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Weight loss medications for obesity in adults

Updated 2014 Jun 16 01:58:00 PM: review of pharmacotherapy for weightloss in adults (BMJ 2014 Jun 6) view update Show

more updates

Related Summaries:

Obesity (list of topics)

Weightloss medications for obesity in children and adolescents

Weightloss nonprescription medications and supplements

Weightloss medications withdrawn from market

Obesity in adults

Obesity in children and adolescents

Orlistat

Overview:

weightloss medications may be useful as adjunct to diet and physical activity for patients with

body mass index (BMI) 30 kg/m without concomitant obesity-related risk factors or diseases

BMI 27 kg/m with concomitant obesity-related risk factors or diseases (diabetes, hypertension or dyslipidemia)

medications FDA approved for weightloss include

orlistat (Xenical) 120 mg 3 times daily

orlistat appears modestly effective with mean difference in weightloss 2.9 kg (6.4 lbs) (level 2 [mid-level] evidence)

half-strength orlistat (Alli) may be modestly effective in helping mildly to moderately overweight patients lose weight (level

2 [mid-level] evidence)

reported adverse effects which may lead to high discontinuation rates include flatus with discharge (40%), oily spotting

(33%), fecal urgency (30%), and fecal incontinence (12%)

adverse effects may be reduced by increasing fiber intake (including use of psyllium) and decreasing dietary fat

lorcaserin (Belviq) 10 mg orally twice daily

discontinue if failure to lose 5% weight after 12 weeks

addition of lorcaserin to diet and exercise counseling may increase weightloss in adults (level 2 [mid-level] evidence)

phentermine monotherapy

approved as adjunct to exercise, behavioral modification and caloric restriction in short-term management (a few weeks)

of exogenous obesity

should not be used in combination with either selective serotonin reuptake inhibitor (SSRI) antidepressants or monoamine

oxidase inhibitors (MAOIs)

phentermine plus extended-release topiramate combination (Qsymia) 7.5 mg/46 mg orally once daily

contraindicated in pregnancy

addition of phentermine plus topiramate to lifestyle intervention may increase weightloss in adults (level 2 [mid-level]

evidence)

diethylpropion associated with weightloss in women with obesity (level 2 [mid-level] evidence)

phendimetrazine

other medications have some efficacy for weightloss, but are not FDA approved for this indication

metformin associated with a small amount of weightloss (level 2 [mid-level] evidence)

addition of lorcaserin to diet and exercise counseling may increase weightloss in adults (level 2 [mid-level] evidence)

zonisamide improves weightloss in obese adults receiving diet and lifestyle counseling (level 1 [likely reliable] evidence)

bupropion may promote weightloss in overweight or obese women with binge eating disorder (level 2 [mid-level] evidence)

addition of bupropion to zonisamide might promote weightloss in obese women (level 2 [mid-level] evidence)

topiramate may reduce weight but use limited by high rate of adverse effects (level 2 [mid-level] evidence)

combination of naltrexone and bupropion may increase weightloss (level 2 [mid-level] evidence)

topiramate and metformin each have evidence for efficacy for managing antipsychotic-associated weight gain (level 2

[mid-level] evidence)

in patients with diabetes, medications with some evidence for modest weightloss at 6-12 months include orlistat, canagliflozin,

fluoxetine, GLP-1 agonists (such as exenatide and liraglutide), amylin agonists (including pramlintide) and bupropion (level 2

2

2

DynaMed http://web.b.ebscohost.com.etechconricyt.idm.oclc.org/dynamed/delivery...

1 de 22 07/02/2015 12:13 p. m.


most nonprescription weightloss supplements (other than orlistat) not recommended

orlistat (Alli) is only FDA approved nonprescription weightloss aid

insufficient evidence to support use of other dietary supplements for weightloss

many supplements associated with FDA warnings and alerts

imported diet pills may contain substances banned in United States

antiobesity medications withdrawn from market include

phentermine/fenfluramine (phen-fen)

dexfenfluramine (Redux),

rimonabant (Acomplia, Zimulti)

sibutramine (Meridia)

metformin prevents weight gain associated with atypical antipsychotics (level 1 [likely reliable] evidence)

all medications only FDA approved for short-term therapy but have also been used long-term (JAMA 2014 Jan 1;311(1):74 full-text)

National Heart Lung and Blood Institute (NHLBI) and National Institute of Diabetes and Digestive and Kidney

Diseases (NIDDK) guidelines:

Academy of Nutrition and Dietetics (AND) position statement on weight management:

Orlistat (Xenical):

Recommendations

weightloss medications approved by FDA for long-term use may be useful as adjunct to diet and physical activity for

patients with body mass index (BMI) 30 kg/m without concomitant obesity-related risk factors or diseases (NHLBI

Evidence B)

2

patients with BMI 27 kg/m with concomitant obesity-related risk factors or diseases (such as hypertension, dyslipidemia,

coronary heart disease, type 2 diabetes, and sleep apnea) (NHLBI Evidence B)

2

Reference - JAMA 2014 Jan 1;311(1):74

only use medications as part of comprehensive program that includes behavior therapy, diet and physical activity (NHLBI

Evidence B)

monitor for side effects and efficacy (NHLBI Evidence B)

follow-up visits

at 2-4 weeks, then monthly for 3 months, then every 3 months for first year after initiating medication

to monitor weight, blood pressure, and pulse; discuss side effects; conduct laboratory tests

Reference - NHLBI and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) guidelines for identification,

evaluation and treatment of overweight and obese adults (Arch Intern Med 1998 Sep 28;158(17):1855), guidelines and related

tools can be found at NHLBI

FDA-approved weightloss medications may be part of comprehensive weight management program

Registered Dietitians should collaborate with other members of healthcare team regarding use of FDA-approved weightloss

medications for patients who meet NHLBI criteria

pharmacotherapy may enhance weightloss in some overweight and obese adults

Reference - Academy of Nutrition and Dietetics (AND) position statement on weight management (J Am Diet Assoc 2009

Feb;109(2):330)

