Presented by Yaowapruek W. 22 Dec 2006. Question When should you start anti obesity agents? When should you start anti obesity agents? What is the agent.

Presented byPresented by

Yaowapruek W.Yaowapruek W.

22 Dec 200622 Dec 2006

QuestionQuestion

When should you start anti obesity When should you start anti obesity agents?agents?

What is the agent of choice for your What is the agent of choice for your patient?patient?

And, how long for the pts use drug? And, how long for the pts use drug?

ContentsContents

IntroductionIntroduction Nonpharmacological approachNonpharmacological approach History of pharmacotherapyHistory of pharmacotherapy Appetite suppressantsAppetite suppressants Nutrient absoption reducerNutrient absoption reducer StrategiesStrategies for use of drugsfor use of drugs Endocannabinoid system and Endocannabinoid system and RimonabantRimonabant

IntroductionIntroduction

Obesity is a Obesity is a heterogeneous diseaseheterogeneous disease involoving genetic, environmental, involoving genetic, environmental, psychological, and other factors.psychological, and other factors.

Occurs when Occurs when energy intake exceeds the energy intake exceeds the amount of energy expended over timeamount of energy expended over time..

Reports warn of a catastrophic impact of Reports warn of a catastrophic impact of the global obesity epidemic on rates of DM the global obesity epidemic on rates of DM and CVS in the upcoming years.and CVS in the upcoming years.


Currently in the U.S., 28% of men and 34% of Currently in the U.S., 28% of men and 34% of women are obese, and the largest increases in women are obese, and the largest increases in obesity rates have affected children and obesity rates have affected children and minorities.minorities.


จากการสำ�ารวจสำ�ขภาพประชากรโดยกระทรวงจากการสำ�ารวจสำ�ขภาพประชากรโดยกระทรวงสำาธารณสำ�ขในป� สำาธารณสำ�ขในป� 2540 2540 พบว�าอุ�บ�ติ�การณ ขอุงภาวะพบว�าอุ�บ�ติ�การณ ขอุงภาวะน�!าหน�กเก�น น�!าหน�กเก�น (BMI > 25) (BMI > 25) ในประชากรไทยท%&อุาย� ≥ในประชากรไทยท%&อุาย� ≥20 20 ป� อุย'�ท%& ป� อุย'�ท%& 28.3% 28.3% โดยพบในผู้')หญิ�งมากกว�าผู้')ชาย โดยพบในผู้')หญิ�งมากกว�าผู้')ชาย (33.9% vs 19.2%) (33.9% vs 19.2%) และพบในผู้')สำ'งอุาย�มากกว�าและพบในผู้')สำ'งอุาย�มากกว�าว�ยหน��มสำาว และในประชากรเม.อุงมากกว�าประชากรว�ยหน��มสำาว และในประชากรเม.อุงมากกว�าประชากรท%&อุย'�ในชนบท ท%&อุย'�ในชนบท (34.8% vs 26.4%) (34.8% vs 26.4%) และพบว�าและพบว�าประชากรในภาคกลางม%อุ�บ�ติ�การณ มากกว�าในภาคประชากรในภาคกลางม%อุ�บ�ติ�การณ มากกว�าในภาคอุ.&น ๆ อุ.&น ๆ (37% (37% ในภาคกลาง ในภาคกลาง vs 22-25 % vs 22-25 % ในภาคอุ.&นในภาคอุ.&น))


Well-established relations between Well-established relations between excess BW and such medical conditions excess BW and such medical conditions as type 2 diabetes, HT, and osteoarthritis.as type 2 diabetes, HT, and osteoarthritis.

Medications for the treatment of obesity Medications for the treatment of obesity are currently approved for use in adults are currently approved for use in adults who have a who have a BMI of ≥ 27 plus obesity-BMI of ≥ 27 plus obesity-related medical conditionsrelated medical conditions or a or a BMI ≥ 30 BMI ≥ 30 in the absence of such conditionsin the absence of such conditions. .

Nonpharmacological ApproachesNonpharmacological Approaches

Only about 20% report restricting caloric Only about 20% report restricting caloric intake and increasing physical activity intake and increasing physical activity simultaneously, despite recommendations simultaneously, despite recommendations indicating that this combination is effective.indicating that this combination is effective. Obese adults can lose about Obese adults can lose about 0.5 kg/wk0.5 kg/wk by decreasing their daily intake to by decreasing their daily intake to 500-500-1,000 kcal1,000 kcal below the caloric intake below the caloric intake required for the maintainace of their required for the maintainace of their current weight.current weight.


