Obesity & its management

Obesity

1. Treatment Strategy And Management Presented by:- Dr . Rupendra Kumar Bharti Department of Pharmacology IGMC, Shimla H.P. OBESITY

2. The definition An appropriate definition of obesity today must include 'excess' adiposity with 'ectopic' fat deposition in non-adipose tissue.

3. Normal Mechanism Of Adipocytes Adipose tissue is the only dedicated storehouse of fat in our body. It stores excess calories as triglycerides (TG) in adipocytes. From an evolutionary perspective, this is the most efficient form of energy conservation, where stored triglyceride is released during periods of fasting or calorie deprivation. The major fat depots in the body are the subcutaneous adipocytes. Subcutaneous adipose tissue (SAT ), accounts for 80% of the total body fat. Another 10% is stored in the body cavities as visceral adipose tissue (VAT), as omental, mesenteric and retroperitoneal fat .

4. Remaining 10% fat is distributed at non-adipose tissues, such as skeletal muscles, nervous system, liver, pancreas, heart, blood vessels and bone-marrow, whereas very small amount of lipids are required for their structural support, normal cellular functions, membrane integrity and fluidity, neural signal transmission, thermo-regulation and cushioning of the organs. These sites are never designed for fat storage. Therefore, they have no capacity to store excess fat without causing harm.

5. More than half of the world's 671 million obese individuals living in just ten countries— the USA (more than 13 per cent), China and India (15 per cent combined), Russia, Brazil, Mexico, Egypt, Germany, Pakistan, and Indonesia. In developed countries having highest rates of obesity prevalence then developing countries. The Epidemiology

6. South Asia....

7. In India prevalence in this age group is 19.5% (18.3%-20.8%) While BMI >30 accounting 3.8% in India

8. In India prevalence in this age group is 3.7% (2.8%-4.7%)

9. In India A study conducted in 15 to 25-year-old Asian Indian adolescents and young adults reported an average total fat intake of 29- 84 g/d in males and 21-72 g/d in females, nearly 4 times the recommended dietary allowance for Asian Indians ( 20-25 g/d).

10. Aetiology…

11. A reason of Childhood obesity

12. Pathophysiology

13. `

14. Diagnosis..

15. BMI (by WHO) WORLDWIDE BMI SOUTH ASIAN Under weight Normal range Pre obese Obese BMI ≤18.5 18.5 - 22.99 23-27.5 ≥27.5 Risk of comorbidities Low (but risk of clinical problem increase due to underweight) Average Increase Very increase Classification 1.

16. 2. Waist circumference 3. Waist-to-hip ratio:- its used to compare the fat distribution b/w abdomen and gluteal region. Normal Male:- <1 Female :- <0.8 Its useful predictor of diabetes and cardiovascular disease risk in adults.

17. 4. Skin fold thickness (Harpenden calliper instrument) :- Normal – Male :- 61-80 mm Female:- 71-90 mm 5. Bioelectrical impedance (BIA):- It is a easy and non invasive technique. Technique was based on the fact, that lean tissue is a good conductor of electricity then fat. It’s used for the measurement for LBM, TBW and water distribution in the various compartment of body. If the total body weight is increase, the impedance was reduced. 6 . CT, MRI, USG for anatomical distribution of fat. 7. Palmitic acid Extended overfeeding challenge test for partition of nutrient storage

18. OTHERS.. Gout, non healing venous ulcer, Ca breast, uterus cervix, oesophagus, colon, pancreas, kidney, Cirrhosis, fatty liver disease, cholesterosis, Pickwinkian syndrome Complication….

19. Prevention 1. Increase physical activity:- as we already known that sedentary life style is increase the risk of obesity. 2. Maintain diet: low energy-dense foods (including wholegrain, cereals, fruits, vegetables and salads) probably protect against weight gain, overweight, and obesity. high energy-dense foods (including foods containing animal fats, other high fat foods, confectionery and sugary drinks) are probably a cause of weight gain, overweight, and obesity , particularly when large portion sizes are consumed regularly. sugary drinks probably cause weight gain, overweight, and obesity. ‘ fast foods’ probably cause weight gain, overweight, and obesity.

