Obesity Obesity PharmacotherapyPharmacotherapy
Fariborz FarsadFariborz Farsad Pharm D Pharm D
, BCPS, BCPS
OutlineOutline Case PresentationCase Presentation Definition, Prevalence, & Comorbidities of Definition, Prevalence, & Comorbidities of
ObesityObesity Indications for Drug TherapyIndications for Drug Therapy FDA Approved Medicines for Obesity FDA Approved Medicines for Obesity
TreatmentTreatment sibutramine, phentermine, orlistatsibutramine, phentermine, orlistat
Other Medicines that Promote Weight LossOther Medicines that Promote Weight Loss DM medicines, antidepressants (SSRIs), anti-DM medicines, antidepressants (SSRIs), anti-
epilepticsepileptics Investigational Medicines: RimonabantInvestigational Medicines: Rimonabant Summary and Case discussionSummary and Case discussion
Case: DBCase: DB49 y/o obese woman with the following 49 y/o obese woman with the following
concerns:concerns: Chronic bilateral knee pain not Chronic bilateral knee pain not
responding to anti-inflammatory responding to anti-inflammatory medicationsmedications
Inability to exercise due to painInability to exercise due to pain Inability to loose weight despite food Inability to loose weight despite food
restrictionrestriction
DB PMHDB PMH Morbid obesityMorbid obesity HTNHTN HyperlipidemiaHyperlipidemia
TG, TG, HDL HDL OSA (Can’t use OSA (Can’t use
CPAP)CPAP) OAOA DepressionDepression Insulin resistanceInsulin resistance HypothyroidismHypothyroidism GERDGERD s/p cholecystectomys/p cholecystectomy
DB MedicationsDB Medications DiclofenacDiclofenac LasixLasix PrevacidPrevacid LevothyroxineLevothyroxine SertralineSertraline BenazeprilBenazeprilDB Social DB Social
HistoryHistory Disabled/ MADisabled/ MA +tobacco, no +tobacco, no
alcoholalcohol
DB ExamDB Exam Morbidly obeseMorbidly obese
285 lb, 5’2”, BMI 52285 lb, 5’2”, BMI 52 Knee exam difficult Knee exam difficult
due to body habitus due to body habitus Diffuse tendernessDiffuse tenderness ROM (0-100°)ROM (0-100°) No ligamentous No ligamentous
laxitylaxity +Retropatellar +Retropatellar
crepituscrepitus
DB Imaging DataDB Imaging DataStanding Plain Films:Standing Plain Films:Severe OA knees Severe OA knees
bilaterallybilaterallyLateral compartment Lateral compartment
on Ron RMedial compartment Medial compartment
on Lon L
DB Assessment & PlanDB Assessment & Plan Morbid obesity and severe bilateral OA of Morbid obesity and severe bilateral OA of
kneesknees Referred to OrthopedicsReferred to Orthopedics
TKA is indicated, TKA is indicated, IFIF she can reduce weight below she can reduce weight below 180 lbs.180 lbs.
Referred to Health ED for dietary counselingReferred to Health ED for dietary counseling Last seen in September, several “no shows.” Last seen in September, several “no shows.”
Referred for possible Bariatric surgeryReferred for possible Bariatric surgery WI Medicaid coverage as of 2/05WI Medicaid coverage as of 2/05 Yes: Gastric bypass for qualified, low risk patients Yes: Gastric bypass for qualified, low risk patients No: Gastric bandingNo: Gastric banding
DB asks whether there are any medications DB asks whether there are any medications she could take to help her lose weightshe could take to help her lose weight
When diet and exercise are not When diet and exercise are not effective, or adequate exercise is not effective, or adequate exercise is not possible, are there medications to treat possible, are there medications to treat obesity that are safe and effective?obesity that are safe and effective?
How do I determine which medications How do I determine which medications are right for which patients?are right for which patients?
What about cost/ coverage by local What about cost/ coverage by local insurance?insurance?
QuestionsQuestions
Definition of ObesityDefinition of Obesity BMI 25-29.9 (Grade 1, overweight)BMI 25-29.9 (Grade 1, overweight) BMI 30-39.9 (Grade 2, obese)BMI 30-39.9 (Grade 2, obese) BMI > 40 (Grade 3, Morbidly obese)BMI > 40 (Grade 3, Morbidly obese) Increased visceral fatIncreased visceral fat
Waist > 94 cm in men (waist-to-hip > Waist > 94 cm in men (waist-to-hip > 0.95)0.95)
Waist > 80 cm in women (waist-to-hip Waist > 80 cm in women (waist-to-hip >0.8)>0.8)
Obesity in the U.S.Obesity in the U.S.
