Israel A. Hartman, MD, FACE Clinical Instructor of ...

Prime Time to Treat ObesityIsrael A. Hartman, MD

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Is It Prime Time to Treat Obesity?

Israel A. Hartman, MD, FACEClinical Instructor of Internal Medicine

UT Southwestern Medical CenterDallas, Texas

Is It Prime Time To Treat Obesity?

! Obesity has many causes, some have a variable genetic component

! Along diet and exercise, drug therapy may be a helpful component for the treatment of the overweight or obese pt

! Role questioned due to efficacy, safety and recurrence

! Decision should be made after careful evaluation of risks and benefits


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Goals of Therapy

! Normal body weight has been proven to be an unrealistic goal

! Weight loss of 5 to 10 percent can significantly reduce the risk for dm and cv disease

! Drug therapy does not cure obesity

Obese Patient Perceptions

! 53% report inappropriate comments from their doctors about their weight.

! Doctors are the second most common source of stigma (69%). (first is family — 72%)

! BMI > 55: 68% report delayed seeking health care because of their weight due to disrespectful treatment, embarrassment, inadequate gowns, equipment and chairs...

Puhl R. Obesit 2006Amy NK. lot J Obes. 2006.


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Lack of Knowledge! "Despite feeling unprepared to treat obesity, 60% of

GPs set stricter weight loss standards for their patients than recommended guidelines.”

! 72% feel poorly prepared by their medical training and report insufficient knowledge regarding nutritional issues

! Feel that treating obesity is professionally unrewarding

Bocquier A. Obes Res. 2005.

When To Use Pharmaceuticals ! Standard of care:

– BMI > 30, BMI > 27 with co morbidities.

! Consider percent body fat – BMI < 27 with high % body fat~sarcopenic obesity – Female > 30% body fat, Male > 25% body fat

! Always use in combination with nutritionalcounseling, behavioral counseling.

! What about maintenance?

!


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PENTHYLAMINES

PHENETHYLAMINESGENERIC NAME TRADE

NAMEDOSE DAILY

DOSAGESERUM HALF LIFE

DEA

PHENTERMINE ADIPEXFASTINIONOMIN

15mg, 30mg, 37.5mg

15mg-37.5mg

19 – 24 hr IV

DIETHYLPROPION TENUATETEPANIL

25MG 75MG

25MG TID75MG TID

4 – 6 HR IV

PHENDIMETRAZINE BONTRIL 35MG 35MG TID 2-10HR III


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SYMPATHOMIMETIC DRUGS

! Approved for short term treatment

! Contraindicated in pt with CAD, HBP, hyperthyroid or HX of drug abuse

! Peak plasma within one or two hr

! Metabolized by liver

! Eliminated by renal route

PHENETHYLAMINES -ANORECTICS

! sympathomimetic effect-release ne from synaptic granules

! work at the level of cns- hypothalamus and limbic system

! appetite suppressant effect- anorectic

! eating behavior effect

! exact mechanism for weight loss unknown


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PHENETHYLAMINESSTUDIES

! Meta-analysis of phentermine and diethylpropion

-3.6 kg weight loss at 6 months for phentermine

-3.0 kg weight loss at 6 months for diethylpropion

Haddock, International J. Obesity, 2002.Li Ann Intern Med. 2005.

ORLISTAT


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ORLISTAT! Approved for long term treatment! Alters fat digestion by inhibiting pancreatic

lipases! Fecal fat is increased on a dose dependent

fashion! Available in 120mg capsules taken 3 times

daily

ORLISTAT EFFICACY

! EXPECTED WEIGHT LOSS OF 8.8 KG

! PLACEBO EFFECT WT LOSS OF 5.5KG

! COST?????

DIABETES CARE 2004;27:55


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ORLISTAT LABEL! May be use long term up to 4 y for weight loss

! Pediatric indication

! Should be accompanied by vitamin supplementation

! Common se: fecal soiling, dyspepsia, flatulence, vitamin malabsorbtion, elevated liver enzymes

! Rare se: severe liver injury

! Contraindications: cholestasis, malabsorbtion, liver disease

LOCARSERIN


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! Mechanism of Action – Selective Serotonin Agonist

– 5-HT2c Receptors in the central nervous system

– Similar to the action of fenfluoramine of Fen-Phen ! Unlike fenfluoramine, lorcaserin presumably does not

stimulate the 5-HT2B receptor on heart valves. ! Shown to reduce hunger and increase satiety.

Lorcaserin

! Three Clinical Studies

! Two studies in patients without DMII

! One study in patients with DMII

! Primary endpoint of all studies– Weight Loss at One Year.

– Assessed as:! Absolute weight loss

! % of patients achieving 5% weight loss

! % of patients achieving 10% weight loss

Lorcaserin – Study Results


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BLOOM

NEJM.!363;!3!July!15,!2010

BLOOM

NEJM.!363;!3!July!15,!2010


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BLOOM

NEJM.!363;!3!July!15,!2010

BLOOM"DM

Obesity!Vol.20!No.7.!July!2012!


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Lorcaserin – Package Insert ! Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMD) –

like reactions. The safety of co administration with otherserotonergic or antidopaminergic agents has not been established.Manage with immediate Belviq discontinuation and providesupportive treatment.