More More severe caloric restrictionsevere caloric restriction, with the , with the use of diets that are very low in calories, use of diets that are very low in calories, increases the rapidity of wt.loss increases the rapidity of wt.loss but not the but not the rate of long-term success in maintaining a rate of long-term success in maintaining a reduced wt.reduced wt.

Combined caloric restriction and exercise Combined caloric restriction and exercise with behavioral Rx may be expected to with behavioral Rx may be expected to lose about lose about 5 – 10 % of BW over 4-6 mo5 – 10 % of BW over 4-6 mo..


For the vast majority, wt. loss is followed For the vast majority, wt. loss is followed by a slow, inexorable climb to the by a slow, inexorable climb to the preintervention BW or even higher.preintervention BW or even higher.

Bariatric surgical RxBariatric surgical Rx, can induce wt.loss , can induce wt.loss , but are appropriate only for selected pts, but are appropriate only for selected pts

with a with a BMI ≥ 40 or ≥ 35 with obesity-BMI ≥ 40 or ≥ 35 with obesity-related medical conditionsrelated medical conditions..

““Losing wt. is difficult Losing wt. is difficult for most obese persons, for most obese persons, yet long-term yet long-term maintenance of a maintenance of a reduced wt. is even more reduced wt. is even more challenging!”challenging!”

History of PharmacotherapyHistory of Pharmacotherapy

For many years, obesity was approached For many years, obesity was approached as if it were either a moral failing or as if it were either a moral failing or evidence of underlying psychopathology.evidence of underlying psychopathology. Medications were proposed as short term Medications were proposed as short term adjuncts -> but unsuccessful.adjuncts -> but unsuccessful. In 1992 by Weintraub et al. concerning In 1992 by Weintraub et al. concerning the efficacy of the combination of the efficacy of the combination of behavioral Rx and 2 med (behavioral Rx and 2 med (fenfluramine fenfluramine and phentermine).and phentermine).

History of PharmacotherapyHistory of Pharmacotherapy

Those studies found that wt.loss could be Those studies found that wt.loss could be sustained for as long as 3.5 yrs with sustained for as long as 3.5 yrs with continuing pharmacotherapy.continuing pharmacotherapy.

-> -> Obesity should be treated in the Obesity should be treated in the same manner as any other chronic dz same manner as any other chronic dz that might be ameliorated through the that might be ameliorated through the long-term use of medication.long-term use of medication.

Mechanisms of Action Mechanisms of Action

2 categories2 categories– Appetite suppressantsAppetite suppressants

– Medications that reduce nutrient Medications that reduce nutrient

absorptionabsorption

Third category, med that Third category, med that increase energy increase energy

expenditureexpenditure, includes , includes ephedrineephedrine, not , not

currently approved.currently approved.

Appetite-Suppressant Appetite-Suppressant

Noradrenergic AgentsNoradrenergic Agents

Serotonergic AgentsSerotonergic Agents

Mixed Noradrenergic-Serotonergic AgentsMixed Noradrenergic-Serotonergic Agents

Noradrenergic AgentsNoradrenergic Agents

Phentermine, diethylpropion, Phentermine, diethylpropion, phendimetrazine, and benzphetaminephendimetrazine, and benzphetamine

Amphetamine -> potential for abuseAmphetamine -> potential for abuse

FDA approved for use of ≤ 12 wks for the FDA approved for use of ≤ 12 wks for the Rx of obesity.Rx of obesity.

SE -> insomnia, drymouth, constipation, SE -> insomnia, drymouth, constipation, euphoria, palpitations, and HT.euphoria, palpitations, and HT.


Increasing the release of serotonin, Increasing the release of serotonin, inhibiting its reuptake, or both.inhibiting its reuptake, or both.

Fenfluramine and dexfenfluramineFenfluramine and dexfenfluramine were were withdrawn in 1997 because of withdrawn in 1997 because of associations with associations with valvular heart diseasevalvular heart disease..

Efficacy appeared similar to that of the Efficacy appeared similar to that of the noradrenergic agents.noradrenergic agents.


Some SSRIs (fluoxetine, sertraline) have Some SSRIs (fluoxetine, sertraline) have induced wt.loss in short term studies, but induced wt.loss in short term studies, but steady regain occurred.steady regain occurred.

Mixed NE-5-HT AgentsMixed NE-5-HT Agents

Sibutramine (Reductil),Sibutramine (Reductil), an inhibitor of an inhibitor of both NE reuptake and 5-HT reuptake that both NE reuptake and 5-HT reuptake that also weakly inhibits DA reuptake.also weakly inhibits DA reuptake.

