Drugs in weight management   Recent developments                   Prof. Renger F. Witkamp                   Nutrition and...
The challenge (1)           Disease risk       2                          VLAG Course 2012
Pharmacological targets in obesity• Decrease food consumption• Reduce energy absorption from GI tract• Reduce body fat by ...
Key messages from pharma R&D:1) Overweight creates big market2) Creativity is unlimited3) No idea is too crazy beforehand4...
Example : physical exercise is             beneficial• Improves symptoms of metabolic syndrome independently  from weight ...
Can’t they make a pill for  this ?          6                             VLAG Course 2012
Yes, they probably can !           7                      VLAG Course 2012
Or perhaps give fat an anti-tumor                     treatment…..Magic bullets melt fatNature Medicine 10, 581 - 582 (200...
Tackling the inflammation process                  might workEbstein, W.: Zur Therapie des Diabetes mellitus, insbesondere...
The challenge (2) : Don’t forget these              patients                      Cachexia and sarcopenia are a           ...
Pharmacological strategies to managebody weight: a battle against the most         powerfull instincts                 11 ...
Big money - strong lobby (1)€   High prevalence€   Clear unmet medical and social need€   Not much competition so far€   S...
Big money - strong lobby (2)   “ Obesity Organizations Encouraged by Positive Outcome for New Treatment Option”           ...
People are longing for “easier alternatives”      nutritional*                                      pharmaceuticalEphedra ...
Hot off the press       Lorcaserin       Phentermine + Topiramate       15                                  VLAG Course 2012
But not (yet ?) in EUCompany makingLorcaserin                                 Share                                 value ...
Story of weight loss drugs is      cumbersome and full of serendipityBray GA & Greenway FL (2007) Pharmacological Reviews ...
Supplements : from innocent to dangerous                   18                                  VLAG Course 2012
Some notorious examples• Dintrophenol (and alikes)• Beta-agonists                   Tainter et al. 24 (10): 1045. (1934)• ...
Some pharmacological targets under development                     Witkamp, Pharm Res (2011) 28:1792–1818             20  ...
The GI tract : reducing energyabsorption or stimulation of satiation     MTP, DGAT1 or MGAT inhibition                    ...
22     VLAG Course 2012
Interfering with the action of satiety and                    adipose tissue hormones                            Blocking/...
Targeting the brain : the most risky and challenging,        though probably the most effective                           ...
Other brain centra        Mono-amine availability                                                        H3 receptor anta...
Satiety signals do not always workWe easily eat while not being hungry            Approx. 1600 kcal                       ...
Regulation of feeding behavior at different levels        hunger/satiation                 motivation / reward      physio...
Two components (phases) of non-homeostatic eating       can [partly-] be targeted separately                “wanting” anti...
29     VLAG Course 2012
Effects of CB1 stimulation:non homeostatic overconsumption and fat storage                                         Hypotha...
Lancet, 200731       VLAG course 2012
32     VLAG Course 2012
Second generation CB1 blockers• Different kinetics : relatively lower brain  concentrations and more peripheral action• Di...
What is achievable (1) ?%-age of individuals achieving 5-10% weight reduction in 1 year                                   ...
What is achievable (2) ?                                                                                    As often : str...
Development pipeline (mid 2012)                    Nature Reviews Drug Discovery sept 2012               36               ...
Final remarks• Weight management drugs :  – Enormous activity in Pharma, many targets  – Several compounds in the pipeline...
For further reading :   (open access)                             Pharm Res (2011) 28:1792–1818                        38 ...
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Weight management drugs - recent developments - Renger Witkamp

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A short (38 slides) update on current and future medicines used against overweight (and its complications)

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Weight management drugs - recent developments - Renger Witkamp

