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

1. Drugs in weight management
Recent developments
Prof. Renger F. Witkamp
Nutrition and Pharmacology

2. The challenge (1)
Disease risk
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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
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4. Key messages from pharma R&D:
1) Overweight creates big market
2) Creativity is unlimited
3) No idea is too crazy beforehand
4) Consider options you thought
unthinkable
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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
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6. Can’t they make a pill for
this ?
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7. Yes, they probably can !
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8. Or perhaps give fat an anti-tumor
treatment…..
Magic bullets melt fat
Nature Medicine 10, 581 - 582 (2004)
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9. Tackling the inflammation process
might work
Ebstein, W.: Zur Therapie des Diabetes mellitus, insbesondere über
die Anwendung des salicylsauren Natron bei demselben. Berl. klin.
Wschr. 13, 337–340 (1876).
British Medical journal 1901
TINSAL-T2D II
study (NCT00799643)
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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
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11. Pharmacological strategies to manage
body weight: a battle against the most
powerfull instincts
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12. Big money - strong lobby (1)
€ High prevalence
€ Clear unmet medical and social need
€ Not much competition so far
€ Succesful drug will become blockbuster
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13. Big money - strong lobby (2)
“ Obesity Organizations Encouraged by Positive Outcome for New Treatment Option”
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14. People are longing for “easier alternatives”
nutritional* pharmaceutical
Ephedra sinica
Hoodia gordonii Orlistat
Cracina combogia Lorcaserin **
Pausinystalia yohimbe Phentermine
Yerba maté +Topiramate**
Guar gum Sibutramine
Glucomannan Rimonabant
Chitosan
Chroom picolinate
Hydroxymethylbutyrate
……etc.
* including supplements and herbal drugs
** approved in US, not in EU
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15. Hot off the press
Lorcaserin
Phentermine + Topiramate
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16. But not (yet ?) in EU
Company
making
Lorcaserin
Share
value !
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17. Story of weight loss drugs is
cumbersome and full of serendipity
Bray GA & Greenway FL (2007) Pharmacological Reviews 59(2): 151-184.
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18. Supplements : from innocent to dangerous
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19. Some notorious examples
• Dintrophenol (and alikes)
• Beta-agonists Tainter et al. 24 (10): 1045. (1934)
• Amfetamine-likes, including methylphenidate
(RitalinR)
www.ergogenics.org
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20. Some pharmacological targets under development
Witkamp, Pharm Res (2011) 28:1792–1818
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21. The GI tract : reducing energy
absorption 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
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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
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24. Targeting the brain : the most risky and challenging,
though probably the most effective
Witkamp, Pharm Res (2011) 28:1792–1818
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25. Other brain centra
Mono-amine availability 
H3 receptor antagonists
MC4R agonists
Orexigenic
Anorexigenic
NPY agonists POMC/
NPY/
AgRP CART
Arcuate nucleus
Reducing leptin
resistance
Witkamp, Pharm Res (2011) 28:1792–1818
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26. Satiety signals do not always work
We easily eat while not being hungry
Approx. 1600 kcal
Approx. 250-300 kcal
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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”
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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
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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
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31. Lancet, 2007
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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
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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
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35. What is achievable (2) ?
As often : strong placebo
effects
Least squares mean patterns of weight loss. Error bars indicate SE.
From: Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled Trial
Arch Intern Med. 2012;():1-8. doi:10.1001/archinternmed.2013.99
Copyright © 2012 American Medical
Date of download: 11/11/2012 35
Association. All rights reserved.
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36. Development pipeline (mid 2012)
Nature Reviews Drug Discovery sept 2012
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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..)
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38. For further reading :
(open access)
Pharm Res (2011) 28:1792–1818
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