More than 97 million More than 97 million adults in US are adults in US are overweight or obese overweight or obese (BMI (BMI >>30)30)
19.9% of men 19.9% of men 24.9% for women24.9% for women
Prevalence of ObesityPrevalence of ObesityMore than 30% of adults in More than 30% of adults in
the US are overweight or the US are overweight or obese, and this percentage obese, and this percentage
is rising.is rising.Percentage of people with BMI ≥ 30 in the US in 2005
CDC’s Behavioral Risk Factor Surveillance System.
Costs the US health-care system more than $99 billion Costs the US health-care system more than $99 billion each year each year
Consumers also spend over $33 billion annually on weight-Consumers also spend over $33 billion annually on weight-reduction products and servicesreduction products and services
Annual health-care costs for patients with BMIs of 20 to Annual health-care costs for patients with BMIs of 20 to 24.9 were 20% lower than costs for patients with BMIs from 24.9 were 20% lower than costs for patients with BMIs from 30 to 34.9 and almost 33% lower than for patients who had 30 to 34.9 and almost 33% lower than for patients who had BMIs of 35 or more.BMIs of 35 or more.
Costs of ObesityCosts of Obesity
Complications of ObesityComplications of Obesity
Obesity Related Obesity Related ComorbiditiesComorbidities
HTN/ HTN/ hyperlipidemhyperlipidemiaia
CAD/CVACAD/CVA DM IIDM II
Cancer Cancer (Breast, (Breast, Colon, Colon, Prostate)Prostate)
Meralgia Meralgia parestheticparestheticaa
Gallbladder Gallbladder diseasedisease
NASH/ NASH/ NAFLDNAFLD
GERDGERD Varicose Varicose veinsveins
Endometrial Endometrial Ca PCOS/ Ca PCOS/ infertilityinfertility
Surgical Surgical Risk/ post-Risk/ post-op op complicaticomplicationsons
LE edema/ LE edema/ cellulitiscellulitis
DepressionDepression OAOA Pulmonary Pulmonary HTN/HTN/OSAOSA
Does weight loss lead to Does weight loss lead to improvement in outcome? improvement in outcome?
10kg loss leads to:10kg loss leads to: Reduction in total cholesterol of 0.25mmol/lReduction in total cholesterol of 0.25mmol/l Reduction in systolic BP of 6mmHgReduction in systolic BP of 6mmHg Reduction in diastolic BP of 3mmHgReduction in diastolic BP of 3mmHg
ANY weight loss in people with an obesity ANY weight loss in people with an obesity related illness leads to:related illness leads to: In women - Reduced risk of death, CVD, cancer In women - Reduced risk of death, CVD, cancer
or diabetes related deathor diabetes related death In men – Reduced risk of diabetes related deathIn men – Reduced risk of diabetes related death
Indications for Drug Therapy Indications for Drug Therapy in Obesityin Obesity
Failure of diet and exercise aloneFailure of diet and exercise alone Significant obesity related Significant obesity related
comorbidities even if BMI < 30 (ie comorbidities even if BMI < 30 (ie 25-30).25-30).
No contraindications to drug therapyNo contraindications to drug therapy Medication interactionsMedication interactions Medical conditions that may be Medical conditions that may be
adversely affected by the obesity drugadversely affected by the obesity drug
Snow, et al , Ann Intern Med, 2005.
