antiobesity agents handout - ku school of...

Antiobesity Agents

Ashley Crowl, PharmD, BCACPClinical Assistant Professor

University of Kansas School of Pharmacy

Goals

• Outline management of obesity• Review pharmacology of antiobesity agents• Compare antiobesity agents for long term use

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Antiobesity Agents Ashley Crowl, PharmD, BCAP

Family Medicine Spring Symposium April 10, 2015

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http://theweightofthenation.hbo.com/films

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Obesity• 34.9% of adults and 16.9% of youth are obese• Estimated annual medical costs =$147 billion relatedto obesity– Medical costs = $1,429 more for obese patients than thoseof normal weight

1. Ogden, et al. JAMA. 20142. Obesity guidelines. AHA/ACC/TOS. 2013.3. Finkelstein, et al. Health Affairs. 2009.

Obesity

Arthritis

CVD

CancerMortality

DM

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15%–<20% 20%–<25% 25%–<30% 30%–<35% 35%

Prevalence* of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2012

*Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011.

CA

MT

ID

NVUT

AZNM

WY

WA

OR

CO

NE

ND

SD

TX

OK

KS

IA

MN

AR

MO

LA

MI

IN

KY

IL OH

TN

MS AL

WI

PA

WV

SC

VA

NC

GA

FL

NY

VT

ME

HI

AK

NHMARICTNJDEMDDC

PRGUAM

Behavioral Risk Factor Surveillance Systems, CDC5

Prevalence* of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2013

*Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011.

CA

MT

ID

NVUT

AZNM

WY

WA

OR

CO

NE

ND

SD

TX

OK

KS

IA

MN

AR

MO

LA

MI

IN

KY

IL OH

TN

MS AL

WI

PA

WV

SC

VA

NC

GA

FL

NY

VT

ME

HI

AK

NHMARICTNJDEMDDC

PRGUAM

15%–<20% 20%–<25% 25%–<30% 30%–<35% 35%

Behavioral Risk Factor Surveillance Systems, CDC6



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Obesity

EnergyOut

EnergyIn

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Managing Obesity

Pt needs to lose weight if BMI 30 orBMI 25 with additional risk factor

Assess readiness to make lifestylechanges [take into account competingpriorities (i.e. uncontrolled DM or HTN)]

Initial weight loss goal of 5 10% ofbaseline weight within 6 months.

Decrease by 500 kcal/day. Manageother risk factors

Obesity guidelines.AHA/ACC/TOS.2013.8



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Managing ObesityStart comprehensive lifestyle

interventions alone or with adjunctivetherapies

Consider addition of pharmacotherapy agentsafter initial lifestyle changes with BMI 30 or

BMI 27 with additional co morbidity

Continue medication if 5% weight loss within 12weeks, d/c if not. Refer for more intensivebehavioral treatment or bariatric surgery.

Obesity guidelines.AHA/ACC/TOS.2013.9

Case 1

• AH 22 yo WF presentswith 5 month hx ofongoing HA. DX withIIH. No previous PMH.

• BP: 118/62 mmHg• HR: 70 bpm• 244 lbs, 64 in• BMI: 41

• BMP: WNL• FLP:

– TC: 183, TG: 190– LDL: 145, HDL: 48

• A1C= 7.5%

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Case 1: What are your first steps in managingAH’s obesity?

A. Implement lifestylechanges

B. Start antiobesityagent

C. Managecomorbidities

D. All of the aboveE. Only A and C

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Obesity= chronic disease

• Maximum weight loss achieved at 6 months• Maintenance treatment

– Continue long term ( 2 years) comprehensiveweight loss programs

• Monthly contact• Reduced calorie diet• Physical activity (>200 min/week)• Pharmacotherapy (studies up to 2 years)

Obesity guidelines.AHA/ACC/TOS.2013. 12



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ANTIOBESITY AGENTSLong term

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Antiobesity AgentsShort term Long term

Phentermine Orlistat

Benzphetamine Lorcaserin

Diethylpropion Phentermine/TopiramateER

Phendimetrazine Naltrexone/Bupropion

Liraglutide14



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Orlistat

Dose

• 120 mg TID before meals (RX)• Can be used 12 yo

• 60 mg TID before meals (OTC)

MOA

• Pancreatic lipase inhibitor: Selectively inhibits lipasesfrom stomach and intestines to reduce digestion offat

Cost• $16/day (RX)• $1.50/day (OTC)

Torgerson J. Orlistat. 2004PL Detail document, Drugs for weight loss. November 2014

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Orlistat

Efficacy

• 4 yr, double blind, RCT, 3304 patients achieved >5kg wtloss of 11% vs. 6% of placebo

• Average weight loss: 3.45 kg (7.6 lbs) > placebo

Safety

• Gas, oily spotting, fecal incontinence, abdominal/rectalpain, nausea.

