Copyright 2017 by Sea Courses Inc.

Transcription

1 Appetite

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Obesity is recognized as a chronic disease and global health issue obesity is a primary disease, and the full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity 1 Obesity is a chronic disease, prevalent in both developed and developing countries, and affecting children as well as adults 3 Recognizing obesity as a disease will help change the way the medical community tackles this complex issue that affects approximately one in three Americans 2 FDA agrees with these comments that obesity is a disease Obesity is a chronic and often progressive condition Mechanick et al. Endocr Pract 2012;18:642 8; 2. AMA position statement. Available at: 3. TOS Obesity as a Disease Writing Group. Obesity 2008;16: ; 4. Canadian Obesity Network. 5As of Obesity Management. Downloaded from on November 17, 2014.

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5 Learning objectives: To review the physiology and pathophysiology of weight maintenance To review which medications can contribute to weight gain/loss

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7 Abnormal Hormone Normal receptor Normal Hormone Abnormal receptor Leptin

8 Leptin Is made by fat The greater the amount of fat, the greater the amount of Leptin Tells the brain the status of the fuel tank i.e. energy stores, i.e. fat stores

9 Insulin controls the amount of weight your body will defend

10 Insulin s effect in insulin resistant rats. Diabetologia 46:1629, 2003

11 Insulin s effect in insulin resistant rats. Diabetologia 46:1629, 2003

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13 Intranasal insulin

14 Leptin/Insulin

15 Leptin and insulin modulate the effect of orexogenic and anorexogenic hormones CCK, PYY, GLP1, Ghrelin, etc release

16 CCK, PYY, GLP1, Ghrelin, etc release

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18 Diet induced weight loss Ghrelin increases

19 2h Food Intake (g) A Role for GLP-1 in the Central Regulation of Feeding Appetite Suppression Requires Increased Levels of GLP-1 Stimulation in Rats * * ** Icv GLP-1 ( g) *p<0.05 **p<0.01 Turton, et al. Nature. January 1996; 379: 69-72

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21 Or is this the pathology? Hypothalamic gliosis (inflammation) which causes LEPTIN RESISTANCE, similar to db/db mouse with defective Leptin receptor (not really but at least decreased action of Leptin at the receptor, requiring greater levels of Leptin to suppress appetite)

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24 This gliosis and proinflammatory cytokine release induces a state of insulin and leptin resistance in the brain. The brain acts as if it were leptin resistant (like an animal with an abnormal receptor giving a subnormal response) and insulin resistant The brain will defend the weight based on the leptin and insulin signal it gets

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30 Summary and conclusions: Body weight and appetite are controlled by an interaction of various hormones and neurotransmitters. When working properly, they protect a normal weight to a high degree of precision. People who are obese generally do NOT want to be obese. However, Obese people and especially obese diabetics may not perceive fullness as you or I might The body (brain) will want to defend the highest weight it has achieved dieting puts into effect hormonal and chemical responses that oppose weight loss by inducing hunger An insulin resistant brain may PRECEDE obesity and may contribute in a causal way to the condition

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39 Glucocorticoids

40 Orlistat in Overweight and obese patients with Type 2 diabetes treated with metformin Diab Care 25: , 2002

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42 XENDOS results Effect of Xenical on body weight Change in weight (kg) 0 Placebo + lifestyle Xenical + lifestyle kg -6.9 kg p<0.001 vs placebo Week

43 Cumulative Incidence of Type 2 Diabetes Based on 2-h OGTT All patients Incidence (%) 10 Placebo + lifestyle Xenical + lifestyle 9.0% % RR* 37% 4 2 p= Week *Reduction in risk of progressing to type 2 diabetes versus placebo + lifestyle Torgerson JS et al. Diabetes Care 2004; 27 (1):

44 Lorcaserin High affinity 5HT2c agonist (activation of cardiac valve tissue involves 5HT2b receptors) In theory might have the benefits of Fenfluramine without the unwanted side effects Has been extensively investigated for cardiac valvular damage and it does not

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49 Topiramate/Phentermine

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55 Bupropion Approved for treatment of depression and smoking cessation Inhibits dopamine and noradrenaline reuptake Stimulates the anorexigenic POMC (ProOpioMelanoCortin system) However, there is tolerance to this effect in part due to beta endorphins

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57 Contrave Combination of Bupropion with the opioid antagonist Naltrexone. Rationale is that the Naltrexone will inhibit the beta-endorphin compensation for the Bupropion induced activation of the POMC system 4 pivotal trials, NB , 304 being in Type 2 diabetics

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63 ADA 2016

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66 Results: Weight Initial weight reduction with dapagliflozin and weight gain with glipizide at 52 weeks remained stable at 104 weeks (Figure 4). Weight difference vs glipizide at 104 weeks 5.06 kg (95% CI; 5.73, 4.4). Figure 4. Change in Total Body Weight over Time

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69 What drugs are available to Canadians? Metformin GLP1 agonists SGLT2 inhibitors Topiramate Bupropion Phentermine Orlistat

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71 What else can be done Stop weight positive drugs that can be stopped Choose antihistamines, antipsychotics, antidepressants that are more neutral for weight Try not to use beta blockers

72 Obesity is a chronic disease! If treatment is stopped, the symptoms return

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75 Summary and conclusions (1) Control of appetite (weight) involves a complex interplay among several hormones the most important of these being Leptin and insulin which both let the brain know how much fat there is These hormones set the gauge in the brain as to how sensitive it will be to other appetite simulating and suppressing hormones

76 Summary and conclusions (2) Once obesity is established, the brain will defend the new weight as if it were the normal desired weight (very analogous to hypertension, etc) Several commonly used drugs predispose to weight gain. More options are becoming available to aid in weight loss As we understand more about appetite and weight physiology, more will certainly come available.

77 Summary and conclusions (3) Obese people do not want to be obese! They have all tried to lose weight already Simply telling them to lose weight is akin to telling a schizophrenic not to hear voices, or telling a depressed person to simply cheer up. It s not going to work Losing weight will often require the use of medications (or other measures topic of another talk)