Medicines for the Medicines for the Treatment of Treatment of

ObesityObesity““But Doc, isn’t there a pill I But Doc, isn’t there a pill I can take?”can take?”

Joanna Ruchala, MDJoanna Ruchala, MD

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: DB

49 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 BenazeprilBenazepril

DB 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 bilaterallybilaterally

Lateral compartment Lateral compartment on Ron R

Medial 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)

Prevalence of ObesityPrevalence of Obesity

More 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.

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

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.

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 Cost: about $105 for a 30 day supply of 10 mg tabletsmg tablets

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

-1

0

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 1 year:224 obese adults randomized to the following for 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 minutes, Lifestyle modification alone (30 group sessions, 90 minutes,

psychologist)psychologist) Sibutramine + lifestyle modification (30 group sessions)Sibutramine + lifestyle modification (30 group sessions) Sibutramine + brief lifestyle modification (PCP 8 visits, brief counseling)Sibutramine + brief lifestyle modification (PCP 8 visits, brief counseling)

All prescribed diet 1200-1500 kcal per day and exercise All prescribed diet 1200-1500 kcal per day and exercise regimenregimen

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 QTQT

Tachyarrhythmia 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, SSRIs

HA, 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 18.75 to 37.5 mg once daily or in divided

dosesdoses Schedule IVSchedule IV

Cost: about $34 for a month supply of Cost: about $34 for a month supply of 37.5 mg tablets37.5 mg 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.

PhenterminePhentermine

Adverse EffectsAdverse EffectsHTN, HTN, tachyarrhythmiatachyarrhythmia

Heart valve disorder Heart valve disorder (rare)(rare)

PPH (rare)PPH (rare)

GI disturbanceGI disturbance

Psychosis, agitationPsychosis, agitation

HA, insomnia, HA, insomnia, tremor, AMS, tremor, AMS, dizzinessdizziness

Decreased libidoDecreased libido

Affect insulin needs Affect insulin needs in DMin DM

ContraindicatioContraindicationsnsCAD, HTN, CAD, HTN, glaucomaglaucoma

HyperthyroidismHyperthyroidism

MAOI, SSRIMAOI, SSRI

History of drug/etoh History of drug/etoh abuseabuse

Psychiatric diseasePsychiatric disease

Orlistat Orlistat Mechanism of ActionMechanism of Action

Inhibits pancreatic lipases preventing hydrolysis of Inhibits pancreatic lipases preventing hydrolysis of ingested fatingested fat

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 Mean of 2.7 kg (2.3-3.1) more wt loss with

orlistatorlistatLi, et al. Ann Intern Med, 2005.

Padwal, et al. Cochrane Database of Systematic Reviews, 2003.

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

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 10.4310.43

OrlistatOrlistat 9.099.09 6.646.64

MetforminMetformin 9.909.90 8.108.10Gokcel A, et al. Diab Obes Metab 2002.

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 < 50% reached goal of <

7% on 10 7% 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 Very low calorie diet (500-550 kcal/day) X 12 wkswks

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 Orlistat before all meals X 8 wks for total of 6 momo

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 not a substitute for diet and exercisediet and exercise

Weight loss is often Weight loss is often not maintained after not maintained after drug is discontinueddrug is discontinued

Most obesity Most obesity medicines are not medicines are not covered by insurancecovered by insurance

DrugDrug Wt lossWt loss

SibutraminSibutraminee

4-5 kg4-5 kg

PhenterminPhenterminee

3-4 kg3-4 kg

OrlistatOrlistat 2-3 kg2-3 kg

MetforminMetformin 2 kg2 kg

ExenatideExenatide 2-3 kg2-3 kg

BupropionBupropion 2-3 kg2-3 kg

FluoxetineFluoxetine MixedMixed

TopamaxTopamax 6-7 kg6-7 kg

RimonabanRimonabantt

6-7 kg6-7 kg

Selecting a Medicine for Obesity Selecting a Medicine for Obesity TreatmentTreatment

Cost an issue?

Co-existing DM or insulin resistance?

Sibutramine contraindicated?

NO

YES

Sibutramine

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

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