• 1 in 28 patients stop orlistat due to ADE

CI• chronic malabsorption syndrome, cholestasis, pregnancy• Liver injury*

Torgerson J. Orlistat. 2004PL Detail document, Drugs for weight loss. November 2014

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Orlistat

• Drug interactions– Separate from levothyroxine by 1 hr– Monitor INR with vitamin K antagonist– Reduced amiodarone efficacy

• Tips– Take with MVI containing A,D,E,K 2hrs prior orafter

PL Detail document, Drugs for weight loss. November 2014 17

Lorcaserin

Dose• 10 mg BID [BMI 30 or BMI 27 with additional comorbidity*]

MOA

• 5 HT2c receptor agonist• promote satiety by decreasing food intake throughmelanocortin system

Cost• $7/day

PL Detail document, Drugs for weight loss. November 2014Product Information: BELVIQ(R) oral tablets, 2012*HTN, T2DM, Dyslipidemia, CVD, sleep apnea

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Lorcaserin

Efficacy• Average wt loss: 3.3 5.8 kg (7.24 12.7 lbs) > placebo• NNT = 4

Safety

• Nausea, dizziness, fatigue, and headache• 1 in 53 patients stop lorcaserin due to ADE• Drop out rates ~50%

CI

• Pregnancy, valvular heart disease, ESRD• Caution: CHF, neuroleptic malignant syndrome,pulmonary hypertension, hyperprolactinemia

PL Detail document, Drugs for weight loss. November 2014Smith.Lorcaserin. NEJM 2010.

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Lorcaserin

• Drug interactions– Caution/avoid use with other serotonergic agents– Increases levels of drugs metabolized by CYP2D6drugs

• Tips– Check CBC periodically– Monitor for suicidal thoughts/behavior– Seek medical attention for erection lasting over 4 hrs– D/C if <5% weight loss from baseline after 12 weeks– Schedule CIV prescription

PL Detail document, Drugs for weight loss. November 2014Product Information: BELVIQ(R) oral tablets, 2012.

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Phentermine/topiramate ER

Dose

• Initial: P:3.75 mg/T:23 mg daily x14 days thenP:7.5mg/T:46 mg daily.

• May P:11.25mg/T:69 mg daily x14 days,P:15mg/T:92 mg daily

MOA

• Phentermine: sympathomimetic, increases release ofNE to reduce appetite.

• Topiramate: Works on GABA receptors and reducesappetite

Cost• $7/day

PL Detail document, Drugs for weight loss. November 2014Product Information: QSYMIA®, 2014.Conquer Trial. Lancet 2011.

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Efficacy• Average wt loss: 9 kg (20 lbs) > placebo [w/ 15 mg]• NNT =2

Safety

• 1 in 12 patients stop phentermine/topiramate ER dueto ADE

• ~50% drop out rates in trials

CI

• Pregnancy, glaucoma, hyperthyroidism, MAOIs, suicidalideation, moderate high CVD

• Caution: Renal or hepatic impairmentPL Detail document, Drugs for weight loss. November 2014Product Information: QSYMIA®, 2014.Conquer Trial. Lancet 2011.

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• Drug interactions– Avoid with carbonic anhydrase inhibitors– Avoid with alcohol– Decreased efficacy of OCPs

• Tips– Check CMP (baseline & periodically); BP & HR; UPT– Monitor for suicidal thoughts/behavior, depression– D/C if <5% weight loss from baseline after 12 weeks

• Taper slowly to prevent withdrawal seizures– Schedule CIV prescription

PL Detail document, Drugs for weight loss. November 2014Product Information: QSYMIA®, 2014. 23

Bupropion/naltrexone

Dose

• Bupropion 90 mg/naltrexone 8 mg• Week 1: 1 tab daily in AM• Week 2: 1 tab BID• Week 3: 2 tabs AM & 1 tab PM• Week 4: 2 tabs BID

MOA

• Bupropion: stimulates melanocortin neurons• Naltrexone: blocks opioid mediated auto inhibition ofmelanocortin system

Cost• $7/day

PL Detail document, Drugs for weight loss. November 2014Product Information: CONTRAVE(R) La Jolla, CA, 2014. 24



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Efficacy• Average wt loss: 4.1 kg (9 lbs) > placebo• NNT= 3

Safety• 1 in 9 patients stop bupropion/naltrexone due to ADE• ~50% drop out rates in trials