Model of Obesity CareModel of Obesity CareLevel 1: Public health initiatives. GP to signpost Level 1: Public health initiatives. GP to signpost patients to community based lifestyle interventionpatients to community based lifestyle intervention
Level 2: 1+ practice based intervention, anti-obesity Level 2: 1+ practice based intervention, anti-obesity drugs, community dietitian, behaviour modificationdrugs, community dietitian, behaviour modification
Level 3: (secondary care)Level 3: (secondary care)Specialist dietitian, endocrinologist, psychologist, Specialist dietitian, endocrinologist, psychologist, genetic screening, anti-obesity drugsgenetic screening, anti-obesity drugsLevel 4: (secondary care)Level 4: (secondary care)Bariatric surgery with support from level 3 serviceBariatric surgery with support from level 3 service
19
Centrally-Acting Anorexigens Centrally-Acting Anorexigens Approved Post-1938Approved Post-193811
1947 – 1947 – Desoxyephedrine/methamphetamine Desoxyephedrine/methamphetamine (available pre-’38)(available pre-’38)
1956 – Phenmetrizine (Preludin)1956 – Phenmetrizine (Preludin) 1959 - Phendimetrazine (Bontril) 1959 - Phendimetrazine (Bontril) 1959 - Phentermine (Fastin, Ionamin) 1959 - Phentermine (Fastin, Ionamin)
– W/D CPMP 2000– W/D CPMP 2000 1959 - Diethylpropion (Tenuate)1959 - Diethylpropion (Tenuate) 1960 - Benzphetamine (Didrex)1960 - Benzphetamine (Didrex) 1972 - Fenfluramine (Pondimin) – W/D 1972 - Fenfluramine (Pondimin) – W/D
1997 1997 1973 - Mazindol (Sanorex)1973 - Mazindol (Sanorex)22
1995 – Dexfenfluramine (Redux) – W/D 1995 – Dexfenfluramine (Redux) – W/D 19971997
1997 – Sibutramine (Meridia) 1997 – Sibutramine (Meridia)
20
Drugs Approved for Long-Term Drugs Approved for Long-Term Treatment of ObesityTreatment of Obesity
1996 - Dexfenfluramine (Redux): w/d ‘97 1996 - Dexfenfluramine (Redux): w/d ‘97 1997 - Sibutramine (Meridia)1997 - Sibutramine (Meridia) 1999 - Orlistat (Xenical)1999 - Orlistat (Xenical)
Efficacy: Long-term indication drugsEfficacy: Long-term indication drugs Mean loss of 5.0 kg vs. placebo Mean loss of 5.0 kg vs. placebo
range of placebo-subtracted means across range of placebo-subtracted means across studies 1.5 to 6.0 kg studies 1.5 to 6.0 kg
21
Drug use data: 1991-Drug use data: 1991-20022002
Annual volume of antiobesity medications reported in the United States, 1991–2002, IMS HEALTH National Disease and Therapeutic Index. Data for 2002 are an estimate (E) based on January to March 2002 figures. HCl indicates hydrochloride. From: Stafford: Arch Intern Med, Volume 163(9).May 12, 2003.1046–1050
SibutramineSibutramine
Mechanism of action:Mechanism of action: Inhibits norepinephrine and serotonin reuptakeInhibits norepinephrine and serotonin reuptake Decreases food intake; ?Thermogenic effect?Decreases food intake; ?Thermogenic effect?
Dosing: 5 -15 mg po daily Dosing: 5 -15 mg po daily Schedule IV, but approved for long-term useSchedule IV, but approved for long-term use
Cost: about $105 for a 30 day supply of 10 mg Cost: about $105 for a 30 day supply of 10 mg tabletstablets
Insurance coverage: NC by Unity, PPlus, or Insurance coverage: NC by Unity, PPlus, or MedicaidMedicaid
Sibutramine: EfficacySibutramine: Efficacy Meta-analysis of healthy obese adults Meta-analysis of healthy obese adults Exclusion: patients with CAD Exclusion: patients with CAD Concomitant lifestyle, dietary, and behavioral Concomitant lifestyle, dietary, and behavioral
modificationmodification Primary outcome: weight lossPrimary outcome: weight loss Secondary outcomes: cardiovascular, metabolicSecondary outcomes: cardiovascular, metabolic
Artburn, et al, Arch Intern Med, 2004.
DoseDose # trials# trials DuratioDurationn
PatientPatientss
10-15 10-15 mgmg
77 8-12 8-12 wkswks
546546
12 (4-5-12 (4-5-3)3)
16-24 16-24 wkswks
10791079
55 44-54 44-54 wkswks
21882188
Results: Mean Difference in Results: Mean Difference in Weight LossWeight Loss
Subgroup A used late-observation-carried-forward analysis and had >70% follow upSubgroup B analyzed only participants who completed the trialSubgroup C had follow up rates less than 70%
-8-7-6-5-4-3-2-10
Kg
8-12 wks16-24 wks Grp A16-24 wks Grp B16-24 wks Grp C44-54 wks
A B C
Artburn, et al, Arch Intern Med, 2004.
2.78
3.43
4.45
Secondary OutcomesSecondary Outcomes Modest increase in BP and HRModest increase in BP and HR Small improvements in TG, HDL, & glycemic Small improvements in TG, HDL, & glycemic
controlcontrol No evidence of improvement of morbidity & No evidence of improvement of morbidity &
mortalitymortality No dose effect for weight loss.No dose effect for weight loss. 1 trial showed weight loss maintained at 2 yrs1 trial showed weight loss maintained at 2 yrs 2 trials showed regain of 50% of weight at 6-12 2 trials showed regain of 50% of weight at 6-12
months after stopping medicine.months after stopping medicine.
