766-81)
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4. INDIAN PERSPECTIVE
• 5% morbidly obese.
• rs12970134
• India’s obesity doubled in last 10 years; Urban-
Rural divide. (NFHS-4, 2015-2016)
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5. DEFINITION AND MEASUREMENT
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Obesity is a state of excess adipose tissue mass.
ICMR
♂:102 cm
(90cm)
♀: 88 cm
(80cm)

6. HOMEOSTATIC MECHANISMS
CONTROLLING ENERGY BALANCE
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• Early 20th Century – hypothalamus damage – wt.
gain.
• 1940s – discrete lesions in rodents – obesity.
• 1953 – hormone from adipose tissue –
hypothalamus.
• Genetic studies in mice – ob (obesity), tub (tubby),
fat, db (diabetes).
• 1994 – Conceptual breakthrough – ob gene cloned;
protein product identified as Leptin.

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• Leptin secreted by adipose cells; acts on hypothalamus.
• Level of Leptin production provides an index of adipose
energy stores.
• “Leptin resistance.”
• The mechanism for leptin resistance is not yet established.
• SOCS3 and PTP1b involved in the leptin resistant state.

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10. Arcuate Nucleus (ARC) :
Anorexigenic (Appetite suppressing) &
Orexigenic (Appetite promoting) neurons
• Role of NA, 5-HT, Dopamine, Endocannabinoids.21/03/2017 Anti-Obesity Drugs : Dr Sahil Kumar 10

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Energy Expenditure
• Energy expenditure is required to maintain
metabolism, physical activity and thermogenesis.
• 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, ↑ UCP-1.

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ETIO-PATHOGENESIS OF OBESITY
• Dietary and socio-cultural factors.
• Genetic susceptibility.
• Specific syndromes.
• Deficiencies in synthesis/ action of leptin.
• Defects in hypothalamic neuronal systems.
• Defects in systems controlling energy expenditure.
• Decreased thermogenesis caused by dysfunction of
proteins that uncouple oxidative phosphorylation.

14. WHY TREAT OBESITY?
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Cancer

15. TREATMENT OF OBESITY
•GOAL: To improve obesity-related comorbid conditions
and to reduce the risk of developing future comorbidities.
•Treatment approaches-
1) Lifestyle modification (meal plan, physical activity
and behavioral interventions).
2) Pharmacotherapy.
3) Surgery.
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16. PHARMACOTHERAPY OF OBESITY
AACE/ACE Guidelines (2016)
• Pharmacotherapy - adjunct to lifestyle therapy and not alone.
• Adding pharmacotherapy produces greater wt. loss & wt. loss
maintenance.
• Short-term t/t (3-6 mo) with weight loss medications is not
recommended.
• Consider differences in efficacy, adverse effects, warnings, as well as
weight-related complications and medical history.
• An algorithm for medication preferences that would apply to all
patients cannot currently be scientifically justified.
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17. 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.

18. PHARMACOTHERAPY: HISTORICAL ASPECTS
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•Soranus of Ephesus (second century AD): Laxatives and
Purgatives.
•1920s and 1930s- Thyroid hormone.
•1933 - 2,4-Dinitrophenol (DNP).
•Late 1930s - Benzedrine. “Rainbow pill" regime.

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• Amphetamines - Second World War. Outlawed - Late 1950s.
•Phentermine (1959) and Fenfluramine (1973).
• 1992 - Fen-phen - 10% weight loss.
• Mid-1990s - Dexfenfluramine (1996).
• Valvular Heart Disease in up to 30% patients.
•1997 - Withdrawal of Fen-phen and dexfenfluramine.

20. ANTI-OBESITY DRUGS
•Orlistat (2007)
•Lorcaserin (2012)
•Phentermine-Topiramate - Qsymia (2012) (Not by EMA)
•Naltrexone-Bupropion – Contrave (2014) (EMA-2015)
•Liraglutide (2014) (EMA-2015)
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21. ORLISTAT
• Lipostatin (Streptomyces toxytricini).
• MOA: Lipase inhibitor (irreversible).
• PK: Virtually all of it excreted in faeces.
• Dose: 120 mg three times a day.
• A/E: Malabsorption of dietary fat, flatus with
discharge, fecal urgency, fatty/oily stool, and
increased defecation. Fat-soluble vit D and E and
β-carotene.
• Interaction – Cyclosporin.
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22. •Orlistat also reported to be effective in patients suffering
from type 2 diabetes. (Curran & Scott, 2004)
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XENDOS
Torgerson, et al. Diabetes Care, 2004.

23. LORCASERIN
•Lorcaserin- selective 5-HT2C receptor agonist.
•MOA: ↓ food intake through pro-opiomelanocortin.
•Dose: 10 mg Two times a day.
•BLOOM trial: Weight loss was 3.6%.
•No difference in the development of valvulopathy between
drug-treated and placebo-treated participants at 1 year.
•A/E: headache, dizziness, and nausea.
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24. PHENTERMINE-TOPIRAMATE (PHEN/TPM)
• Approved by FDA (2012), not by EMA.
• MOA: Not well understood.
• EQUIP and CONQUER trials: Wt loss 9.3% and 8.6%
respectively.
• Dose: 15mg/90 mg (PHEN/TPM) once a day
• A/E: Paresthesias, dry mouth, constipation,
dysgeusia, insomnia.
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25. NALTREXONE-BUPROPION
•MOA: Combined to dampen the motivation that food
brings (dopamine effect) and the pleasure of eating
(opioid effect).
•In a randomized, double-blind, placebo-controlled trial,
1742 enrolled participants - weight loss = 6.1%.
•Dose = 32 mg/ 360 mg (Naltrexone-Bupropion).
•A/E: Nausea, headache, dizziness, vomiting and dry
mouth.
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26. LIRAGLUTIDE
•Liraglutide, GLP-1 receptor agonist.
•MOA: Weight loss effects via hypothalamic neural
activation causing appetite suppression.
•SCALE™ Obesity and Prediabetes trial: 9.2 % weight loss.
•Dose = 3 mg once daily, injected s/c.
•A/E: Nausea, vomiting, change in bowel habits, acute
pancreatitis.
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27. AGENTS WITHDRAWN IN THE LAST DECADE
•Sibutramine (2010) – ↑ Cardiovascular risks.
•Rimonabant (2008) - Serious psychiatric side effects.
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28. FUTURE DEVELOPMENTS
•Cetilistat - inhibits pancreatic lipase, Phase 3 trials.
•GT 389255 - pancreatic lipase inhibitor and fat-binding
hydrogel polymer. Phase-II.
•TM-38837 - antagonist of the CB1 cannabinoid receptor,
phase I.
•Experimental:
•Inhibit anabolic molecules.
•Stimulate catabolic signals.
•Gastric peptides.
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29. CONCLUDING REMARK
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30. THANK YOU
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