CI

• uncontrolled HTN, seizures, bulimia, anorexia, orpregnancy

• Caution: Renal or hepatic impairment

PL Detail document, Drugs for weight loss. November 2014Product Information: CONTRAVE(R) La Jolla, CA, 2014. 25


• Drug interactions– Avoid with opioids or acutealcohol/benzodiazepines/barbiturates withdrawal

– Caution with inhibitors/inducers of CYP2D6

• Tips– Monitor depression/suicidal behavioral– D/C if <5% weight loss from baseline after 12weeks

• Taper slowly to prevent withdrawal seizuresPL Detail document, Drugs for weight loss. November 2014Product Information: CONTRAVE(R) La Jolla, CA, 2014. 26



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Liraglutide

Dose• Start 0.6 mg SQ daily and increase by 0.6 mg weeklyto dose of 3 mg daily

MOA• Glucagon like peptide 1 receptor agonist, reduceappetite and energy intake

Cost• $40/day

PL Detail document, Drugs for weight loss. November 2014Product Information: SAXENDA(R) Plainsboro, NJ, 2014.

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Liraglutide

Efficacy• Average wt loss: 3.9 5.2 kg (8.1 11.4 lbs) > placebo• NNT = 2

Safety

• 1 in 19 patients stop liraglutide due to ADE• Nausea! (48%)

• Drop out rate ~40% [injection did not effect]

CI• Medullary thyroid cancer, pregnancy, pancreatitis• Caution: renal and hepatic impairment

PL Detail document, Drugs for weight loss. November 2014Product Information: SAXENDA(R) Plainsboro, NJ, 2014. 28



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Liraglutide

• Drug interactions– Hypoglycemia with insulin/sulfonylureas

• Tips– A1c not further reduced– Can not use Victoza at this dose– Monitor HR (increases)

PL Detail document, Drugs for weight loss. November 2014Product Information: SAXENDA(R) Plainsboro, NJ, 2014. 29

Summary chartOrlistat Lorcaserin Phen/Top Bup/Nalt Liraglutide

Dose 120 mg 10 mg 3.75 mg/23 mg 15mg/92 mg

90 mg/8mg 300mg/ 32mg

0.6 3 mg

Frequency TID BID Qday BID Qday

Cost $16 $7 $7 $7 $40 ?

ADE ++ + +++ +++ ++

Efficacy + + +++ ++ +++30



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Co‐morbidities

Systolic BP Diastolic BP LDL GlucoseLorcaserin ‐1.9 ‐1.9 ‐0.7 ‐27.4Phen/Top ‐2.9 ‐1.5 ‐8.4 0.6Liraglutide ‐4.9 ‐2.8 ‐0.43 ‐26

‐30

‐25

‐20

‐15

‐10

‐5

0

5

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Lorcaserin Efficacy

Blossom: RCT47.2% achieved 5% wt‐lossvs. 25% (p<0.001)

Bloom: RCT; Year 1: 47.5% achieved 5% wt‐loss vs. 20.3% (p<0.001). Maintained wt‐loss in year 2.

Smith et al. BLOOM. NEJM 2010Fidler et al. Blossom.Endocrine 2011

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Lorcaserin Safety

Smith et al. BLOOM. NEJM 201033



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Phentermine/Topiramate Efficacy

RCT, 66.7% pts w/ 5% wt‐loss vs. 17.3% (p<0.0001)

Fig.3 Garvey et al. SEQUEL. AJCN. 2012Fig.2 Allison et al. EQUIP. Obesity. 2011

RCT, 84% completed 2 yrs & 79%maintained 5% wt‐loss 34



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Phentermine/Topiramate Safety

Fig.3 Garvey et al. SEQUEL. AJCN. 201235



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Bupropion/Naltrexone Efficacy

Greenway et al. COR‐I. Lancet 2010. 36



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Bupropion/Naltrexone Safety

Greenway et al. COR‐I. Lancet 2010. 37



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Liraglutide Efficacy

Astrup et al. Liraglutide. Lancet. 200938



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Case 2• MG 48 yo AAF “I’m in too

much pain to exercise”• PMH: depression, chronic

pain, hyperlipidemia– No CVD hx

• BP: 128/78 mmHg• HR: 84 bpm• 285 lbs, 66 in.• BMI: 32.9

• Meds:– bupropion 300 mg XL qday– Fluoxetine 40 mg qday– tramadol 50 mg 2 tabs

q12H– atorvastatin 20 mg HS

• FLP: WNL• BMP: WNL• Has failed lifestyle

changes, but willing toenroll in intensebehavioral program

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You are going to initiate tx for MG,which agent would you select?