Artburn, et al, Arch Intern Med, 2004.
Cochrane Review:Cochrane Review:Sibutramine Long-term EfficacySibutramine Long-term Efficacy Meta-analysis of RCTs, Sibutramine vs. placeboMeta-analysis of RCTs, Sibutramine vs. placebo
3 trials -- weight loss at more than 1 year follow up3 trials -- weight loss at more than 1 year follow up 2 trials -- weight maintenance at 2 years2 trials -- weight maintenance at 2 years
Inclusion: adults BMI>30 or BMI>27 + Inclusion: adults BMI>30 or BMI>27 + comorbiditiescomorbidities
Exclusion: patients with DM or uncontrolled HTNExclusion: patients with DM or uncontrolled HTN Results: Results: 4.3 kg (3.6-4.9) more wt loss with 4.3 kg (3.6-4.9) more wt loss with
sibutraminesibutramine 27% more patients maintained 80% of original weight 27% more patients maintained 80% of original weight
loss at 2 years with sibutramineloss at 2 years with sibutramine Adverse effects: Small increase in HR and BPAdverse effects: Small increase in HR and BP
Padwal, et al. Cochrane Database of Systematic Reviews, 2003.
Sibutramine with & without Sibutramine with & without Lifestyle ChangesLifestyle Changes
Wadden TA et al. NEJM, 2005.
224 obese adults randomized to the following for 224 obese adults randomized to the following for 1 year:1 year: 15 mg sibutramine daily (PCP 8 visits, no counseling)15 mg sibutramine daily (PCP 8 visits, no counseling) Lifestyle modification alone (30 group sessions, 90 Lifestyle modification alone (30 group sessions, 90
minutes, psychologist)minutes, psychologist) Sibutramine + lifestyle modification (30 group sessions)Sibutramine + lifestyle modification (30 group sessions) Sibutramine + brief lifestyle modification (PCP 8 visits, Sibutramine + brief lifestyle modification (PCP 8 visits,
brief counseling)brief counseling) All prescribed diet 1200-1500 kcal per day and All prescribed diet 1200-1500 kcal per day and
exercise regimenexercise regimen
SibutramineSibutramineAdverse EffectsAdverse Effects ContraindicationContraindication
ssIncrease BP, HRIncrease BP, HR History of CAD, CHF, History of CAD, CHF,
CVA, glaucoma CVA, glaucoma Palpitations, prolong Palpitations, prolong QTQTTachyarrhythmia Tachyarrhythmia (rare)(rare)
History of arrhythmiaHistory of arrhythmia
ThrombocytopeniaThrombocytopenia Predisposition to Predisposition to bleedingbleeding
P450 metabolismP450 metabolism Severe liver or renal Severe liver or renal diseasedisease
Serotonin syndromeSerotonin syndrome MAOIs, SSRIsMAOIs, SSRIsHA, insomnia, Sz HA, insomnia, Sz (rare)(rare)
History of seizureHistory of seizure
GI disturbanceGI disturbance
Phentermine and Phentermine and DiethylpropionDiethylpropion
Mechanism of action: Stimulate NE Mechanism of action: Stimulate NE release and inhibit re-uptakerelease and inhibit re-uptake
Dosing (Dosing (short-term use only -- < 12 short-term use only -- < 12 weeksweeks)) 18.75 to 37.5 mg once daily or in divided doses18.75 to 37.5 mg once daily or in divided doses Schedule IVSchedule IV
Cost: about $34 for a month supply of 37.5 Cost: about $34 for a month supply of 37.5 mg tabletsmg tablets
Insurance coverage: NC by Unity, PPlus, Insurance coverage: NC by Unity, PPlus, or Medicaidor Medicaid
Phentermine: Efficacy Phentermine: Efficacy and Safetyand Safety
Meta-analysis: Included 6 RCTsMeta-analysis: Included 6 RCTs Duration: 2-24 wksDuration: 2-24 wks Dose: 15-30 mg per dayDose: 15-30 mg per day Results: Results: 3.6kg (0.6-6.0) more wt loss 3.6kg (0.6-6.0) more wt loss
with phenterminewith phentermine No data on side effects or adverse events No data on side effects or adverse events
reportedreported
Haddock et al, J Obes Relat Metabolic Disord, 2002.