Medications FDA Approved for WeightLoss

brand name Xenical for prescription orlistat and Alli for nonprescription orlistat

reversible inhibitor of gastric and pancreatic lipases

orlistat FDA approved as adjunct to reduced-calorie diet in obesity management for patients with initial body mass index > 30

kg/m or > 27 kg/m with other risk factors (for example, hypertension, diabetes, dyslipidemia)2 2

dose 120 mg orally 3 times daily with each of 3 main meals containing fat, may be taken during or up to 1 hour after meal, skip

dose if meal skipped

efficacy

in overweight and obesity

orlistat appears modestly effective in promoting weightloss (level 2 [mid-level] evidence) with mean difference in

weightloss 2.9 kg (6.4 lbs) in Cochrane review of 15 randomized trials

orlistat taken with appropriate diet promotes clinically significant weightloss and reduces weight regain in obese patients

over 2-3 years (level 1 [likely reliable] evidence) with mean difference in weightloss 4.2 kg (9.3 lbs) in single

high-quality randomized trial

half-strength orlistat may be modestly effective in helping mildly to moderately overweight patients lose weight (level 2



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Lorcaserin (Belviq):

orlistat associated with more weightloss in obese patients with binge eating disorder

in patients with diabetes

orlistat may produce modest weightloss (2 kg [4.4 lbs]) over 12-57 weeks in patients with type 2 diabetes (level 2


orlistat may reduce weight and use of antidiabetic medications (level 2 [mid-level] evidence)

addition of orlistat to oral hypoglycemic agents associated with weightloss and improved glycemic control (level 2


for reduction in diabetic or cardiovascular risk factors

orlistat may reduce incidence of type 2 diabetes (level 3 [lacking direct] evidence)

orlistat may prevent or improve impaired glucose tolerance (level 3 [lacking direct] evidence)

orlistat may improve serum lipid levels (level 3 [lacking direct] evidence)

orlistat may reduce blood pressure (level 3 [lacking direct] evidence)

in other diseases

orlistat may reduce weight more than metformin in patients with polycystic ovarian syndrome (level 2 [mid-level]

evidence)

orlistat has mixed results for effects on nonalcoholic fatty liver disease in 2 trials (level 3 [lacking direct] evidence)

cautions and adverse effects

take vitamin supplement containing fat-soluble vitamins at least 2 hours before or after orlistat dose

gastrointestinal side effects common

reported rates include flatus with discharge (40%), oily spotting (33%), fecal urgency (30%), and fecal incontinence

(12%)

may be reduced by increasing fiber intake (including use of psyllium) and decreasing dietary fat

Pregnancy Category B, but use not recommended

contraindicated in patients with chronic malabsorption syndrome or cholestasis

do not administer concomitantly with cyclosporine

FDA warnings include

32 reports of serious liver injury

counterfeit version of Alli sold over the Internet

efficacy of orlistat may not differ in ethnic minorities compared to white Caucasians (level 2 [mid-level] evidence)

based on systematic review with indirect comparisons

systematic review of 18 randomized trials evaluating antiobesity medications in ethnic minorities and white Caucasians 18

years old in the West for 6 months

17 trials in United States and 1 in United Kingdom

comparing ethnic minorities vs. white Caucasians

weightloss with orlistat -2.3 kg (-5.1 lbs) vs. -2.8 kg (-6.2 lbs) (not significant) in analysis of 12 trials with 934 ethnic

minorities and 2,166 white Caucasians

weightloss with sibutramine -2.7 kg (-5.9 lbs) vs. -4.4 kg (-9.7 lbs) (p = 0.0326) in analysis of 6 trials with 341 ethnic

minorities and 964 white Caucasians

Reference - Diabetes Obes Metab 2011 May;13(5):385 EBSCOhost Full Text

DynaMed commentary -- sibutramine has been withdrawn from market due to adverse effects

orlistat may reduce waist circumference in overweight or obese adults (level 3 [lacking direct] evidence)

based on systematic review without clinical outcomes

systematic review of 39 randomized trials evaluating orlistat or lorcaserin in overweight or obese adults

mixed treatment comparison meta-analyses and pair-wise analyses used

orlistat significantly reduced waist circumference at 6 and 12 months in network meta-analysis

compared to placebo (-2.32 cm at 12 months, 95% credible interval -0.98 to -3.65 cm)

compared to standard care (-2.63 cm at 12 months, 95% credible interval -0.26 to 5 cm)

no significant differences in waist circumference at 6 months comparing orlistat vs. metformin; 12-month follow-up not

performed

orlistat significantly increased adverse events compared to placebo

Reference - Diabetes Obes Metab 2014 Mar;16(3):237

see Orlistat for details

lorcaserin (Belviq) FDA approved for chronic weight management as adjunct to reduced-calorie diet and exercise

lorcaserin 10 mg twice daily approved for use in adults with either

body mass index (BMI) 30 kg/m2

BMI 27 kg/m and at least 1 weight-related condition such as2

hypertension


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type 2 diabetes

dyslipidemia

lorcaserin activates serotonin 2C receptor in brain which may increase satiety and reduce amount of food eaten

lorcaserin should be discontinued if failure to lose 5% body weight after 12 weeks

avoid in pregnancy

most common side effects include

in patient without diabetes

headache

dizziness

fatigue

nausea

dry mouth

constipation

in patient without diabetes

hypoglycemia

headache

back pain

cough

fatigue

serious but uncommon side effects may include

serotonin syndrome

disturbances in attention or memory

Reference - FDA Press Release 2012 Jun 27

lorcaserin may reduce waist circumference in overweight or obese adults (level 3 [lacking direct] evidence)

based on systematic review without clinical outcomes

systematic review of 39 randomized trials evaluating orlistat or lorcaserin in overweight or obese adults

mixed treatment comparison meta-analyses and pair-wise analyses used

lorcaserin significantly reduced waist circumference at 3 and 12 months in pair-wise analysis

compared to placebo -2.3 cm at 3 months (95% CI -3.89 to -0.71 cm)

compared to placebo -2.51 cm at 12 months (95% CI -1.99 to -3.04 cm)

no significant difference in adverse events comparing lorcaserin to placebo, standard care, or orlistat

Reference - Diabetes Obes Metab 2014 Mar;16(3):237

addition of lorcaserin to diet and exercise counseling may increase weightloss in adults (level 2 [mid-level]

evidence)

based on 2 randomized trials with high (about 50%) loss to follow-up

4,008 patients aged 18-65 years (80% female) with BMI 30-45 kg/m or BMI 27-29.9 kg/m plus obesity-related condition

had diet and exercise counseling and randomized to lorcaserin 10 mg twice daily vs. lorcaserin 10 mg once daily vs. placebo

for 52 weeks

2 2

55.5% completed trial and 96% analyzed

Efficacy vs. placebo:

Lorcaserin 10 mg Twice Daily Lorcaserin 10 mg Once Daily Placebo

Loss of 5% body weight 47.2% (NNT 5)* 40.2% (NNT 7)* 25%

Loss of 10% body weight 22.6% (NNT 8)* 17.4% (NNT 13)* 9.7%

Mean weightloss 5.8%* 4.7%* 2.8%

Echocardiographic valvulopathy 2% 1.4% 2%

* p < 0.001 vs. placebo.

most common lorcaserin-associated adverse events were

headache (15.6%)

upper respiratory infection (12.7%)

nasopharyngitis (12.5%)

nausea (9.1%)

dizziness (8.7%)

fatigue (8.4%)

statistical comparisons to placebo not reported


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Phentermine monotherapy:

Phentermine-topiramate (Qsymia):

Reference - BLOSSOM trial (J Clin Endocrinol Metab 2011 Oct;96(10):3067)

3,182 obese or overweight adults (mean BMI 36.2 kg/m ) had diet and exercise counseling and were randomized to

lorcaserin 10 mg vs. placebo twice daily for 52 weeks

2

at 52 weeks

patients taking lorcaserin randomized to continue lorcaserin vs. switch to placebo

patients taking placebo continued to receive placebo

55.4% with lorcaserin and 45.1% with placebo completed trial to 52 weeks

comparing lorcaserin vs. placebo at 52 weeks

loss of 5% body weight in 47.5% vs. 20.3% (p < 0.001, NNT 4)

mean weightloss 5.8 kg (12.8 lbs) vs. 2.2 kg (4.9 lbs) (p < 0.001)

of patients taking lorcaserin and losing 5% body weight at 1 year, weightloss maintained during year 2 in 67.9%

continuing lorcaserin vs. 50.3% switching to placebo (p < 0.001, NNT 6)

most common lorcaserin-associated adverse events were

headache (18%)

upper respiratory infection (14.8%)

nasopharyngitis (13.4%)

dizziness (8.2%)

nausea (7.5%)

sinusitis (7.2%)

statistical comparisons to placebo not reported

no significant differences in rates of FDA-defined cardiac valvulopathy at 1 year (2.7% with lorcaserin vs. 2.3% with

placebo)

Reference - BLOOM trial (N Engl J Med 2010 Jul 15;363(3):245 full-text), editorial can be found in N Engl J Med 2010

Jul 15;363(3):288

phentermine FDA approved as adjunct to exercise, behavioral modification, and caloric restriction in short-term management (a

few weeks) of exogenous obesity

should not be used in combination with either

selective serotonin reuptake inhibitor (SSRI) antidepressants

monoamine oxidase inhibitors (MAOIs)

phentermine diffuse-controlled release may increase weightloss (level 2 [mid-level] evidence)

based on randomized trial with high dropout rate

74 patients with obesity and controlled diabetes, hypertension, or dyslipidemia were randomized to phentermine diffuse-

controlled release (DCR) 30 mg vs. placebo once daily for 12 weeks

77% completed trial

comparing phentermine DCR vs. placebo

mean weightloss of 8.1 kg (17.9 lbs) vs. 1.7 kg (3.7 lbs) (p < 0.001)

mean waist circumference reduction of 7.2 cm vs. 2.1 cm (p < 0.001)

5% weightloss in 87% vs. 18% (p < 0.001, NNT 2)

10% weightloss in 49% vs. 3% (p < 0.001, NNT 3)

no significant difference in systolic or diastolic blood pressure

common side effects include

palpitations

tachycardia

increased BP

overstimulation

restlessness

phentermine DCR associated with significant improvement in total cholesterol and low-density lipoprotein cholesterol

Reference - Diabetes Obes Metab 2010 Oct;12(10):876 EBSCOhost Full Text

phentermine plus topiramate combination (Qsymia) FDA approved for treatment of obesity in adults with body mass index (BMI)

30 kg/m or adults with BMI 27 kg/m with 1 weight-related condition2 2

recommended daily dose phentermine 7.5 mg plus topiramate 46 mg extended-release (phentermine 15 mg plus topiramate

92 mg extended-release available for select patients)

contraindicated in pregnancy

Reference - FDA Press Release 2012 Jul 17

addition of phentermine plus topiramate to lifestyle intervention may increase weightloss in adults (level 2


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2,487 overweight or obese adults (mean body mass index [BMI] 27-45 kg/m ) with 2 weight-related comorbidities

(hypertension, dyslipidemia, diabetes or prediabetes, or abdominal obesity) were randomized to 1 of 3 treatments once daily

for 56 weeks

2

controlled-release phentermine 7.5 mg plus topiramate 46 mg

controlled-release phentermine 15 mg plus topiramate 92 mg

placebo

all patients received physician office-based diet and lifestyle intervention for weightloss and metabolic risk reduction

38% discontinued treatment, outcome data unavailable for 31%

mean weightloss at 52 weeks

8.1 kg with phentermine 7.5 mg plus topiramate 46 mg (p < 0.0001 vs. placebo)

10.2 kg with phentermine 15 mg plus topiramate 92 mg (p < 0.0001 vs. placebo)

1.4 kg with placebo

weightloss 5% in

62% with phentermine 7.5 mg plus topiramate 46 mg (p < 0.0001 vs. placebo, NNT 3)

70% with phentermine 15 mg plus topiramate 92 mg (p < 0.0001 vs. placebo, NNT 3)

21% with placebo

phentermine plus topiramate associated with increased dry mouth, paresthesia, constipation, dizziness, and dysgeusia

Reference - CONQUER trial (Lancet 2011 Apr 16;377(9774):1341), correction can be found in Lancet 2011 Apr

30;377(9776):1494, editorial can be found in Lancet 2011 Apr 16;377(9774):1295, commentary can be found in Lancet 2011

Jul 9;378(9786):126

weightloss on phentermine/topiramate at 1 year appears maintained at 2 years with continued treatment

(level 2 [mid-level] evidence)

based on extension of CONQUER trial

866 patients who completed CONQUER trial on treatment and complied with protocol requirements, had BMI 27-45

kg/m , and had 2 weight-related comorbidities were eligible to continue randomized blinded treatment in SEQUEL

extension study

2

females of childbearing age required to continue contraception

676 patients chose to continue in SEQUEL study for additional 52 weeks, representing 85.5% eligible high-dose group,

79.4% eligible low-dose group, and 69.4% eligible placebo group

84% of patients in SEQUEL completed study

in all 3 treatment arms weight remained stable from 56 weeks (completion of CONQUER) to 108 weeks (completion of

SEQUEL)

mean weightloss from baseline to 108 weeks

-1.8% with placebo

-9.3% with phentermine/topiramate 7.5/46 mg (p < 0.0001)