Approved by the FDA for wt.loss and Approved by the FDA for wt.loss and wt.maitaince in conjunction with a wt.maitaince in conjunction with a reduced-calorie diet. reduced-calorie diet.


Dosage : 10 -15 mg once daily (may be 5 Dosage : 10 -15 mg once daily (may be 5 mg if do not tolerate)mg if do not tolerate)

Over 6 mo with reduced-calorie diet -> Over 6 mo with reduced-calorie diet -> loss 5-8 % vs 1-4 % placebo loss 5-8 % vs 1-4 % placebo

Wt.reduction mostly maintained for Wt.reduction mostly maintained for periods of up to one year.periods of up to one year.


SE -> SE -> increases in BP and pulseincreases in BP and pulse (5% (5% discontinuation) , dry mouth, headache, discontinuation) , dry mouth, headache, insomnia, and constipation.insomnia, and constipation.

Other metabolic risk fators improve; Other metabolic risk fators improve; hyperlipidemia, hyperuricemia, as well as hyperlipidemia, hyperuricemia, as well as glycemic control, plasma insulin levels in glycemic control, plasma insulin levels in type 2 diabetes.type 2 diabetes.

Nutrient Absorption ReducerNutrient Absorption Reducer

Only FDA-approved is Only FDA-approved is orlistat (Xenical)orlistat (Xenical)

Acts by binding to Acts by binding to GI lipasesGI lipases in the lumen in the lumen of the gut, preventing hydrolysis of dietary of the gut, preventing hydrolysis of dietary fat (TG) into absorbable free fatty acids fat (TG) into absorbable free fatty acids and monoacylglycerols.and monoacylglycerols.


120 mg of orlistat with or up to one hr 120 mg of orlistat with or up to one hr after meals after meals excrete in the stool excrete in the stool approximately one third of the dietary fatapproximately one third of the dietary fat..

Moderate efficacy for wt. loss in aduls. Moderate efficacy for wt. loss in aduls. (9% vs 5.8% placebo)(9% vs 5.8% placebo)

Metabolic risk factors also improved.Metabolic risk factors also improved.


SE -> flatulence with discharge, fecal SE -> flatulence with discharge, fecal urgency, fecal incontinence, steatorrhea, urgency, fecal incontinence, steatorrhea, oily spotting, and increased frequency of oily spotting, and increased frequency of defecation.(mild to moderate)defecation.(mild to moderate)

Decreases absorption of fat-soluble Decreases absorption of fat-soluble vitamins, so daily MTV at least 2 hr before vitamins, so daily MTV at least 2 hr before or after a dose of orlistat needed.or after a dose of orlistat needed.

Dietary Supplements and HerbalDietary Supplements and Herbal

Cannot claim that it treats a disease Cannot claim that it treats a disease but may claim that it reduces the risk of but may claim that it reduces the risk of a disease in a populationa disease in a population.. Chitosan, chromium picolinate, Chitosan, chromium picolinate, conjugated linoleic acid, ephedra alkaloids conjugated linoleic acid, ephedra alkaloids (ma huang), and garcinia cambogia(ma huang), and garcinia cambogia There were insufficient data to provide There were insufficient data to provide evidence of any as agents promoting evidence of any as agents promoting wt.loss.wt.loss.


Ephedra alkaloids and caffeineEphedra alkaloids and caffeine are the are the only types for which there are data from only types for which there are data from RCTs indicating efficacy.(in short term)RCTs indicating efficacy.(in short term)

Case reports concerning ephedra Case reports concerning ephedra alkaloids -> serious CVS and CNS side alkaloids -> serious CVS and CNS side events( HT, arrhythmia, stroke, seizure, MI events( HT, arrhythmia, stroke, seizure, MI and sudden death)and sudden death)


Because of the unpredictable amounts of Because of the unpredictable amounts of active ingredients ant the potential for active ingredients ant the potential for harmful effects. harmful effects.

NIH -> NIH -> herbal preparations are not herbal preparations are not recommended as part of a wt.loss recommended as part of a wt.loss program.program.

Other medicationsOther medications

BupropionBupropion

Topiramate (Topamax)Topiramate (Topamax)

Metformin (Glucophage)Metformin (Glucophage)

Investigational MedicationsInvestigational Medications

Levels of Levels of leptinleptin, a hormone secreted by , a hormone secreted by adipocytes, reflect the lipid content of the adipocytes, reflect the lipid content of the total body of a nonfasting person.total body of a nonfasting person.

Severe, early-onset obesity has been Severe, early-onset obesity has been associated with an inability to produce associated with an inability to produce functional leptin protein.functional leptin protein.