! Valvular heart disease.! Cognitive impairment: May cause disturbances in attention or

memory.

! Psychiatric Disorders: including euphoria and dissociation.! Monitor for depression or suicidal thoughts. Discontinue if

symptoms develop.! Use of Antidiabetic Medications: not been studied in patients

taking insulin.

! Priapism.

!

Phentermine/Topiramate


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! Mechanism of Action – Phentermine

! Sympathomimetic

! Anorectic effect likely mediated by catecholamine release in the hypothalamus.

– Topiramate ! Mechanism of Action for weight loss unknown

! GABAerigic and Carbonic Anhydrase Inhibitor


! Available Doses– 3.75 mg/23 mg– 7.5 mg/46 mg– 11.25 mg/69 mg– 15 mg/92 mg



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!EQUIP: Weight Loss Over Time

!*Data from patients that completed 56 weeks on treatment. !†Statistically greater number of patients completing study on PHEN/TPM ER vs placebo, P<0.0001.

!EQUIP: Weight Loss Over Time

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!(Completer population)*

!Patients Placebo PHEN/TPM ER 7.5/46 PHEN/TPM ER 15/92

!*Data from patients that completed 56 weeks on treatment. !† Statistically greater number of patients completing study on PHEN/TPM ER vs placebo, P<0.0001.

!CONQUER: Weight Loss Over Time CONQUER: Weight Loss Over Time


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Phentermine/Topiramate Package Insert

! Fetal Toxicity:– Females of reproductive potential: Obtain negativepregnancy test before treatment and monthly thereafter.– Use Effective contraception

! Increase in Heart Rate– Monitor heart rate in all patients, especially those withcardiac or cerebrovascular disease history

! Suicidal Behavior/Ideation– Monitor for depression or suicidal thoughts– Discontinue if present

! Acute Myopia and Secondary Angle Closure Glaucoma

! Mood and Sleep Disorders– Consider dose reduction or withdrawal for clinicallysignificant ore persistent symptoms

!

PACKAGE INSERT! Cognitive Impairment

– May cause disturbances in attention or memory.– Caution patients about operating automobiles

or hazardous machinery when starting treatment

! Metabolic Acidosis– Measure electrolytes before/during treatment– Calculate Anion Gap

! Elevated Creatinine– Measure before and during treatment

! Use of Anti-diabetic Medications– Weight loss may cause hypoglycemia– Measure serum glucose before and during treatment


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! GLP-1 Agonists Liraglutide 3mg! Bupropion + Naltrexone

Other Medications Not Yet FDA Approved to Treat Obesity

Similarities Between Food Addiction and Drug Addiction

! PET!scans!show!obese!patients!have!lower!dopamine!levels!

"makes!them!less!sensitive!to!reward!stimuli

"Takes!more!stimulus!(food)!to!gain!pleasure

! Obese!patients!are!more!vulnerable!to!food!intake!as!a!source!of!pleasure!

Wang Jg, Journal Addictive Diseases, 2004


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Bupropion/Naltrexone

! Not currently FDA approved ! Was recommended by FDA committee but FDA

did not approve until a Cardiovascular outcomes study is performed.

! The Light Study is underway. ! Unique Mechanism of Action

– Somewhat independent of the individual mechanisms. – Bupropion ~ Dopamine/nor adrenaline reuptake

inhibitor , stimulates POMC neurons

– Naltrexone ~Opioid receptor antagonist.

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Bupropion + Naltrexone

!

Greenway, F. L., et al. 2009). Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring, Md.) 17(1), 30-9.


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!* Wettergren A, Schjoldager B, Mortensen PE et al. Truncated GLP-!1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665–73.

GLP–1 Mechanisms of Action

! Direct Gut Effect ~ Decreased Gastric Emptying*

! Central Nervous System Effects ~ Mediated through vagal afferents, affecting both the Para ventricular and arcuate nucleus’ in the hypothalamus.

!5 !10 !15 !- 3 I I

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Liraglutide

International Journal of Obesity (2012) 36, 843–854


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Components of Behavioral Therapy

! Social support from family members and friends important for modifying lifestyle behaviors

! Cognitive restructuring teaches patients to think in a positive manner; replace thoughts that undermine weight management effort (cognitive distortions are sabotaging)

! Relapse prevention: expect setbacks; be prepared, view as temporary

! Rewards: congratulate self on successes, not mistakes; plan rewards for achieving goals

Defining Weight Maintenance

! Institute of Medicine—Intentional weight loss of 5% or more maintained for 1 year

! National Institute of Health (NIH) Intentional weight loss of 10% or more maintained for 1 year

! National Weight Control Registry (NWCR)--Weight loss of 30 lbs. or more and maintained for 1 year

Wing RR. Am J Clin Nutr. 2005. Wadden TA. Int J Eat Disord. 1997.


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! Opportunities for pharmacologic treatment have increased significantly in the last year

! Combination therapy is likely to be the mainstay of pharmacologic treatment for obesity in the foreseeable future.

! Combination therapy may include combining bariatric surgery with pharmaceuticals

Conclusions

Israel A. Hartman, MD, FACE Clinical Instructor of ...

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