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Presented by Yaowapruek W. 22 Dec 2006 Question When should you start anti obesity agents? What is the agent of choice for your patient? And, how long for the pts use drug? Contents Introduction Nonpharmacological approach History of pharmacotherapy Appetite suppressants Nutrient absoption reducer Strategies for use of drugs Endocannabinoid system and Rimonabant Introduction Obesity is a heterogeneous disease involoving genetic, environmental, psychological, and other factors. Occurs when energy intake exceeds the amount of energy expended over time. Reports warn of a catastrophic impact of the global obesity epidemic on rates of DM and CVS in the upcoming years. Introduction Currently in the U.S., 28% of men and 34% of women are obese, and the largest increases in obesity rates have affected children and minorities. Introduction จากการสารวจสุ ขภาพประชากรโดยกระทรวงสาธารณสุ ขในปี 2540 พบว่าอุบตั ิการณ์ของภาวะน้ าหนักเกิน (BMI > 25) ในประชากร ไทยที่อายุ ≥ 20 ปี อยูท่ ี่ 28.3% โดยพบในผูห้ ญิงมากกว่าผูช้ าย (33.9% vs 19.2%) และพบในผูส้ ู งอายุมากกว่าวัยหนุ่มสาว และในประชากรเมืองมากกว่าประชากรที่อยูใ่ นชนบท (34.8% vs 26.4%) และพบว่าประชากรในภาคกลางมีอุบตั ิการณ์มากกว่าใน ภาคอื่น ๆ (37% ในภาคกลาง vs 22-25 % ในภาคอื่น) Introduction Well-established relations between excess BW and such medical conditions as type 2 diabetes, HT, and osteoarthritis. Medications for the treatment of obesity are currently approved for use in adults who have a BMI of ≥ 27 plus obesityrelated medical conditions or a BMI ≥ 30 in the absence of such conditions. Nonpharmacological Approaches Only about 20% report restricting caloric intake and increasing physical activity simultaneously, despite recommendations indicating that this combination is effective. Obese adults can lose about 0.5 kg/wk by decreasing their daily intake to 5001,000 kcal below the caloric intake required for the maintainace of their current weight. Nonpharmacological Approaches More severe caloric restriction, with the use of diets that are very low in calories, increases the rapidity of wt.loss but not the rate of long-term success in maintaining a reduced wt. Combined caloric restriction and exercise with behavioral Rx may be expected to lose about 5 – 10 % of BW over 4-6 mo. Nonpharmacological Approaches For the vast majority, wt. loss is followed by a slow, inexorable climb to the preintervention BW or even higher. Bariatric surgical Rx, can induce wt.loss , but are appropriate only for selected pts with a BMI ≥ 40 or ≥ 35 with obesityrelated medical conditions. “Losing wt. is difficult for most obese persons, yet longterm maintenance of a reduced wt. is even more challenging!” History of Pharmacotherapy For many years, obesity was approached as if it were either a moral failing or evidence of underlying psychopathology. Medications were proposed as short term adjuncts -> but unsuccessful. In 1992 by Weintraub et al. concerning the efficacy of the combination of behavioral Rx and 2 med (fenfluramine and phentermine). History of Pharmacotherapy Those studies found that wt.loss could be sustained for as long as 3.5 yrs with continuing pharmacotherapy. -> Obesity should be treated in the same manner as any other chronic dz that might be ameliorated through the long-term use of medication. Mechanisms of Action 2 categories – Appetite suppressants – Medications that reduce nutrient absorption Third category, med that increase energy expenditure, includes ephedrine, not currently approved. Appetite-Suppressant Noradrenergic Agents Serotonergic Agents Mixed Noradrenergic-Serotonergic Agents Noradrenergic Agents Phentermine, diethylpropion, phendimetrazine, and benzphetamine Amphetamine -> potential for abuse FDA approved for use of ≤ 12 wks for the Rx of obesity. SE -> insomnia, drymouth, constipation, euphoria, palpitations, and HT. Serotonergic Agents Increasing the release of serotonin, inhibiting its reuptake, or both. Fenfluramine and dexfenfluramine were withdrawn in 1997 because of associations with valvular heart disease. Efficacy appeared similar to that of the noradrenergic agents. Serotonergic Agents Some SSRIs (fluoxetine, sertraline) have induced wt.loss in short term studies, but steady regain occurred. Mixed NE-5-HT Agents Sibutramine (Reductil), an inhibitor of both NE reuptake and 5-HT reuptake that also weakly inhibits DA reuptake. Approved by the FDA for wt.loss and wt.maitaince in conjunction with a reduced-calorie diet. Mixed NE-5-HT Agents Dosage : 10 -15 mg once daily (may be 5 mg if do not tolerate) Over 6 mo with reduced-calorie diet -> loss 5-8 % vs 1-4 % placebo Wt.reduction mostly maintained for periods of up to one year. Mixed NE-5-HT Agents SE -> increases in BP and pulse (5% discontinuation) , dry mouth, headache, insomnia, and constipation. Other metabolic risk fators improve; hyperlipidemia, hyperuricemia, as well as glycemic control, plasma insulin levels in type 2 diabetes. Nutrient Absorption Reducer Only FDA-approved is orlistat (Xenical) Acts by binding to GI lipases in the lumen of the gut, preventing hydrolysis of dietary fat (TG) into absorbable free fatty acids and monoacylglycerols. Nutrient Absorption Reducer 120 mg of orlistat with or up to one hr after meals excrete in the stool approximately one third of the dietary fat. Moderate efficacy for wt. loss in aduls. (9% vs 5.8% placebo) Metabolic risk factors also improved. Nutrient Absorption Reducer SE -> flatulence with discharge, fecal urgency, fecal incontinence, steatorrhea, oily spotting, and increased frequency of defecation.