Rx of a leptin-deficient girl with rh-leptin -> Rx of a leptin-deficient girl with rh-leptin -> dramatic reduction in BW.dramatic reduction in BW.

Strategies for Use of DrugsStrategies for Use of Drugs

Pharmacotherapy should be initiated with Pharmacotherapy should be initiated with the expectation that long-term use will the expectation that long-term use will most likely be needed.most likely be needed.

Risk of long term medications VS Risk of long term medications VS potential improvements in the pt’s risk of potential improvements in the pt’s risk of obesity-related disease.obesity-related disease.

Strategies for Use of DrugsStrategies for Use of Drugs

Identification of pts. with a response to Identification of pts. with a response to treatmenttreatment

Pharmacotherapy for the prevention of wt. Pharmacotherapy for the prevention of wt. regainregain

Off-label use of FDA-approved drugsOff-label use of FDA-approved drugs– Intermittent useIntermittent use

– Drug combinationsDrug combinations

– Treatment of children and adolescentsTreatment of children and adolescents

Journal of the American College of CardiologyVol.47, No. 10, 2006


New combined approach to treating the New combined approach to treating the obesity and glucose intolerance obesity and glucose intolerance features of metabolic syndromefeatures of metabolic syndrome, as well , as well as as aiding smoking cessationaiding smoking cessation, involves , involves manipulation of the endogenous manipulation of the endogenous cannabinoid system, specifically with the cannabinoid system, specifically with the cannabinoid receptor type 1 (CBcannabinoid receptor type 1 (CB11) )

antagonist antagonist rimonabantrimonabant..

Endocannabinoid SystemEndocannabinoid System

CannabisCannabis– main psychoactive alkaloid is main psychoactive alkaloid is ΔΔ-9--9-

tetrahydrocannabinol (THC)tetrahydrocannabinol (THC)– synthetic THC (dronabinol) is used to rx post-synthetic THC (dronabinol) is used to rx post-

chemotherapy nausea and emesis, as well as chemotherapy nausea and emesis, as well as anorexia ass with HIVanorexia ass with HIV


Cannabinoid receptors and ligandsCannabinoid receptors and ligands– CBCB1 1 receptorsreceptors -> -> brain and adipose tissue ,brain and adipose tissue ,

but also found in myocardium, vascular but also found in myocardium, vascular endothelium, and sympathetic nerve terminalsendothelium, and sympathetic nerve terminals

– CBCB2 2 receptors -> lymphoid tissue and receptors -> lymphoid tissue and

peripheral macrophagesperipheral macrophages– Both receptors function as transmembrane Both receptors function as transmembrane

G-proteins.G-proteins.


Cannabinoid receptors and ligandsCannabinoid receptors and ligands– At least 2 endogenous ligands : At least 2 endogenous ligands :

arachidonylethanolamide (arachidonylethanolamide (anandamideanandamide), 2-), 2-arachidonoylglycerol (arachidonoylglycerol (2-AG2-AG))

Under normal conditions, the system in Under normal conditions, the system in not tonically activenot tonically active, rather , rather endocannabinoids are produced on endocannabinoids are produced on demand, act locally, and are rapidly demand, act locally, and are rapidly inactivated via cellular uptake and inactivated via cellular uptake and enzymatic hydrolysis.enzymatic hydrolysis.

Physiology of the Cannabinoid Physiology of the Cannabinoid SystemSystem

Cardiovascular effectsCardiovascular effects– Acute -> vasodilatation and tachycardia with Acute -> vasodilatation and tachycardia with

variable net effect on systemic BPvariable net effect on systemic BP– Long term -> Long term -> CB CB1 1 –mediated hypotension –mediated hypotension

and bradycardiaand bradycardia– Seem to be involved in regulation of vascular Seem to be involved in regulation of vascular

tone in hepatic disease, HT, and other tone in hepatic disease, HT, and other disorders.disorders.

– Recently, system also plays a role in Recently, system also plays a role in hemodynamics of shock states.hemodynamics of shock states.


Metabolic effectsMetabolic effects– Central role in regulating metabolism and Central role in regulating metabolism and

body composition by body composition by

Enhancing the central orexigenic drive Enhancing the central orexigenic drive

Increasing peripheral lipogenesis.Increasing peripheral lipogenesis.


Endocannabinoids and addictionEndocannabinoids and addiction– Regions of the brain thought to be involved in Regions of the brain thought to be involved in

drug relapse behaviordrug relapse behavior contain contain high levels of high levels of CBCB1 1 receptors receptors, and compelling evidence , and compelling evidence

suggests a role for the endocannabinoid suggests a role for the endocannabinoid system in system in formulation and propagation of formulation and propagation of addiction to psychoactive substances.addiction to psychoactive substances.