-10.5% with phentermine/topiramate 15/92 mg (p < 0.0001)

Reference - SEQUEL study (Am J Clin Nutr 2012 Feb;95(2):297 PDF)

addition of phentermine plus topiramate to lifestyle intervention associated with reduced rate of type 2

diabetes in overweight adults with prediabetes or metabolic syndrome (level 3 [lacking direct] evidence)

based on nonclinical outcome from subgroup analysis of randomized extension trial above

475 adults (55% of those in extension trial) with prediabetes or metabolic syndrome at beginning of extension trial

were followed for 108 weeks

cumulative incidence rate for type 2 diabetes

2.5% with phentermine 15 mg plus topiramate 92 mg (p < 0.05 vs. placebo, NNT 12)

3.5% with phentermine 7.5 mg plus topiramate 46 mg (p < 0.05 vs. placebo, NNT 13)

11.4% with placebo

mean percent weightloss

12.1% with phentermine 15 mg plus topiramate 92 mg (p < 0.05 vs. placebo)

10.9% with phentermine 7.5 mg plus topiramate 46 mg (p < 0.05 vs. placebo)

2.5% with placebo

Reference - Diabetes Care 2014 Apr;37(4):912 full-text

phentermine/topiramate controlled-release may increase weightloss over 1 year but high dropout rate with

adverse effects of paresthesia, dry mouth, constipation, and dysgeusia (level 2 [mid-level] evidence)


1,267 patients aged 18-70 years with BMI 35 kg/m , triglycerides 200 mg/dL (2.3 mmol/L), blood pressure 140/90

mm Hg, and fasting serum glucose 110 mg/dL (6.1 mmol/L) were randomized to 1 of 3 groups

2


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Diethylpropion (Tenuate):

placebo

phentermine 3.75 mg/topiramate 23 mg controlled-release

phentermine 15 mg/topiramate 92 mg controlled-release

study drug titrated over 4 weeks then given for 52 weeks (total treatment duration 56 weeks)

83% patients were female, 16%-18% were black, mean age 42.7 years, mean BMI 42 kg/m2

60% patients completed the study, 54% took study drug for full intended treatment course

results in intention-to-treat analysis of all randomized patients

Placebo Phentermine/Topiramate 3.75/23 mg Phentermine/Topiramate 15/92 mg

Mean percent weightloss -1.24% -5.25% (p < 0.0001) -12.2% (p < 0.0001)

Weightloss 5% 24.8% 51.1% (p < 0.0001, NNT 4) 74.4% (p < 0.0001, NNT 2)

Weightloss 10% 11.1% 23.1% (p < 0.0001, NNT 9) 57% (p < 0.0001, NNT 3)

Weightloss 15% 4.6% 9.5% (p = 0.0001, NNT 21) 38.4% (p = 0.004, NNT 3)

adverse effects with > 3% incidence and significant differences comparing phentermine 15 mg/topiramate 92 mg vs.

placebo

paresthesia in 18.8% vs. 1.9% (p < 0.0001)

dry mouth in 17% vs. 3.7% (p < 0.0001)

constipation in 14.1% vs. 6.8% (p = 0.0001)

dysgeusia in 8.4% vs. 1% (p < 0.0001)

depression in 4.7% vs. 1.2% (p = 0.0007)

irritability in 4.5% vs. 0.6% (p < 0.0001)

alopecia in 4.3% vs. 1% (p = 0.0008)

anxiety in 3.7% vs. 1.2% (p = 0.0084)

disturbance in attention in 3.5% vs. 0.6% (p = 0.0007)

hypoesthesia in 3.3% vs. 0.8% (p = 0.0039)

Reference - EQUIP trial (Obesity (Silver Spring) 2012 Feb;20(2):330 EBSCOhost Full Text)

phentermine/topiramate extended-release may promote weightloss compared to either drug alone in obese

adults (level 2 [mid-level] evidence)

based on randomized trial with allocation concealment not stated

756 obese adults (mean age 46 years, 79% female) randomized to phentermine/topiramate extended-release (ER) 15/92

mg vs. phentermine/topiramate 7.5/46 mg vs. phentermine 15 mg vs. phentermine 7.5 mg vs. topiramate ER 92 mg vs.

topiramate ER 46 mg vs. placebo for 28 weeks

all patients received lifestyle counseling intervention

phentermine/topiramate 7.5/46 mg and 15/92 mg each associated with higher mean percent weightloss compared to each

monotherapy and placebo (p < 0.05 for each)

5 percent weightloss in

66% with phentermine/topiramate 15/92 mg (p < 0.05 vs. monotherapies and placebo)

62% with phentermine/topiramate 7.5/46 mg (p < 0.05 vs. monotherapies and placebo)

43.3%-46.2% with phentermine monotherapy

39.2%-48.6% with topiramate monotherapy

15.5% with placebo

Reference - EQUATE trial (Obesity (Silver Spring) 2013 Nov;21(11):2163)

common side effects include

paresthesia

dizziness

altered taste sensation

insomnia

constipation

dry mouth

Reference - FDA approval July17 2012

DynaMed commentary -- some of these side effects may be related to the individual drugs, not the drug combination. See

Phentermine and Topiramate for details on specific side effects of individual drugs.

dosing of diethylpropion

conventional tablets (25 mg) orally 3 times daily, 1 hour before meals, give additional 25 mg in midevening if needed to

overcome hunger

extended release tablets (75 mg) once daily in midmorning


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Phendimetrazine (Bontril):

Long-term therapy:

see Diethylpropion drug topic for full prescribing information including use in children

cautions

diethylpropion associated with increased risk of pulmonary hypertension, hyperthyroidism, severe hypertension, glaucoma,

or advanced arteriosclerosis

diethylpropion should not be used within 14 days of monoamine oxidase inhibitors (MAOIs) or in combination with other

anorexigenic drugs

see Diethylpropion drug topic for full cautions and adverse effects

diethylpropion associated with weightloss in women with obesity (level 2 [mid-level] evidence)


180 premenopausal women with obesity were randomized to 1 of 5 regimens for 52 weeks

diethylpropion 75 mg/day

fenproporex 25 mg/day

mazindol 2 mg/day

uoxetine 20 mg/day

sibutramine 15 mg/day

placebo

129 (71.6%) women completed study

comparing diethylpropion vs. placebo

mean weightloss 10 kg (22 lbs) vs. 3.1 kg (6.8 lbs) (p < 0.001)

5% weightloss in 71.4% vs. 33.3% (p < 0.02)