PhenterminePhentermineAdverse EffectsAdverse EffectsHTN, HTN, tachyarrhythmiatachyarrhythmiaHeart valve disorder Heart valve disorder (rare)(rare)PPH (rare)PPH (rare)GI disturbanceGI disturbancePsychosis, agitationPsychosis, agitationHA, insomnia, HA, insomnia, tremor, AMS, tremor, AMS, dizzinessdizzinessDecreased libidoDecreased libidoAffect insulin needs Affect insulin needs in DMin DM
ContraindicatioContraindicationsnsCAD, HTN, CAD, HTN, glaucomaglaucomaHyperthyroidismHyperthyroidismMAOI, SSRIMAOI, SSRIHistory of drug/etoh History of drug/etoh abuseabusePsychiatric diseasePsychiatric disease
Orlistat Orlistat Mechanism of ActionMechanism of Action
Inhibits pancreatic lipases preventing hydrolysis of ingested Inhibits pancreatic lipases preventing hydrolysis of ingested fatfat
Less than 1% absorbedLess than 1% absorbed Dosing: 60 – 120 mg prior to each meal.Dosing: 60 – 120 mg prior to each meal.
Lower dose OTC (My Alli)Lower dose OTC (My Alli) Cost: about $224 for a 1 month supply of 120 mg Cost: about $224 for a 1 month supply of 120 mg
dosedose Insurance coverage: NC by Unity, PPlus, or MedicaidInsurance coverage: NC by Unity, PPlus, or Medicaid GI side effects: diarrhea, cramping, flatus, oily GI side effects: diarrhea, cramping, flatus, oily
discharge, malabsorption of fat soluble vitamins.discharge, malabsorption of fat soluble vitamins. Only drug interaction: CSAOnly drug interaction: CSA
Orlistat: EfficacyOrlistat: Efficacy Meta-analysis, 29 RCTs includedMeta-analysis, 29 RCTs included 12 trials with 6 months follow up12 trials with 6 months follow up
Mean of 2.59 kg (1.74-3.46) more wt loss with Mean of 2.59 kg (1.74-3.46) more wt loss with orlistatorlistat
22 trials with 12 months follow up22 trials with 12 months follow up Mean of 2.89 kg (2.27-3.51) more wt loss with Mean of 2.89 kg (2.27-3.51) more wt loss with
orlistatorlistat RR diarrhea 3.40, flatus 3.10, and dyspepsia 1.48RR diarrhea 3.40, flatus 3.10, and dyspepsia 1.48
No difference between 6 and 12 monthsNo difference between 6 and 12 months Cochrane review meta-analysisCochrane review meta-analysis
11 trials with at least 12 months follow up11 trials with at least 12 months follow up Mean of 2.7 kg (2.3-3.1) more wt loss with orlistatMean of 2.7 kg (2.3-3.1) more wt loss with orlistat
Li, et al. Ann Intern Med, 2005.Padwal, et al. Cochrane Database of Systematic Reviews, 2003.
Orlistat (Xenical) Orlistat (Xenical) IndicationsIndications
Among obese patients who meet the criteria Among obese patients who meet the criteria for anti-obesity drug therapy, orlistat is for anti-obesity drug therapy, orlistat is most likely to benefit those who: most likely to benefit those who: Do not feel hungryDo not feel hungry Are not preoccupied with foodAre not preoccupied with food Eat out or order-in oftenEat out or order-in often Have increased cardiovascular disease risk or Have increased cardiovascular disease risk or
multiple cardiovascular risk factorsmultiple cardiovascular risk factors Are olderAre older Take multiple medications Take multiple medications
Orlistat is taken 3 times daily with mealsOrlistat is taken 3 times daily with meals
Orlistat- Effect on Orlistat- Effect on HgbA1C in T2DMHgbA1C in T2DM
DIABETES CARE, VOLUME 25, NUMBER 6, JUNE 2002
Figure 4—Figure 4—HbA1c over 1 year of double-blind treatment with placebo (HbA1c over 1 year of double-blind treatment with placebo (EE) or 120 mg ) or 120 mg orlistat (orlistat (FF).).PP0.002, least-squares mean difference from placebo in the change from baseline over 52 0.002, least-squares mean difference from placebo in the change from baseline over 52 weeks.weeks.
The improvementin HbA1c achieved with orlistat therapyexceeded that of the placebo group and there was a 0.62% improvementin HbA1c relative to the baseline value for the participants randomized toorlistat.