20. 3. Avoid medicines which is associated with obesity, like Atypical antipsychotics, including clozapine Beta adrenergic blockers, particularly propranolol Lithium Sodium valproate Sulphonylureas , including chlorpropamide, glibenclamide , glimepiride and glipizide Thiazolidinediones , including pioglitazone Tricyclic antidepressants, including amitriptyline

21. Treatment strategy Primary Prevention Of Obesity In Children, Young People And Adults ƒƒ Treatment Of Overweight/Obesity By Diet And Lifestyle Interventions ƒƒTreatment Of Obesity By Pharmacological Therapy And Bariatric Surgery ƒPrevention Of Weight Regain Following Treatment.

22. Guideline By Indian Endocrinology And Metabolism Society

23. Treatment Strategy surgery

24. Are indicated for use in patients with a BMI >30 or BMI >27 with obesity related comorbidities. When used under the medical supervision of a physician and dietician, VLEDs are able to induce rapid weight loss and have been shown to achieve an average weight loss of 18–20% with better sustained weight reduction. It also improve glycaemic control in patients with type 2diabetes , improve blood pressure and reduce total cholesterol. This high protein-low carbohydrate diets induce fat burning and mild ketosis , which results in suppression of hunger and promotion of satiety. Treatment duration with a VLED is generally 8–12 weeks. Non pharmacological treatment Very low energy diets ( VLEDs) (< 800 kcal/day or <3350 kJ/day)

25. Pregnant or lactating women, infants, children, adolescents (under 18 years ). Elderly (over 65 years), patients with a history of Psychological disturbances, alcohol misuse or drug abuse, in the presence of porphyria, recent myocardial infarction or unstable angina. Monitoring and support of patients on VLEDs is required for success . VLEDs Contraindicated

26. Pharmacotherapy…

27. Phenteramine Sibutramine GLP1

28. Phentermine, Amphetamine MOA:- Appetite suppressant. Its stimulates the anorexic signaling in hypothalamus or dopamine receptor in the hippocampus. It’s also having sympathomimetic action similar to norepinephrine with CNS stimulatory activity. Phentermine Weight loss ≥ 3.6 kg then placebo. ADR :- Appetite suppression and weight loss, including dry mouth , dizziness, sleeplessness, N/V/D with withdrawal symptoms. Approved by FDA in 1959 Amphetamine Effect:- Weight loss ≥ 1kg then placebo. ADR:- with withdrawal symptoms, patient may will developed headache, fear anxiety, raise BP and HR. Its approved for ADHD with weight lowering drug

29. Lorcaserin, Desvenlafaxine, Sibutramine MOA:- It is a serotonin, dopamine, norepinephrine reuptake inhibitor that potentiates the neurotransmitter activity in the CNS. Lorcaserin 5HT2C agonist Effect :- mean body weight loss 5.8 0.2 kg ADR :- limited weight loss efficacy and possible increase cancer risk(breast cancer), while m/c ADR is headache, followed by sinusitis nausea depression anxiety Approved by USFDA in 2012   Desvenlafaxine Effect :- mean body weight loss 2.2 1.41 kg ADR :- nausea, headache, dizziness, Xerostomia , hyperhidrosis, diarrhea, Insomnia, Constipation, Fatigue, High blood pressure. Approved Antidepressant in February 2008 with lowering obesity by USFDA   Sibutramine Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in 2010

30. Bupropion MOA : - its inhibits neuronal uptake of dopamine, norepinephrine and serotonin. is a drug primarily used as an antidepressant and smoking cessation. its seems that bupropion decrease body weight then placebo. Effect :- Bupropion SR 400 mg/day reduces weight 5.1% and in 300mg /day reduced 2.2% ADR :- Insomnia, Headache, pyrexia, Asthenia, Dizziness, Agitation, Alopecia, Tremor, N/V/C, Pruritus, Urticaria due to hypersensitivity Approved for Anti depression By USFDA in 30 December 1985.