(mild to moderate) Decreases absorption of fat-soluble vitamins, so daily MTV at least 2 hr before or after a dose of orlistat needed. Dietary Supplements and Herbal Cannot claim that it treats a disease but may claim that it reduces the risk of a disease in a population. Chitosan, chromium picolinate, conjugated linoleic acid, ephedra alkaloids (ma huang), and garcinia cambogia There were insufficient data to provide evidence of any as agents promoting wt.loss. Dietary Supplements and Herbal Ephedra alkaloids and caffeine are the only types for which there are data from RCTs indicating efficacy.(in short term) Case reports concerning ephedra alkaloids -> serious CVS and CNS side events( HT, arrhythmia, stroke, seizure, MI and sudden death) Dietary Supplements and Herbal Because of the unpredictable amounts of active ingredients ant the potential for harmful effects. NIH -> herbal preparations are not recommended as part of a wt.loss program. Other medications Bupropion Topiramate (Topamax) Metformin (Glucophage) Investigational Medications Levels of leptin, a hormone secreted by adipocytes, reflect the lipid content of the total body of a nonfasting person. Severe, early-onset obesity has been associated with an inability to produce functional leptin protein. Rx of a leptin-deficient girl with rh-leptin -> dramatic reduction in BW. Strategies for Use of Drugs Pharmacotherapy should be initiated with the expectation that long-term use will most likely be needed. Risk of long term medications VS potential improvements in the pt’s risk of obesity-related disease. Strategies for Use of Drugs Identification of pts. with a response to treatment Pharmacotherapy for the prevention of wt. regain Off-label use of FDA-approved drugs – Intermittent use – Drug combinations – Treatment of children and adolescents Journal of the American College of Cardiology Vol.47, No. 10, 2006 Introduction New combined approach to treating the obesity and glucose intolerance features of metabolic syndrome, as well as aiding smoking cessation, involves manipulation of the endogenous cannabinoid system, specifically with the cannabinoid receptor type 1 (CB1) antagonist rimonabant. Endocannabinoid System Cannabis – main psychoactive alkaloid is Δ-9tetrahydrocannabinol (THC) – synthetic THC (dronabinol) is used to rx postchemotherapy nausea and emesis, as well as anorexia ass with HIV Endocannabinoid System Cannabinoid receptors and ligands – CB1 receptors -> brain and adipose tissue , but also found in myocardium, vascular endothelium, and sympathetic nerve terminals – CB2 receptors -> lymphoid tissue and peripheral macrophages – Both receptors function as transmembrane G-proteins. Endocannabinoid System Cannabinoid receptors and ligands – At least 2 endogenous ligands : arachidonylethanolamide (anandamide), 2arachidonoylglycerol (2-AG) Under normal conditions, the system in not tonically active, rather endocannabinoids are produced on demand, act locally, and are rapidly inactivated via cellular uptake and enzymatic hydrolysis. Physiology of the Cannabinoid System Cardiovascular effects – Acute -> vasodilatation and tachycardia with variable net effect on systemic BP – Long term -> CB1 –mediated hypotension and bradycardia – Seem to be involved in regulation of vascular tone in hepatic disease, HT, and other disorders. – Recently, system also plays a role in hemodynamics of shock states. Physiology of the Cannabinoid System Metabolic effects – Central role in regulating metabolism and body composition by Enhancing the central orexigenic drive Increasing peripheral lipogenesis. Physiology of the Cannabinoid System Endocannabinoids and addiction – Regions of the brain thought to be involved in drug relapse behavior contain high levels of CB1 receptors, and compelling evidence suggests a role for the endocannabinoid system in formulation and propagation of addiction to psychoactive substances. Rimonabant First described in 1994 Selective CB1 receptor antagonist RIO = Rimonabant in Obesity Rimonabant In pts with obesity, including those with cardiovascular comorbidities Significant reduction in BW and waist circumference Improvement in – – – – Cardiometabolic risk Glycemic control in type 2 DM Lipid profile (except LDLc) Overall decrease in the prevalence of metaboloic syndrome Other study STRADIVARIUS – Obese with smoking or metabolic syndrome and in whom clinically indicated coronary angiography reveals a 20%-50% stenosis – End point = change in the volume of target atheroma at 18 mo. Other study STRATUS – Potential role of rimonabant as an adjunct in smoking cessation – Smoked ≥ 10 cigarettes/day for at least 2 mo and who were motivated to quit – Receive rimonabant or placebo for 10 wks – Rate of abstinence was significantly higher in the high-dose(20 mg/d) group compared with placebo (36.2% vs 20.6%, p < 0.001) Rimonabant Adverse effects – Generally well tolerated – One-yr dropout rates were high (36%-49%) , but were typical of obesity trials and did not differ from placebo – Most common was mild nausea – The percentage of pts experiencing neuropsychiatric(anxiety,depression) side effects is small. Rimonabant Cochrane review 2006, Issue 4 To assess the effects of rimonabant and obese people Compared with placebo – Rimonabant 20 mg -> 4.9 kg greater reduction in BW in trials with one yr result. – Improvements in waist circumference, HDL, TG, and systolic and diastolic BP were also seen Rimonabant However, the results with rimonabant 5 mg -> wt.reduction only 1.3 kg, no relevant effects on lipids and BP. Rimonabant 20 mg -> more adverse effects both of general and serious nature, esp of nervous system, psychiatric or GI. Attrition rates were approximately 40% at the end of one yr. Rimonabant The observed results should be interpreted with some caution, though, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer F/U after the end of Rx and of more rigorous quality should be done before definitive recommendations can be made. Contents Introduction Nonpharmacological approach History of pharmacotherapy Appetite suppressants Nutrient absoption reducer Strategies for use of drugs Endocannabinoid system and Rimonabant