Obesity and Sibutramine

What is Obesity?: 

What is Obesity? Obesity means excess accumulation of fat in the body Once it develops it is difficult to ‘cure’ and usually persists throughout life Obesity is usually diagnosed on the basis of calculation of Body mass index Measurement of waist-hip ratio

Classification of Overweight and Obese by Body Mass Index: 

Classification of Overweight and Obese by Body Mass Index BMI (kg/m2) WHO guidelines Proposed Asia Pacific guidelines Underweight andlt; 18.5 andlt; 18.5 Normal 18.5-24.9 18.5-22.9 Overweight 25.0-29.9 andgt; 23 At risk - 23-24.9 Obesity 30-34.9 (Class I) 25-29.9 (Class I) 35-39.9 (Class II) andgt; 30 (Class II) Extremely Obese andgt; 40 (Class III) - BMI = Weight (kg) [Height (m)]2

Waist-to-hip ratio: 

Waist-to-hip ratio Ratio = WAIST HIPS TO FIND RATIO Waist: Measure at narrowest point with stomach relaxed Hips: Measure at fullest point Desired Ratio Women : andlt;0.8 Men : andlt; 1.0 Risk increases if waist circumference is andgt;94 cm in men and andgt;80 cm in women

Co-morbidities risk associated with different levels of BMI and suggested waist circumference in adult Asians: 

Co-morbidities risk associated with different levels of BMI and suggested waist circumference in adult Asians Classification BMI Risk of co-morbidities Waist circumference andlt; 90 cm (men) andgt; 90 cm (men) andlt; 80 cm (women) andgt; 90 cm (women) Underweight andlt; 18.5 Low Average Normal range 18.5-22.9 Average Increased Overweight andgt; 23 At risk 23-24.9 Increased Moderate Obese I 25-29.9 Moderate Severe Obese II andgt; 30 Severe Very severe

Obesity – An imbalance in energy intake and energy expenditure: 

Obesity – An imbalance in energy intake and energy expenditure Proteins (20%) BMR (60-65%) ENERGY INTAKE ENERGY EXPENDITURE Carbohydrates (55%) Physical activity (25-30%) Fats (25%) Thermic effect of food (10%)

Role of hypothalamus in mediation ofhunger and satiety: 

Role of hypothalamus in mediation of hunger and satiety Thalamus Paraventricular HO conserv Oxytocin rel. 2 Anterior hypothalamic Body temp Optic tract Arcuate Neuroendocrine Fornix Rage, Hunger Supraoptic Vasopresin rel. Dorsomedial GI stimuli Periventricular Neuroendocrine Ventromedial Satiety Lateral hypothalamic Hunger, thirst

Classification of obesity as per fat distribution: 

Classification of obesity as per fat distribution Android (or abdominal or central, males) Collection of fat mostly in the abdomen (above the waist) apple-shaped Associated with insulin resistance and heart disease Gynoid (below the waist, females) Collection of fat on hips and buttocks pear-shaped Associated with mechanical problems

Diseases and conditions forwhich obesity is a risk factor: 

Diseases and conditions for which obesity is a risk factor Coronary artery disease** Type II Diabetes Mellitus*** Hypertension** Dyslipidemia*** Respiratory disease*** Gout** Reflux disease Psychological problems Gallbladder disease*** Osteoarthritis** Infertility* Venous circulatory disease Increased anaesthetic risk* Low back pain* Polycystic ovary disease* Cancer* (ovarian, breast, endometrial, gallbladder, prostate, colon)

Prevalence of overweight and obesity in different income groups of Delhi (Nutrition Foundation of India Study): 

Prevalence of overweight and obesity in different income groups of Delhi (Nutrition Foundation of India Study) Prevalence (%) Slums Middle-Class Total Overweight (BMI andgt; 25) Males ND ND 19.6 Females ND ND 44.5 Obesity (BMI andgt; 30) Males 1 32.3 ND Females 4 50 ND Abdominal obesity Males ND 49.7 ND Females ND 34.9 ND ND: Not determined http://www.nutritionfoundationin.org/NEW/OBESITY.HTM

The Five City Study: 

The Five City Study n=3257; aged 25-64 yrs Cities: Moradabad (n=902), Trivandrum (n=760), Calcutta (n=410), Nagpur (n=405), Bombay (n=780) Social Class BMIandgt;27 WHRandgt;0.85 Sedentary life style I (n=985) 21.2% 96.9% 92.2% II (n=790 16.4% 57.2% 71.4% III (n=674) 8.9% 39.3% 42.3% IV (n=602) 3.0% 11.9% 14.9% V (n=206) 3.8% 8.7% 8.7% Int J Cardiol 1999;69:139-147

Advantages of weight loss: 

Advantages of weight loss Weight loss of 0.5-9 kg (n=43,457) associated with 53% reduction in cancer-deaths, 44% reduction in diabetes-associated mortality and 20% reduction in total mortality Survival increased 3-4 months for every kilogram of weight loss Reduced hyperlipidemia, hypertension and insulin resistance Improvement in severity of diseases Person feels ‘fit’ and mentally more active  

Treatment goals: 

Treatment goals Prevention of further weight gain Weight loss to achieve a realistic, target BMI Long-term maintenance of a lower body-weight

How much weight loss is significant?: 

How much weight loss is significant? A 5-10% reduction in weight (within 6 months) and weight maintenance should be stressed in any weight loss program and contributes significantly to decreased morbidity

Approaches to obesity management: 

Approaches to obesity management

Drug therapy : 