10% weightloss in 64.3% vs. 7.45% (p < 0.001)

adverse events with diethylpropion included constipation (p < 0.01), anxiety (p = 0.01) and irritability (p = 0.02)

Reference - Int J Obes (Lond) 2014 Aug;38(8):1097

DynaMed commentary -- sibutramine has been withdrawn from market due to adverse effects

dosing of phendimetrazine

give conventional tablets (35 mg) orally 2 or 3 times daily, 1 hour before meals

extended-release capsules (105 mg) orally once daily, 30-60 minutes before the morning meal

see Phendimetrazine drug topic for full prescribing information including use in children

cautions

phendimetrazine associated with increased risk of symptomatic cardiovascular disease, hyperthyroidism, moderate to severe

hypertension, pulmonary hypertension, glaucoma, or advanced arteriosclerosis

phendimetrazine should not be used within 14 days of monoamine oxidase inhibitors (MAOIs) or in combination with other

central nervous system (CNS) stimulants or other anorexigenic drugs

see Phendimetrazine drug topic for full cautions and adverse effects

phendimetrazine reported to be prescribed for weightloss in 18% of adults with obesity and 39% reported to

continue long-term use with phendimetrazine

based on survey of 266 physicians specializing in obesity

60% of physicians report prescribing phendimetrazine for weightloss

18% of patients (average) were prescribed phendimetrazine by physicians

39% of physicians report prescribing phendimetrazine longer than approved use

Reference - Obesity (Silver Spring) 2009 Sep;17(9):1730

phendimetrazine for weightloss in adults with obesity evaluated in 2 older studies (Curr Ther Res Clin Exp 1962 May;4:270, J Clin

Pharmacol J New Drugs 1968 Mar-Apr;8(2):113); no recent trials or systematic reviews found evaluating phendimetrazine for

weightloss in adults with obesity

most medication approved for short-term (a few weeks) treatment of obesity, but obesity is a chronic condition requiring

long-term treatment

long-term orlistat, lorcaserin, or phentermine plus topiramate extended release associated with additional

weightloss when prescribed with lifestyle interventions in adults with obesity (level 2 [mid-level] evidence)

based on systematic review without assessment of trial quality

review of 21 studies (20 randomized trials and 1 systematic review) evaluated orlistat, lorcaserin or top dose (15/92 mg)

phentermine plus topiramate-extended releaseweightloss in adults with obesity treated with nonadrenergic agents with

lifestyle interventions

proportion of patients losing 5% of baseline weight at 1 year

orlistat ranging from 35% to 75%

lorcaserin ranging from 37% to 47%


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Antidiabetic agents:

Metformin:

Glucagon-like peptide-1 receptor (GLP-1) agonists:

phentermine plus topiramate-extended release 67%-70%

all 3 medications may improve cardio-metabolic risk factors, none were shown to reduce cardiovascular mortality or

morbidity

Reference - JAMA 2014 Jan 1;311(1):74 full-text, commentary can be found in JAMA 2014 May 7;311(17):1807

phentermine monotherapy associated with weightloss in adults with obesity (level 2 [mid-level] evidence)

based on systematic review without assessment of trial quality

systematic review of 6 randomized trials comparing phentermine monotherapy to placebo for weightloss in adults with

obesity

trial duration ranged from 2-24 weeks

phentermine associated with average 6.3 kg weightloss compared to 2.8 kg with placebo in analysis of 6 trials (no p value

reported)

Reference - Int J Obes Relat Metab Disord 2002 Feb;26(2):262

Off-label Use of Other Prescription Drugs

metformin FDA approved for type 2 diabetes but not FDA approved for obesity

metformin may be associated with small amount of weightloss (level 2 [mid-level] evidence)

based on systematic review without meta-analysis

systematic review of 9 randomized blinded trials of metformin in adults with body mass index 25 kg/m or waist-to-hip

ratio > 0.8

2

trials excluded if patients had diabetes mellitus, polycystic ovary syndrome or descriptors of polycystic ovary syndrome, HIV

infection, or concomitant antipsychotics

2 of 9 trials showed statistically significant reductions in weight

6 other trials reported nonsignificant reductions in weight

1 trial did not report weight outcome but found no differences in body mass index or waist-to-hip ratio

mean weight reductions compared with placebo ranged from 0.4 kg (1 lb) to 2.15 kg (4.7 lbs) in these trials

insufficient similar information from each trial to conduct a meta-analysis

Reference - Ann Fam Med 2005 Sep-Oct;3(5):457 full-text, commentary can be found in Ann Fam Med 2005

Nov-Dec;3(6):556

see below for use of metformin in patients taking antipsychotics

see Metformin for additional information

exenatide (Byetta) FDA approved for diabetes mellitus type 2 but not FDA approved for obesity

exenatide twice daily plus lifestyle modification may increase weightloss in obese patients with and without

prediabetes (level 2 [mid-level] evidence)


163 obese adults without diabetes and with normal or impaired glucose tolerance or impaired fasting glucose were

randomized to exenatide 10 mcg twice daily vs. placebo for 24 weeks

all patients had lifestyle intervention

63% completed treatment

comparing exenatide vs. placebo

mean weightloss 5.1 kg (11.2 lbs) vs. 1.6 kg (3.5 lbs) (p < 0.001)

5% body weight reduction in 32% vs. 17% (p = 0.039, NNT 7)

withdrawal rate 34% vs. 32% (not significant)

no deaths, serious adverse events, or hypoglycemia observed

Reference - Diabetes Care 2010 Jun;33(6):1173 full-text

liraglutide

high-dose liraglutide associated with greater weightloss compared to placebo or orlistat (level 2 [mid-level]

evidence)

based on randomized trial without blinding

564 adults without diabetes type 2 and with body mass index (BMI) 30-40 kg/m randomized to liraglutide (1.2 mg, 1.8

mg, 2.4 mg, or 3 mg) vs. placebo subcutaneously once daily vs. orlistat 120 mg orally 3 times daily for 20 weeks

2

all adults had 500 kcal/day energy-deficit diet and increased physical activity throughout trial

mean weightloss

4.8-7.2 kg with liraglutide

2.8 kg with placebo (p = 0.0001 vs. any liraglutide dose)


9 de 22 07/02/2015 12:13 p. m.