Orlistat: Long-term Orlistat: Long-term EfficacyEfficacy
4-year double blind placebo controlled RCT4-year double blind placebo controlled RCT 3,305 patients, BMI>303,305 patients, BMI>30 Lifestyle changes + orlistat (120 mg) or Lifestyle changes + orlistat (120 mg) or
placeboplacebo Primary outcomes: wt loss, time to onset Primary outcomes: wt loss, time to onset
DM IIDM II Mean of 2.8 kg more wt loss with orlistat Mean of 2.8 kg more wt loss with orlistat
(P<0.001)(P<0.001) Incidence of diabetes 6.2% vs 9% (P=0.0032)Incidence of diabetes 6.2% vs 9% (P=0.0032)
Torgerson, et al. Diabetes Care, 2004.
Combination TherapyCombination Therapy 3 small trials3 small trials
34 women after 1 year on sibutramine with 11.6% 34 women after 1 year on sibutramine with 11.6% mean wt loss randomized to S+O or S + placebo mean wt loss randomized to S+O or S + placebo for 16 wksfor 16 wks
89 women randomized to diet+O, diet+S, or 89 women randomized to diet+O, diet+S, or diet+O+S for 6 monthsdiet+O+S for 6 months
86 pts randomized to S, O, S+O, or diet for 12 wks86 pts randomized to S, O, S+O, or diet for 12 wks Sibutramine alone as good as Sibutramine alone as good as
Combination & better than Orlistat aloneCombination & better than Orlistat alone
Wadden et al. Obes Res, 2000.Kaya et al. Biomed Phamacother, 2004.Sari et al. Endocrin Res, 2004.
Li, Z. et. al. Ann Intern Med 2005;142:532-546
Weight loss with bupropion & fluoxetine vs. placebo at 6 - 12 months
Antidepressants: EfficacyAntidepressants: Efficacy
Note: High doses usedFluoxetine 60 mg dailyBupropion 400 mg/day
TopiramateTopiramate
Topiramate is a novel antiepileptic drug approved by Topiramate is a novel antiepileptic drug approved by the FDA as an antiseizure medication. the FDA as an antiseizure medication.
When reports surfaced that patients enrolled in initial When reports surfaced that patients enrolled in initial trials of the drug and also in clinical practice were trials of the drug and also in clinical practice were experiencing unexpected weight loss, the effects of experiencing unexpected weight loss, the effects of the drug on weight began to be studied.the drug on weight began to be studied.
Mechanism for weight loss is still poorly understoodMechanism for weight loss is still poorly understood
TopiramateTopiramate
34 patients being treated for epilepsy. 34 patients being treated for epilepsy. 12-month open-label trial without dietary 12-month open-label trial without dietary
intervention, patients took combinations of drugs intervention, patients took combinations of drugs to treat their epilepsy. to treat their epilepsy.
Dr. Ulf Smith, Sahlgrenska University Hospital, Göteborg, Sweden
Weight loss with topiramate versus placebo at 6 months
Li, Z. et. al. Ann Intern Med 2005;142:532-546
Antiepileptic: EfficacyAntiepileptic: Efficacy
Note: High dose, 192 mg/day
MetforminMetformin 3234 nondiabetic adults with impaired glucose tolerance3234 nondiabetic adults with impaired glucose tolerance
Mean BMI 34, mean age 51, 68% womenMean BMI 34, mean age 51, 68% women Randomized to placebo, metformin 850 mg po BID or Randomized to placebo, metformin 850 mg po BID or
lifestyle changes for 2.8 yearslifestyle changes for 2.8 years
Knowler et al. NEJM 2002.
Metformin Compared to OthersMetformin Compared to Others 150 women with BMI >30 randomized to the following150 women with BMI >30 randomized to the following
Sibutramine 10 mg po BID (Higher than normal dose)Sibutramine 10 mg po BID (Higher than normal dose) Orlistat 120 mg po TIDOrlistat 120 mg po TID Metformin 850 mg po BIDMetformin 850 mg po BID
All groups also with lifestyle interventions/ nutrition All groups also with lifestyle interventions/ nutrition counselingcounseling
No placebo groupNo placebo group 6 months follow up6 months follow up
% decrease % decrease BMIBMI
% decrease % decrease waist waist circumferencircumferencece
SibutramineSibutramine 13.5713.57 10.4310.43OrlistatOrlistat 9.099.09 6.646.64MetforminMetformin 9.909.90 8.108.10Gokcel A, et al. Diab Obes Metab 2002.
LeptinLeptin
•Naturally occurring hormone that plays a role in satiety and weight maintenance. •Produced in adipocytes•Its role in weight regulation is related to its effects on the hypothalamus, where it leads to:
• satiety •decreased food intake•increased energy expenditure in the periphery
LeptinLeptin
Initial human trials with recombinant leptin were Initial human trials with recombinant leptin were modestly successful. modestly successful.