RimonabantRimonabant

First described in First described in 1994 1994

Selective Selective CBCB1 1

receptor antagonistreceptor antagonist

RIO = Rimonabant RIO = Rimonabant in Obesityin Obesity


In pts with obesity, including those with In pts with obesity, including those with cardiovascular comorbiditiescardiovascular comorbidities

Significant reduction in BW and waist Significant reduction in BW and waist circumferencecircumference

Improvement inImprovement in– Cardiometabolic risk Cardiometabolic risk – Glycemic control in type 2 DMGlycemic control in type 2 DM– Lipid profile (except LDLc)Lipid profile (except LDLc)– Overall decrease in the prevalence of metaboloic Overall decrease in the prevalence of metaboloic

syndromesyndrome

Other studyOther study

STRADIVARIUSSTRADIVARIUS– Obese with smoking or metabolic syndrome Obese with smoking or metabolic syndrome

and in whom clinically indicated coronary and in whom clinically indicated coronary angiography reveals a 20%-50% stenosisangiography reveals a 20%-50% stenosis

– End point = change in the volume of target End point = change in the volume of target atheroma at 18 mo.atheroma at 18 mo.

Other studyOther study

STRATUSSTRATUS– Potential role of rimonabant as an adjunct in Potential role of rimonabant as an adjunct in

smoking cessationsmoking cessation– Smoked ≥ 10 cigarettes/day for at least 2 mo Smoked ≥ 10 cigarettes/day for at least 2 mo

and who were motivated to quitand who were motivated to quit– Receive rimonabant or placebo for 10 wksReceive rimonabant or placebo for 10 wks– Rate of abstinence was significantly higher in Rate of abstinence was significantly higher in

the high-dose(20 mg/d) group compared with the high-dose(20 mg/d) group compared with placebo (36.2% vs 20.6%, p placebo (36.2% vs 20.6%, p < 0.001)< 0.001)


Adverse effectsAdverse effects– Generally well toleratedGenerally well tolerated– One-yr dropout rates were high (36%-49%) , One-yr dropout rates were high (36%-49%) ,

but were typical of obesity trials and did not but were typical of obesity trials and did not differ from placebodiffer from placebo

– Most common was mild nauseaMost common was mild nausea– The percentage of pts experiencing The percentage of pts experiencing

neuropsychiatric(anxiety,depression) side neuropsychiatric(anxiety,depression) side effects is small.effects is small.


Cochrane review 2006, Issue 4Cochrane review 2006, Issue 4 To assess the effects of rimonabant and To assess the effects of rimonabant and obese peopleobese people Compared with placeboCompared with placebo– Rimonabant 20 mg -> 4.9 kg greater Rimonabant 20 mg -> 4.9 kg greater

reduction in BW in trials with one yr result.reduction in BW in trials with one yr result.– Improvements in waist circumference, HDL, Improvements in waist circumference, HDL,

TG, and systolic and diastolic BP were also TG, and systolic and diastolic BP were also seenseen


However, the results with rimonabant 5 However, the results with rimonabant 5 mg -> wt.reduction only 1.3 kg, no relevant mg -> wt.reduction only 1.3 kg, no relevant effects on lipids and BP.effects on lipids and BP.

Rimonabant 20 mg -> more adverse Rimonabant 20 mg -> more adverse effects both of general and serious nature, effects both of general and serious nature, esp of nervous system, psychiatric or GI.esp of nervous system, psychiatric or GI.

Attrition rates were approximately 40% at Attrition rates were approximately 40% at the end of one yr.the end of one yr.


The observed results should be The observed results should be interpreted with some caution, though, interpreted with some caution, though, since since the evaluated studies presented the evaluated studies presented some deficiencies in methodological some deficiencies in methodological qualityquality.. Studies with longer F/U after the end of Studies with longer F/U after the end of Rx and of more rigorous quality should be Rx and of more rigorous quality should be done before definitive recommendations done before definitive recommendations can be made.can be made.

ContentsContents

IntroductionIntroduction Nonpharmacological approachNonpharmacological approach History of pharmacotherapyHistory of pharmacotherapy Appetite suppressantsAppetite suppressants Nutrient absoption reducerNutrient absoption reducer StrategiesStrategies for use of drugsfor use of drugs Endocannabinoid system and Endocannabinoid system and RimonabantRimonabant

Presented by Yaowapruek W. 22 Dec 2006. Question When should you start anti obesity agents? When should you start anti obesity agents? What is the agent.

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