A. Bupropion/NaltrexoneB. Phentermine/

TopiramateC. LorcaserinD. Liraglutide

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Case 3• CG 41 yo WM “I just can’t

get rid of this tire aroundmy waist”

• PMH: DMT2,hyperlipidemia, tobaccoabuse, GERD

• BP: 116/70 mmHg• HR: 80 bpm• BMI: 30.5• BMP: WNL• LDL: 173

• A1C= 11.3%• Medications:

– Atorvastatin 40 HS– Lantus 20 u HS– Lisinopril 2.5 mg Qday– Metformin 1000 mg BID

• Attempted 3 months oflifestyle changes,achieved 5% weight loss

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What would be the best agent to helpfurther reduce CG’s weight?


TopiramateC. LorcaserinD. Saxenda

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Case 4• KC 54 yo WF “I just want

to lose those last fewpounds and need somehelp”

• PMH: HTN, tobaccoabuse, GERD, MI (2013)

• BP: 136/78 mmHg• HR: 84 bpm• 145 lbs, 53 in.• BMI: 36.3• BMP: WNL• FLP: WNL

• Medications:– Atorvastatin 80 HS– Lisinopril 20 mg Qday– Metoprolol XL 50 mg Qday– Aspirin 81 mg Qday

• Attempted 3 months oflifestyle changes,achieved 10% weight loss

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What medication will assist KC to helplose additional weight?


TopiramateC. LorcaserinD. Liraglutide

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Summary

• Start with lifestyle changes– This needs to be ingrained!

• Add pharmacotherapy agents– Most studies only looked at 18 65 yo, BMI 27 45– Avoid bupropion/naltrexone with opioids– Avoid phentermine/topiramate in moderate highCV risk

– Avoid lorcaserin with other serotonin agents

Individualize treatment! 45

References1. Ogden C, Carroll M, Kit B, et al. Prevalence of childhood and adult obesity in the united states, 2011 2012. JAMA

2014;311(8):806 814.2. Jensen M, Ryan D, Loria C, et al. 2013 AHA/ACC/TOS Guideline for the management of overweight and obesity in

adults. JACC 2014;63(25):2985 3023.3. Finkelstein E, Trogdon J, Cohen J, et al. Annual medical spending attributable e to obesity: payer and service specific

estimates. Health Affairs 2009;8(5):822 831.4. Torgerson J, Hauptman J, Boldrin M, Sjostrom L. Xenical in the prevention of diabetes in obese subjects study: a

randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obesepatients. 2004;155 161

5. PL Detail Document, Drugs for weight loss. Pharmacist’s Letter/Prescriber’s Letter. November 2014.6. Smith S, Weissman N, Anderson C, et al. Multicenter, placebo controlled trial of lorcaserin for weight management.

NEJM 2010;363:245 56.7. Product Information: BELVIQ(R) oral tablets, lorcaserin hydrochloride oral tablets. Eisai Inc. (per manufacturer),

Woodcliff Lake, NJ, 2012.8. Product Information: QSYMIA(R) oral extended release capsules, phentermine topiramate oral extended release

capsules. VIVUS, Inc (per FDA), Mountain View, CA, 2014.9. Gadde K, Allison D, Ryan D, et al. Effects of low dose, controlled release, phentermine plus topiramate combination

on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebocontrolled, phase 3 trial. Lancet 2011;377:1341 52.

10. Product Information: CONTRAVE(R) oral extended release tablets, naltrexone HCl and bupropion HCl oral extendedrelease tablets. Orexigen Therapeutics, Inc. (per manufacturer), La Jolla, CA, 2014.

11. Greenway F, Fuijaka K, Plodkowski R, et al. Effect of naltrexone plus bupropion on weight loss in overweight andobese adults (COR I): a multicentre, randomised, double blind, placebo controlled, phase 3 trial. Lancet.2010;376:595 605

12. Product Information: SAXENDA(R) subcutaneous injection solution, liraglutide (rDNA origin) subcutaneous injectionsolution. Novo Nordisk Inc. (per manufacturer), Plainsboro, NJ, 2014.

13. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once dailyhuman GLP 1 analog, liraglutide. Obesity. 2012;36:843 854.

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Resources for patients:

• http://www.cdc.gov/healthyweight/• http://win.niddk.nih.gov/publications/choosing.htm

• https://www.supertracker.usda.gov/• http://www.nhlbi.nih.gov/health/educational/lose_wt/index.htm

• http://theweightofthenation.hbo.com/films

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