Most subjects in the initial trial developed local Most subjects in the initial trial developed local reactions at the injection site.reactions at the injection site.
Weight loss was relatively modest.Weight loss was relatively modest. However, the hormone needs to be given However, the hormone needs to be given
subcutaneously and has a short half-life.subcutaneously and has a short half-life. Thus a modified recombinant human leptin (m-Thus a modified recombinant human leptin (m-
leptin) was created that has a longer half-life.leptin) was created that has a longer half-life.
ExenatideExenatide 336 pts, BMI 34.2+/-5.9336 pts, BMI 34.2+/-5.9 DM II, mean A1c 8.2+/- DM II, mean A1c 8.2+/-
1.11.1 4 wks placebo4 wks placebo 4 wks 5 4 wks 5 g exenatide BID g exenatide BID
or placeboor placebo 26 wks 5 or 10 26 wks 5 or 10 g g
exenatide BID or placeboexenatide BID or placebo All on metforminAll on metformin End of study mean A1c End of study mean A1c
7.4%7.4% 50% reached goal of < 7% 50% reached goal of < 7%
on 10 on 10 g doseg dose
DeFronzo RA, et al. Diab Care, 2005.
Pi-Sunyer, F. X. et al. JAMA 2006.
RimonabantRimonabant Cannabinoid-1 receptor blockerCannabinoid-1 receptor blocker
Reduces overactivation of the central & peripheral Reduces overactivation of the central & peripheral endocannabinoid systemendocannabinoid system
3045 pts with BMI>27 and HTN or dyslipidemia3045 pts with BMI>27 and HTN or dyslipidemia 4-wk single blind placebo + diet run-in4-wk single blind placebo + diet run-in
Randomized to 5 mg daily, 20 mg daily, or placebo for 1 yearRandomized to 5 mg daily, 20 mg daily, or placebo for 1 year Treated pts re-randomized to placebo or continued rimonibant Treated pts re-randomized to placebo or continued rimonibant
for 2nd yearfor 2nd year High drop out rate~ 50% in all groupsHigh drop out rate~ 50% in all groups Most common side effect was nausea (11.2% vs 5.8%)Most common side effect was nausea (11.2% vs 5.8%)
Surgery vs. Surgery vs. PharmacotherapyPharmacotherapy
RCT, 80 adults BMI 30-35RCT, 80 adults BMI 30-35 Laparoscopic adjustable gastric bandingLaparoscopic adjustable gastric banding Intensive non-surgical programIntensive non-surgical program
Very low calorie diet (500-550 kcal/day) X 12 wksVery low calorie diet (500-550 kcal/day) X 12 wks Orlistat 120 mg added before some meals X 4 Orlistat 120 mg added before some meals X 4
wkswks Orlistat before all meals X 8 wks for total of 6 moOrlistat before all meals X 8 wks for total of 6 mo Continued low calorie diet or orlistat + Continued low calorie diet or orlistat +
behavioral therapy for long-term maintenancebehavioral therapy for long-term maintenance Primary endpoint: Change in weightPrimary endpoint: Change in weight
O'Brien, P. E. et. al. Ann Intern Med 2006;144:625-633
O'Brien, P. E. et. al. Ann Intern Med 2006;144:625-633
Mean % of initial weight lost (initial data carried forward for missing values)
Statistically significant improvement in metabolic syndrome in Statistically significant improvement in metabolic syndrome in surgical group: 35% of pts in both groups initially, 24% of pts surgical group: 35% of pts in both groups initially, 24% of pts in non-surgical group and 3% of pts in surgical group at 2 yrs in non-surgical group and 3% of pts in surgical group at 2 yrs
Surgical group adverse events: 1 port site infection, 4 Surgical group adverse events: 1 port site infection, 4 prolapse of posterior gastric wall, 1 cholecystitisprolapse of posterior gastric wall, 1 cholecystitis
Non-surgical group adverse events: 1 diet intolerance, 8 Non-surgical group adverse events: 1 diet intolerance, 8 orlistat intolerance, 4 cholecystitisorlistat intolerance, 4 cholecystitis
SummarySummary Weight loss with Weight loss with
obesity medicines is obesity medicines is modestmodest
Obesity medicines are Obesity medicines are not a substitute for diet not a substitute for diet and exerciseand exercise
Weight loss is often not Weight loss is often not maintained after drug maintained after drug is discontinuedis discontinued