Pramlintide:

4.1 kg with orlistat (p < 0.01 vs. liraglutide 2.4 and 3 mg doses only)

> 5% weightloss

52.1%-76.1% with any liraglutide dose

30% with placebo (p < 0.05 vs. any liraglutide dose)

44% with orlistat (p < 0.0001 vs. liraglutide 3 mg only)

all liraglutide doses associated with reduced blood pressure, and doses > 1.2 mg associated with reduction in

prediabetes

Reference - Lancet 2009 Nov 7;374(9701):1606, correction can be found in Lancet 2010 Mar 20;375(9719):984,

editorial can be found in Lancet 2009 Nov 7;374(9701):1570

editorial discussion on FDA approval of liraglutide can be found in N Engl J Med 2010 Mar 4;362(9):774

glucagon-like peptide-1 (GLP-1) receptor agonists for 20 weeks associated with increased weightloss

compared to control in overweight or obese patients with or without type 2 diabetes (level 2 [mid-level]

evidence)

based on systematic review limited by heterogeneity

systematic review of 25 randomized trials comparing GLP-1 agonists to control in overweight or obese (body mass index

[BMI] 25) adults with or without type 2 diabetes

GLP-1 agonists included exenatide twice daily, exenatide once weekly, or liraglutide once daily for 20 weeks

control included placebo, oral antidiabetic drugs, or insulin

GLP-1 agonists associated with significantly greater weightloss

mean difference -2.9 kg (-6.4 lbs) (95% CI -3.6 to -2.2 kg [-7.9 to -14.8 lbs]) in overall analysis of 21 trials with 6,411

adults, results limited by significant heterogeneity

mean difference -3.2 kg (-7 lbs) (95% CI -4.3 to -2.1 kg [-9.5 to -4.6 lbs]) in analysis of 3 trials of adults without type 2

diabetes

mean difference -2.8 kg (-6.2 lbs) (95% CI -3.4 to -2.3 kg [-7.5 to -5.1 lbs]) in analysis of 18 trials of adults with type 2

diabetes

GLP-1 agonists also associated with significantly greater improvement in blood pressure, cholesterol levels, and glycemic

control

Reference - BMJ 2012 Jan 10;344:d7771 full-text, editorial can be found in BMJ 2012 Jan 10;344:d7282

GLP-1 receptor agonists do not appear to increase risk of pancreatitis in patients with type 2 diabetes (level 2


based on systematic review with assessment of trial quality not reported

systematic review of 41 randomized trials 12 weeks evaluating effect of GLP-1 receptor agonists in 14,972 patients with

type 2 diabetes (14,333 patient-years of exposure)

in 9 trials that reported presence of pancreatitis events, comparators included sitagliptin, glargine, glimepiride, pioglitazone,

rosiglitazone, and placebo

no significant difference in pancreatitis between GLP-1 receptor agonists and comparators in analysis of 9 trials with 5,351

patients (odds ratio 1.01, 95% CI 0.37-2.76)

Reference - Diabetes Res Clin Pract 2014 Feb;103(2):269

pramlintide associated with weightloss in patients with obesity (level 2 [mid-level] evidence)

based on systematic review of trials with methodologic limitations

systematic review of 8 randomized trials evaluating pramlintide 120-150 mcg twice or three times daily in 1,616 obese

patients (with or without type 2 diabetes)

methodologic limitations included unclear or inadequate randomization method, allocation concealment and blinding

4 trials compared pramlintide to placebo in obese patients without type 2 diabetes

pramlintide associated with significantly greater weightloss (- 2.27 kg, 95% CI -2.88 to -1.86 kg [-5 lbs, 95% CI -6.35 to -4.1

lbs]) than control in analysis of 9 comparisons of 755 obese patients without type 2 diabetes

no significant difference in nausea in analysis of 3 studies of obese patients without diabetes, results limited by

heterogeneity

Reference - Diabetes Obes Metab 2011 Feb;13(2):169 EBSCOhost Full Text

addition of pramlintide to lifestyle intervention associated with short-term weightloss, which might be

maintained at 12 months with high doses (level 2 [mid-level] evidence)

based on randomized trial with high dropout rates

411 obese patients receiving lifestyle intervention for weightloss randomized to pramlintide (120, 240, and 360 mcg 2-3

times daily) vs. placebo for 4 months

67.9% completed 4-month trial

mean weightloss from baseline 3.8-6.1 kg with pramlintide vs. 2.8 kg with placebo (p < 0.05 for 120 mcg twice daily and

360 mcg 2 or 3 times daily only)


10 de 22 07/02/2015 12:13 p. m.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors:

8-month extension in 209 patients

72% of patients who entered extension withdrew before completion

initial 4-month weightloss maintained in all groups except 120 mcg twice daily and placebo groups

Reference - Diabetes Care 2008 Sep;31(9):1816 full-text

combination pramlintide plus metreleptin (recombinant human leptin) may be associated with more weightloss

than either drug alone in overweight and obese patients (level 2 [mid-level] evidence)


177 patients aged 18-55 years with BMI 27-35 kg/m entered 4-week run-in period with 40% caloric deficit diet and

pramlintide (180 mcg subcutaneously twice daily before breakfast and dinner, then increased to 360 mcg twice daily)

2

139 patients who achieved 2%-8% weightloss during run-in period were randomized to 1 of 3 groups (and continued 20%

caloric deficit diet) for 20 weeks

pramlintide 360 mcg plus placebo subcutaneously twice daily

metreleptin 5 mg plus placebo subcutaneously twice daily

pramlintide 360 mcg plus metreleptin 5 mg subcutaneously twice daily

comparing pramlintide vs. metreleptin vs. combination

mean weightloss 7.5% vs. 7.9% vs. 10.8% (p < 0.05)

mean weightloss 7.2 kg vs. 7.2 kg vs. 9.9 kg (p < 0.05)

Reference - Proc Natl Acad Sci U S A 2008 May 20;105(20):7257 full-text

canagliflozin (Invokana) tablets FDA approved for use in combination with diet and exercise to improve glycemic control in adults

with type 2 diabetes (FDA Press Release 2013 Mar 29)

addition of canagliflozin to physical activity and nutritional intervention may decrease body weight and body

mass index in patients without type 2 diabetes but may increase genital mycotic infection in women (level 2


based on randomized trial with differential loss to follow-up

376 patients (mean age 45 years) without type 2 diabetes and with body mass index 30-49 kg/m or 27 kg/m and

relevant comorbidities were randomized to 1 of 4 oral capsule treatments for 12 weeks

2 2

placebo (20.2% did not complete treatment)

canagliflozin 50 mg (21.4% did not complete treatment)



all patients received nutritional counseling and were encouraged to engage in physical activity for 4-week run-in period prior

to randomization; patients encouraged to maintain these changes throughout trial

comparing canagliflozin (all doses) vs. placebo

Treatment Body Weight (Mean

Change From Baseline)

BMI (Mean Change

From Baseline)

Proportion of Patients With 5% Loss

in Body Weight (From Baseline)

Placebo -1.1 kg (-2.4 lbs) -0.4 kg/m 8%

Canagliflozin 50

mg

-1.9 kg* (-4.2 lbs) -0.7 kg/m * 13%

Canagliflozin

100 mg

-2.8 kg* (-6.2 lbs) -1 kg/m * 19%* (NNT 9)

Canagliflozin

300 mg

-2.4 kg* (-5.3 lbs) -0.9 kg/m * 17%* (NNT 11)

Abbreviation: BMI, body mass index.