31. Orlistat (Tetrahydrolipstatin ) Its primary function is preventing the absorption of fats from the human diet by acting as a intestinal lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet . Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases. Effect :- Mean body weight loss ≥ 4.2 kg ADR :- Weight loss, increase of bowel movement and potential changes in the bowel function ( steatorrhea), Long term used may lead to Breast carcinoma. Approved in 1999 by USFDA.

32. Topiramate Is an   anticonvulsant (anti epilepsy ) drug. In late 2012, topiramate was approved by the  USFDA in combination with  phentermine for weight loss. MOA :- Its enhancing GABA signaling to promote anorexigenic signaling, with inhibition of voltage gated channels and AMPA( α - amino-3-hydroxy-s- methyl-4- isoxazole propionate) receptor in the orexigenic neurons. Effect :- weight loss is greater then placebo was 6.5kg. ADR :- Dizziness, Weight loss, Paraesthesia, Somnolence, Nausea, Diarrhea, Fatigue, Nasopharyngitis, Depression, acute myopia, secondary angle closure glaucoma.

33. GLP 1 receptor agonist GLP-1 secretion by ileal L cells is dependent on the presence of nutrients in the lumen of the small intestine. It is a secretogogus analog, which increase the secretion of insulin and delayed gastric empty time. Once in the circulation, GLP-1 has a half-life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4, which is inhibited by sitagliptin. Exenatide Effect :- mean body weight loss with extentide (2.49 ) and with placebo (0.43 ± 0.63 kg) ADR :- Decrease blood glucose and body weight along with GIT symptoms, pancreatitis, dizziness and headache. It might increase sulfonylurea-induced hypoglycemia and thyroid cancer. Approved by USFDA for Diabetes   Liraglutide Effect :- Weight loss greater then placebo was 4.4kg ADR :- Maintained normal blood glucose and body weight, with increase risk of C-cell carcinoma and thyroid C- cell focal hyperplasia were observed in rat and mice. Approved by USFDA for Diabetes

34. Amylin analog   Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone . It is co secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1. Amylin plays a role in glycaemic regulation by slowing gastric emptying and promoting satiety, hereby preventing post-prandial spikes in blood glucose levels.

35. Cocktail drug… The combination of Phenteramine (PHEN) and Topiramate (TPM) Effect:- weight loss from baseline was placebo-2.2% (PHEN 7.5mg/ TPM 46mg) control release 9.3%, (PHEN 15mg/ TPM 92mg) control release – 10.7%

36. BIGUANIDE METFORMIN MOA : Its nonsecretogogus drug, which do not enhance insulin but by inhibiting hepatic genolysis by inhibiting enzyme AMP kinase, decreasing renal neoglucogenesis, decrease intestinal absorption and increase exhibits glucose to muscles and adipose tissue, its enhance insulin metabolism and maintain body glucose level. Effect :- it may lead to infertility in pregnant women, without diabetes treated with atypical anti psychotics, reduces weight 4.8% following 12-14 weeks treatment. ADR :- Most frequent S/E is Nausea. Other are megaloblastic anemia, hepatitis.

37. Rimonabant It is a arachidonic acid derivative known as endocannabinoids, were identified as endogenous substance that activate cannabinoid receptor(CB1, CB2, CB3). It’s regulate energy regulator hormones and neuropeptide. This receptor were overactive in the case of overweight and obesity. Rimonabant which is CB1 antagonist, is present more in brain and peripheral tissue (liver, GIT, adipocyte, cardiac muscles). It’s inhibits excess food intake and maintain nutrient metabolism. USFDA Approved in 2007.