Most obesity medicines Most obesity medicines are not covered by are not covered by insuranceinsurance
DrugDrug Wt lossWt lossSibutraminSibutraminee
4-5 kg4-5 kg
PhenterminPhenterminee
3-4 kg3-4 kg
OrlistatOrlistat 2-3 kg2-3 kgMetforminMetformin 2 kg2 kgExenatideExenatide 2-3 kg2-3 kgBupropionBupropion 2-3 kg2-3 kgFluoxetineFluoxetine MixedMixedTopamaxTopamax 6-7 kg6-7 kgRimonabanRimonabantt
6-7 kg6-7 kg
Novel treatments Novel treatments Neuroendocrine Neuroendocrine
regulation of energy regulation of energy balancebalance
Inhibit anabolic Inhibit anabolic moleculesmolecules Neuropeptide Y, Melanin Neuropeptide Y, Melanin
concentrating hormoneconcentrating hormone Stimulate catabolic Stimulate catabolic
signalssignals Leptin receptor agonistsLeptin receptor agonists
Gastric peptidesGastric peptides GLP-1, Ghrelin inhibitorsGLP-1, Ghrelin inhibitors
NICE Indications for NICE Indications for Bariatric SurgeryBariatric Surgery
BMI>40BMI>40 BMI>35 + co-morbidity eg DM, high BPBMI>35 + co-morbidity eg DM, high BP Failure to achieve/ maintain adequate weight Failure to achieve/ maintain adequate weight
loss after 6/12 non-surgical interventionloss after 6/12 non-surgical intervention Receiving specialist obesity service treatmentReceiving specialist obesity service treatment Commitment to long-term follow-upCommitment to long-term follow-up Fit for anaesthetic / procedureFit for anaesthetic / procedure
First line treatment if BMI>50First line treatment if BMI>50
Types of ProcedureTypes of Procedure RestrictiveRestrictive
Gastric band (reversible)Gastric band (reversible) Sleeve gastrectomy (irreversible)Sleeve gastrectomy (irreversible)
MalabsorptiveMalabsorptive Biliopancreatic diversion +/- duodenal switch Biliopancreatic diversion +/- duodenal switch
(gastric pouch attached to ileum)(gastric pouch attached to ileum) Mixed Restrictive / MalabsorpitveMixed Restrictive / Malabsorpitve
Roux-en-Y bypassRoux-en-Y bypass Mini gastric bypass (less small bowel Mini gastric bypass (less small bowel
bypassed)bypassed)
Laparoscopic Gastric Laparoscopic Gastric BandBand
Complications: Slippage, leakage, infection, migration
Roux-en-Y BypassRoux-en-Y Bypass
Complications: Anastamotic leak, stoma stenosis, GI ulcers or bleeding, small bowel obstruction
Long-term surgical Long-term surgical complications complications
Nausea and vomitingNausea and vomiting Over-eating, band too tight, stenosisOver-eating, band too tight, stenosis
Dumping syndromeDumping syndrome Flushing, light-headed, palpitations, fatigue, diarrhoea Flushing, light-headed, palpitations, fatigue, diarrhoea
(triggered by sugar intake)(triggered by sugar intake) MalnutritionMalnutrition
Thiamine, B12, Copper (neurological signs)Thiamine, B12, Copper (neurological signs) Iron, folate, calcium, fat soluble vitaminsIron, folate, calcium, fat soluble vitamins Hyperoxaluria Hyperoxaluria
Inadequate weight loss or weight regainInadequate weight loss or weight regain BehaviouralBehavioural Inadequate pre-operative assessmentInadequate pre-operative assessment
Selecting a Medicine for Obesity Selecting a Medicine for Obesity TreatmentTreatment
Cost an issue?
Co-existing DM or insulin resistance?
Sibutramine contraindicated?
NO
YESSibutramine
NO
Orlistat
YES
On metformin?
YES
Co-existing depression?
NOMetformin
NO
Consider adding exenatide
YES
Consider bupropion
YES/No
Case ApplicationCase Application Benefit of medications without lifestyle changes is Benefit of medications without lifestyle changes is
questionablequestionable Sibutramine and orlistat likely cost prohibitive for Sibutramine and orlistat likely cost prohibitive for
this patient with Medicaid.this patient with Medicaid. Consider changing anti-depressant to bupropionConsider changing anti-depressant to bupropion Consider adding metformin due to insulin Consider adding metformin due to insulin
resistanceresistance Gastric banding best option, but likely not coveredGastric banding best option, but likely not covered Gastric bypass next best option, but not without Gastric bypass next best option, but not without
riskrisk
Recommended