* p < 0.05 compared to placebo.

2

2

2

2

no significant differences in waist circumference, hip circumference, or waist/hip ratio among groups

overall incidence of adverse events was similar across groups and most adverse events were mild to moderate

among adverse events occurring in 5% in any group, canagliflozin associated with higher incidence of vulvovaginal

mycotic infection, nausea, and sinusitis compared to placebo

Reference - Obesity (Silver Spring) 2014 Apr;22(4):1042 full-text

addition of canagliflozin associated with weightloss in patients with type 2 diabetes inadequately controlled with

metformin (level 2 [mid-level] evidence)


451 adults with type 2 diabetes inadequately controlled with metformin randomized to 1 of 7 treatments for 12 weeks


11 de 22 07/02/2015 12:13 p. m.

Selective serotonin reuptake inhibitors (SSRIs):

Fluoxetine:

canagliflozin 50 mg once daily




canagliflozin 300 mg twice daily

sitagliptin 100 mg once daily

placebo

mean body mass index 31.5 kg/m , and 56% were classified as obese (BMI 30 kg/m )2 2

body weight reduced by

mean 2-2.9 kg (4.4-6.4 lbs) with all canagliflozin doses vs. 0.8 kg (1.8 lbs) with placebo (p < 0.001 for all)

mean 0.4 kg (0.9 lbs) with sitagliptin (not significant vs. placebo)

adverse events were mainly mild to moderate and balanced across arms, except canagliflozin associated with increased

incidence of genital infections in females

Reference - Diabetes Care 2012 Jun;35(6):1232 full-text

canagliflozin may reduce body weight compared to sitagliptin in patients with type 2 diabetes inadequately

controlled with metformin plus sulfonylurea (level 2 [mid-level] evidence)


755 patients with type 2 diabetes inadequately controlled with metformin plus sulfonylurea were randomized to canagliflozin

300 mg vs. sitagliptin 100 mg orally once daily and followed for 52 weeks

39% did not complete trial but all patients included in modified intention-to-treat analysis

patients continued to receive metformin and sulfonylurea at maximal or near-maximal effective doses for trial duration

mean body mass index 31.6 kg/m2

comparing canagliflozin vs. sitagliptin, mean change from baseline in

body weight -2.3 kg (5.1 lbs) vs. +0.1 kg (0.2 lbs) (p < 0.001)

HbA1c -1% vs. -0.7% (p < 0.05)

similar risk of hypoglycemia and overall incidence of adverse events, but canagliflozin associated with increased risk of

genital mycotic infection (no p value reported)

Reference - Diabetes Care 2013 Sep;36(9):2508

canagliflozin 100 mg and 300 mg associated with more weightloss than glimepiride in patients with type 2

diabetes inadequately controlled with metformin (level 2 [mid-level] evidence)

based on secondary outcome from randomized noninferiority trial

1,452 patients aged 18-80 years with type 2 diabetes inadequately controlled with metformin (HbA1c 7%-9.5%) randomized

to canagliflozin (300 mg vs. 100 mg) vs. glimepiride (titrated to 6 or 8 mg/day) orally once daily for 1 year

at baseline

all patients received metformin 1,500 mg/day for 10 weeks

mean body mass index 31 kg/m2

noninferiority defined as margin of 0.3% for the comparison of each canagliflozin dose with glimepiride for mean change in

HbA1c in modified intention-to-treat analyses

80% completed trial and 99% were included in modified intention-to-treat analyses

mean change in body weight from baseline

+0.7 kg (1.5 lbs) with glimepiride

-3.7 kg (8.1 lbs) with canagliflozin 100 mg (p < 0.0001 vs. glimepiride)

-4 kg (8.8 lbs) with canagliflozin 300 mg (p < 0.0001 vs. glimepiride)

genital mycotic infections more frequent with canagliflozin 100 mg and 300 mg (no p values reported vs. glimepiride)

Reference - CANTATA-SU trial (Lancet 2013 Sep 14;382(9896):941), editorial can be found in Lancet 2013 Sep

14;382(9896):917

DynaMed commentary -- glimepiride usual maintenance dosage is 1-4 mg once daily with maximum of 8 mg once daily

fluoxetine use may be associated with weightloss (level 2 [mid-level] evidence)

based on systematic review and meta-analysis of trials with uncertain allocation concealment

11 randomized trials of fluoxetine vs. placebo for treatment of obesity reviewed

mean duration of treatment 28 weeks

mean additional weightloss with fluoxetine 3.3 kg (7.2 lbs) vs. placebo (approximate effect size 0.5, 95% CI 0.3 -0.6)

Reference - Int J Obes Relat Metab Disord 2002 Feb;26(2):262 EBSCOhost Full Text

"phen-pro" regimen has been used instead of "phen-fen" since fenfluramine withdrawn from market, but not

recommended


12 de 22 07/02/2015 12:13 p. m.

Sertraline:

Antiepileptic drugs:

Topiramate:

Zonisamide:

"phen-pro" consists of phentermine 30 mg and fluoxetine 10 or 20 mg, but published evidence extremely limited

"phen-pro" not associated with valvular heart disease in random testing of 60 patients (Arch Intern Med 1998 Jun

8;158(11):1278)

combination of "phen-pro" and cognitive behavioral therapy reported to be reduce binge eating (level 3 [lacking direct]

evidence)

based on case series of 16 obese women

significant weight regain (especially after medication discontinuation)

Reference - Int J Eat Disord 2000 Nov;28(3):325 EBSCOhost Full Text

sertraline associated with weightloss in patients with night eating syndrome (level 2 [mid-level] evidence)

based on small randomized trial

34 patients with night eating syndrome randomized to sertraline 50-200 mg/day vs. placebo for 8 weeks