38. Off- label medicines not approved by USFDA “Fen- P hen” (fenfluramine+ phenteramine) causing hyperthyroidism and major CVS disease Dinitrophenol (cataracts and neuropathy) Rainbow diet pill (mixture of digitalis and diuretics) arrhythmias and electrolyte imbalance Aminorex is a 2-amino-5-aryl oxazoline class drug (pulmonary hypertension) Phenylpropanolamine (MI and Stroke) Axokine (ciliary neurotropic factor) Increase obesity due to inhibition of anorexigenic signaling receptors . (DM2) SSRI (Fluoxetine) Methylephenidate Zonisamide Octreotide Ephedrine

39. Chromium Ephedral Alkaloids St. John’s Wort Pyruvate Hoodia White Willow Bark Guarana and Tea extract Chitosan Alternative therapy for lowering body weight

40. Surgical Management

41. Criteria…. Patient should have a BMI of 40 kg/m2 or more, or between 35 kg/m2 and 40 kg/m2 and other significant disease (for example, type 2 diabetes or high blood pressure) that could be improved if they lost weight. All appropriate non-surgical measures have been tried but have failed to achieve or maintain adequate, clinically beneficial weight loss for at least 6 months.

42. The Three Most Commonly Performed Procedures Laparoscopic Adjustable Gastric Banding ( LAGB ) 5 4% weight loss at 3–5 yr . Gradual Pattern of weight loss 4-6% Morbidity at 1 year Advantage Effective , with good long term weight maintenance. Ability to adjust the degree of restriction. Reversible. Maintains gastric. integrity Disadvantage Gastric pouch dilatation. Erosion of band into the stomach. leaks to the LAGB system. Weight regain. Iron vitamin B12 and folate

43. Roux-en-Y gastric bypass (RYGB) 60% weight loss at 3–5 years Rapid, maximal weight loss in 1–2 years 14.9% Morbidity at 1 year Advantage Very effective with good long term weight maintenance Few failures Disadvantage Abdominal pain, staple line leak, stomach ulcer, Intestinal obstruction , Gallstones Nutritional deficiency Weight regain Deficiencies in iron, vitamin B12 , folate , calcium, vitamin D , copper , zinc

44. Sleeve gastrostomy (SG ) 50- 60 % weight loss at 3–5 years Rapid, maximal weight loss in 1–2 years 10.8% Morbidity at 1 year Advantage Allows for rapid weight loss. No dumping syndrome as pyloric portion of the stomach is intact Provides fixed restriction and does not require adjustment Disadvantage Staple line leak Gastroesophageal reflux disease, Dilatation of the gastric remnant, Weight regain Deficiencies in iron , vitamin B12, folate, calcium, vitamin D , copper, zinc, thiamine

45. Novel Development And Trials ….

46. TRIALS PHASE I Intestinal Peptide Hormone Signaling GLP1R agonist with OXM gut hormone mimicking Oxyntomodulin TKS 1225 PHASE II Melanocortin receptor agonist (MC4R agonist) a. MK-0493 b. RM- 493 Neuropeptide Y (NPY blocker) a. MK-0557 Amylin agonist a. Duvalintide

47. PHASE III TRAILS.. Neuropeptide Y (NPY Blocker (Y5 #) ) Velneperit (S-2367) Dopamine, serotonin, norepinephrine reuptake inhibitor Contrave (III completed NDA submission) GLP 1 agonist Liraglutide (III completed NDA submission ) Byetta Adipose tissue hormone signaling (LEPTIN agonist) Metreleptin(Phase III recruiting) Inhibitor of lipase (Pancreatic lipase inhibitor) Its inhibits intestinal lipid absorption Cetilistat ATL-962 (Phase III completed)

48. Let's have Discussion…

49. American Society For Clinical Pharmacology And Therapeutics NICE (National Institute For Health And Care Excellence) Indian Journal Of Pharmacology Indian Journal Of Public Health World Health Organization Institute for Health Metrics and Evaluation Internal Medicine Goodmen Gilmen Katzung Pharmacology Medscape PubMed Guidance From Dr. Atal Sood Reference….

50. Thanks for appreciation