Drug therapy Appetite suppressants Adrenergic agents (e.g. amphetamine, methamphetamine, phenylpropanol amine, phentermine) Serotonergic agents (e.g. fenfluramine, dexfenfluramine, SSRIs like sertraline, fluoxetine) Thermogenic agents ephedrine, caffeine New ones Sibutramine ; Orlistat

Sibutramine inhibits serotonin andnoradrenaline reuptake: 

Noradrenaline Serotonin Sibutramine inhibits serotonin and noradrenaline reuptake

STORM Study : Effect of sibutramine on weight loss: 

STORM Study : Effect of sibutramine on weight loss 98 104 102 100 96 94 92 90 0 12 22 24 20 18 16 14 10 8 6 4 2 Placebo Sibutramine Month Weight loss Weight maintenance Bodyweight (kg) Lancet 2000; 356:2119-2125

STORM Study:Mean Weight Loss at Two Years: 

STORM Study: Mean Weight Loss at Two Years Mean Weight Loss (Kg)

STORM Study : Proportion of patients maintaining at least 5% and 10% weight loss: 

STORM Study : Proportion of patients maintaining at least 5% and 10% weight loss 100 20 40 60 80 0 6 12 18 24 6 12 18 24 5% responders 10% responders Sibutramine Placebo Lancet 2000; 356:2119-2125 Proportion of patients (%)

STORM Study:Effect on Waist Circumference and Waist/Hip Ratio: 

STORM Study: Effect on Waist Circumference and Waist/Hip Ratio Decrease in waist circumference (cm) Change (a) Waist Circumference (b) Waist/Hip Ratio

STORM Study : Effects on lipids: 

STORM Study : Effects on lipids 5 0 -5 -10 -15 -20 -25 Placebo Sibutramine Triglycerides % c h a n g e 0 0 24 18 12 6 5 0 -5 -10 -15 -20 -25 Placebo Sibutramine VLDL cholesterol 18 0 24 12 6 % c h a n g e Lancet 2000; 356:2119-2125

STORM Study : Effects on lipids (Contd.): 

STORM Study : Effects on lipids (Contd.) 18 0 24 12 6 25 20 15 10 5 0 HDL cholesterol % c h a n g e Sibutramine Placebo Month of assessment Weight loss Weight maintenance Lancet 2000; 356:2119-2125 30

STORM Study : Effect on Insulin and HbA1c: 

Month of Assessment Placebo Sibutramine Lancet 2000; 356:2119-2125 % Change HbA1c . STORM Study : Effect on Insulin and HbA1c Month of Assessment Placebo Sibutramine % Change Insulin

STORM study: Other metabolic effects: 

STORM study: Other metabolic effects Variable Baseline Month 6 Month 24 SIB PLAC SIB PLAC SIB PLAC Uric acid 0.32 0.33 0.29 0.30 0.30 0.32 Glucose 5.20 5.11 5.07 5.01 5.13 5.17 Insulin 17.7 16.7 12.7 12.4 13.8 16.2 C-peptide 3.21 3.05 2.54 2.46 2.38 2.69 HbA1c 5.86 5.75 5.56 5.50 5.56 5.66

STORM study: Conclusions: 

STORM study: Conclusions Almost all patients who persist with a weight management program consisting of sibutramine, diet and exercse can achieve at least a 5% weight loss with sibutramine Over half can lose more than 10% weight within 6 months Weight loss was sustained in most patients continuing therapy for two years

Sibutramine vs. Dexfenfluramine: 

Sibutramine vs. Dexfenfluramine -3.2 -4.5 -5 -4.5 -4 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0 Weight loss (kg) Sibutramine 10 mg Dexfenfluramine 30 mg n=226; 12 wks Int J Obes 1995; 19. Suppl 2: 144

Adverse effects occurring in >5% of patients treated with Sibutramine compared with placebo: 

Adverse effects occurring in andgt;5% of patients treated with Sibutramine compared with placebo Sibutramine % Placebo % Adverse Effects Incidence (n=2068) Incidence (n=884) Headache 30.3 18.6 Dry Mouth 17.2 4.2 Anorexia 13.0 3.5 Constipation 11.5 6.0 Insomnia 10.7 4.5 Dizziness 7.0 3.4 Nausea 5.9 2.8 Nervousness 5.2 2.9 Dyspepsia 5.0 2.6 Ann Pharmacother 1999;33:968-978

Sibutramine: Safety: 

Sibutramine: Safety Discontinuation rates: 9% with placebo and 7% with sibutramine Has been associated with a mean increase in BP and heart rate of approximately 1-3mmHg and 4-5 beats/min Cardiac side effects viz. hypertension, tachycardia and palpitations andlt; 2.6% vs 0.6-0.9% in placebo group Caution to be exercised in patients with history of hypertension and should not be given to patients with uncontrolled or poorly controlled hypertension Not associated with cardiac valve abnormalities or primary pulmonary hypertension

STORM Study :Withdrawals due to BP increase: 

STORM Study : Withdrawals due to BP increase Dose of Sibutramine % patients who withdrew due to increase in BP 10 mg 1% 15 mg 2% 20 mg 3% Lancet 2000; 356:2119-2125

Indications & Dosage: 

Indications andamp; Dosage Recommended for obese patients with a BMI andgt; 30 kg/m2 or andgt; 27 kg/m2 in the presence of other risk factors (e.g. hypertension, diabetes, dyslipidemia) In Indian patients, sibutramine could be considered in patients with BMI andgt; 25 kg/m2 or those with BMI of 23 kg/m2 with comorbid conditions Recommended starting dose is 10 mg once daily. If there is inadequate weight loss, the dose may be titrated after four weeks to a total of 15 mg once daily. The 5 mg dose should be reserved for patients who do not tolerate the 10 mg dose.