  1. 1. Drugs in weight management Recent developments Prof. Renger F. Witkamp Nutrition and Pharmacology
  2. 2. The challenge (1) Disease risk 2 VLAG Course 2012
  3. 3. Pharmacological targets in obesity• Decrease food consumption• Reduce energy absorption from GI tract• Reduce body fat by stimulating energy expenditure or inhibiting energy• Reduce inflammatory status• Modulate body fat distribution, energy fluxes or mimick physical exercise• Minimize pathophysiological complications 3 VLAG Course 2012
  4. 4. Key messages from pharma R&D:1) Overweight creates big market2) Creativity is unlimited3) No idea is too crazy beforehand4) Consider options you thought unthinkable 4 VLAG Course 2012
  5. 5. Example : physical exercise is beneficial• Improves symptoms of metabolic syndrome independently from weight loss• Improves cardiometabolic fitness• Improves muscle metabolism• Stimulates immune system• Contributes to weight management 5 VLAG Course 2012
  6. 6. Can’t they make a pill for this ? 6 VLAG Course 2012
  7. 7. Yes, they probably can ! 7 VLAG Course 2012
  8. 8. Or perhaps give fat an anti-tumor treatment…..Magic bullets melt fatNature Medicine 10, 581 - 582 (2004) 8 VLAG Course 2012
  9. 9. Tackling the inflammation process might workEbstein, W.: Zur Therapie des Diabetes mellitus, insbesondere überdie Anwendung des salicylsauren Natron bei demselben. Berl. klin.Wschr. 13, 337–340 (1876). British Medical journal 1901 TINSAL-T2D II study (NCT00799643) 9 VLAG Course 2012
  10. 10. The challenge (2) : Don’t forget these patients Cachexia and sarcopenia are a huge medical and social problem, so is anorexia (chronic disease related as well as a. Nervosa) Pharmacological (and other medical) options still limited But not dicussed today... NEJM July 2012 10 VLAG Course 2012
  11. 11. Pharmacological strategies to managebody weight: a battle against the most powerfull instincts 11 VLAG Course 2012
  12. 12. Big money - strong lobby (1)€ High prevalence€ Clear unmet medical and social need€ Not much competition so far€ Succesful drug will become blockbuster 12 VLAG Course 2012
  13. 13. Big money - strong lobby (2) “ Obesity Organizations Encouraged by Positive Outcome for New Treatment Option” 13 VLAG Course 2012
  14. 14. People are longing for “easier alternatives” nutritional* pharmaceuticalEphedra sinicaHoodia gordonii OrlistatCracina combogia Lorcaserin **Pausinystalia yohimbe PhentermineYerba maté +Topiramate**Guar gum SibutramineGlucomannan RimonabantChitosanChroom picolinateHydroxymethylbutyrate……etc. * including supplements and herbal drugs ** approved in US, not in EU 14 VLAG Course 2012
  15. 15. Hot off the press Lorcaserin Phentermine + Topiramate 15 VLAG Course 2012
  16. 16. But not (yet ?) in EUCompany makingLorcaserin Share value ! 16 VLAG Course 2012
  17. 17. Story of weight loss drugs is cumbersome and full of serendipityBray GA & Greenway FL (2007) Pharmacological Reviews 59(2): 151-184. 17 VLAG Course 2012
  18. 18. Supplements : from innocent to dangerous 18 VLAG Course 2012
  19. 19. Some notorious examples• Dintrophenol (and alikes)• Beta-agonists Tainter et al. 24 (10): 1045. (1934)• Amfetamine-likes, including methylphenidate (RitalinR) www.ergogenics.org 19 VLAG Course 2012
  20. 20. Some pharmacological targets under development Witkamp, Pharm Res (2011) 28:1792–1818 20 VLAG Course 2012
  21. 21. The GI tract : reducing energyabsorption or stimulation of satiation MTP, DGAT1 or MGAT inhibition Lipase inhibition Alternatives to orlistat, e.g. cetilistat GPR 119 agonists EEC enterocyte CB 1 antagonists Blood capillary Vagal afferent Witkamp, Pharm Res (2011) 28:1792–1818 21 VLAG Course 2012
  22. 22. 22 VLAG Course 2012
  23. 23. Interfering with the action of satiety and adipose tissue hormones Blocking/reducing Stable GLP-1 analogues, Amylin Ghrelin activity ? e.g. exenatide, liraglutide analogues PP analogues GLP-1 analogues PYY analogues?Leptin analogues CCK agonists ? Metreleptin (leptin- analogue) + pramlintide (amylin analogue) Witkamp, Pharm Res (2011) 28:1792–1818 23 VLAG Course 2012
  24. 24. Targeting the brain : the most risky and challenging, though probably the most effective Witkamp, Pharm Res (2011) 28:1792–1818 24 VLAG Course 2012
  25. 25. Other brain centra Mono-amine availability  H3 receptor antagonists MC4R agonists Orexigenic AnorexigenicNPY agonists POMC/ NPY/ AgRP CART Arcuate nucleus Reducing leptin resistance Witkamp, Pharm Res (2011) 28:1792–1818 25 VLAG Course 2012
  26. 26. Satiety signals do not always workWe easily eat while not being hungry Approx. 1600 kcal Approx. 250-300 kcal 26 VLAG Course 2012
  27. 27. Regulation of feeding behavior at different levels hunger/satiation motivation / reward physiology/homeostasis psychology/non-homeostatic hypothalamus (and brainstem) (cortico)-limbic system energy uptake energy use “wanting” “liking” 27 VLAG Course 2012
  28. 28. Two components (phases) of non-homeostatic eating can [partly-] be targeted separately “wanting” anticipatory/approach phase of the feeding important mediator : Dopamine “liking” hedonic aspects of the consummatory act important mediators : Endocannabinoids and opioids 28 VLAG Course 2012
  29. 29. 29 VLAG Course 2012
  30. 30. Effects of CB1 stimulation:non homeostatic overconsumption and fat storage Hypothalamus: hunger N. Accumbens: motivation to eat Entero endocrine regulation: continue eating Liver and adipose tissue: lipogenesis en lipid storage ^ Insuline resistance HDL-cholesterol ^ Triglycerides Glucose uptake Adiponectine 30 VLAG Course 2012
  31. 31. Lancet, 200731 VLAG course 2012
  32. 32. 32 VLAG Course 2012
  33. 33. Second generation CB1 blockers• Different kinetics : relatively lower brain concentrations and more peripheral action• Different dynamics : no inverse agonists like rimonabant, but neutral antagonists or partial agonists 33 VLAG Course 2012
  34. 34. What is achievable (1) ?%-age of individuals achieving 5-10% weight reduction in 1 year Lean, M. et al. BMJ 2006;333:794-797 34 VLAG Course 2012
  35. 35. What is achievable (2) ? As often : strong placebo effectsLeast squares mean patterns of weight loss. Error bars indicate SE.From: Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled TrialArch Intern Med. 2012;():1-8. doi:10.1001/archinternmed.2013.99 Copyright © 2012 American MedicalDate of download: 11/11/2012 35 Association. All rights reserved. VLAG course 2012
  36. 36. Development pipeline (mid 2012) Nature Reviews Drug Discovery sept 2012 36 VLAG course 2012
  37. 37. Final remarks• Weight management drugs : – Enormous activity in Pharma, many targets – Several compounds in the pipeline but no breakthroughs or miracles on the horizon yet – From a medical point of view bariatric surgery is more effective for severe obesity• Medicines to reduce complications of obesity are thus far more promising• Pay attention to pharmacology aiming to increase food-intake (...next time..) 37 VLAG Course 2012
  38. 38. For further reading : (open access) Pharm Res (2011) 28:1792–1818 38 VLAG Course 2012

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