71% sertraline vs. 18% placebo patients were much or very much improved (NNT 2)

among 28 overweight and obese patients, mean weightloss was 2.9 kg (6.4 lbs) with sertraline vs. 0.3 kg (0.7 lbs) with

placebo

Reference - Am J Psychiatry 2006 May;163(5):893

topiramate may reduce weight but use limited by high rate of adverse effects (level 2 [mid-level] evidence)

based on 3 randomized trials with high dropout rates or early trial termination

topiramate associated with reductions in weight and systolic blood pressure (level 2 [mid-level] evidence)

based on randomized trial with early trial termination

531 patients with obesity (mean body mass index [BMI] 35 kg/m ) and hypertension (mean blood pressure 144/90 mm

Hg) randomized to placebo vs. topiramate 96 mg/day vs. topiramate 192 mg/day for 60 weeks

2

trial terminated early with plans to develop controlled-release formulation; 214 patients with potential for being in trial

for 28 weeks were evaluated

topiramate doses titrated from initial 16 mg/day

comparing placebo vs. topiramate 96 mg/day vs. topiramate 192 mg/day

mean weightloss 1.9% vs. 5.9% vs. 6.5%

mean reduction in systolic blood pressure 4.9 vs. 8.6 vs. 9.7 mm Hg

15% rate of adverse effects in high-dose group including paresthesia, fatigue, taste perversion, loss of appetite, and

difficulty concentrating

Reference - Am J Cardiol 2005 Jul 15;96(2):243

topiramate may decrease binge eating and increase weightloss (level 2 [mid-level] evidence)


61 patients with binge eating disorder and BMI > 30 kg/m were randomized to topiramate (initially 25 mg/day, titrated

to maximum 600 mg/day) vs. placebo for 14 weeks

2

topiramate reduced binge frequency and binge day frequency

topiramate improved global impression and obsessive compulsive scores

mean weightloss 5.9 kg (13 lbs) with topiramate vs. 1.2 kg (2.6 lbs) with placebo

only 58% patients completed 14 weeks of treatment

20% topiramate vs. 9.7% placebo patients discontinued due to adverse effects, most common reasons for stopping

topiramate were headache and paresthesias

Reference - Am J Psychiatry 2003 Feb;160(2):255 full-text, commentary can be found in Am Fam Physician 2003 Jun

15;67(12):2580

zonisamide 400 mg improves weightloss more than zonisamide 200 mg or placebo in obese adults receiving diet

and lifestyle counseling (level 1 [likely reliable] evidence)

based on randomized trial

225 obese adults (mean age 43 years, mean body mass index 37.6 kg/m ) without diabetes randomized to zonisamide 200

mg or 400 mg per day vs. placebo, in addition to dietitian-led diet and lifestyle counseling for 1 year

2

97% analyzed at 1 year

weightloss at 1 year

7.3 kg (16.1 lbs) for zonisamide 400 mg (p = 0.009 vs. placebo)

4.4 kg (9.7 lbs) for zonisamide 200 mg (not significant vs. placebo)

4 kg (8.8 lbs) for placebo


13 de 22 07/02/2015 12:13 p. m.

Naltrexone plus bupropion:

10% weightloss in

32% for zonisamide 400 mg (p < 0.001 vs. placebo, NNT 5)

22.4% for zonisamide 200 mg (p = 0.02 vs. placebo, NNT 7)

8.1% for placebo

gastrointestinal, nervous system, and psychiatric adverse events more common with zonisamide 400 mg (no p values

reported vs. placebo)

Reference - Arch Intern Med 2012 Nov 12;172(20):1557, editorial can be found in Arch Intern Med 2012 Nov

12;172(20):1565 and commentary can be found in JAMA 2013 Aug 14;310(6):637

zonisamide associated with weightloss (level 2 [mid-level] evidence)


60 obese adults (mean BMI 36.3 kg/m ) randomized to zonisamide (100 mg/day increased up to 400-600 mg/day) vs.

placebo orally for 16 weeks

2

all given reduced-calorie diet instructions

51 (85%) completed 16 weeks of treatment

mean weight change was -0.9 kg (2 lbs) with placebo vs. -5.9 kg (13 lbs) with zonisamide

5% weightloss attained in 10% placebo patients vs. 57% zonisamide patients

Reference - JAMA 2003 Apr 9;289(14):1820, commentary can be found in J Fam Pract 2003 Aug;52(8):600 EBSCOhost

Full Text

DynaMed commentary

FDA declined to approve extended-release naltrexone/bupropion combination tablet (Contrave)

reconsideration planned after long-term study to evaluate cardiac risk

summary of Contrave data can be found in FDA Briefing Document 2010 Dec 7 PDF

sustained-release naltrexone plus bupropion associated with increased weightloss (level 2 [mid-level] evidence)

based on randomized trial without intention-to-treat analysis

1,742 patients aged 18-65 years with body mass index (BMI) 30-45 kg/m and uncomplicated obesity or BMI 27-45 kg/m

with dyslipidemia or hypertension randomized to 1 of 3 treatments for 56 weeks

2 2

sustained-release naltrexone 16 mg plus bupropion 180 orally twice daily

sustained-release naltrexone 8 mg plus bupropion 180 orally twice daily

placebo orally twice daily

50% dropped out

1,453 patients (83%) included in analysis (patients with baseline and postbaseline weight measurements)

mean change in bodyweight (comparison vs. placebo)

-6.1 kg (-13 lbs) with naltrexone 32 mg plus bupropion (p < 0.0001)

-4.9 kg (-11 lbs) with naltrexone 16 mg plus bupropion (p < 0.0001)

-1.4 kg (-4 lbs) with placebo

patients achieving 5% decrease in bodyweight (comparison vs. placebo)

48% with naltrexone 32 mg plus bupropion (p < 0.0001)

39% with naltrexone 16 mg plus bupropion (p < 0.0001)

16% with placebo

naltrexone plus bupropion associated with increased risk of nausea, headache, constipation, dizziness, vomiting and dry

mouth

Reference - COR-I trial (Lancet 2010 Aug 21;376(9741):595), corrections can be found in Lancet 2010 Aug

21;376(9741):594, Lancet 2010 Oct 22;376(9750):1392, editorial can be found in Lancet 2010 Aug 21;376(9741):567,

commentary can be found in Evid Based Med 2011 Apr;16(2):53

addition of naltrexone plus bupropion to intensive behavior modification and diet associated with increased

weightloss (level 2 [mid-level] evidence)


793 patients aged 18-65 years with body mass index (BMI) 30-45 kg/m or BMI 27-45 kg/m with controlled hypertension or

dyslipidemia randomized to combination tablet containing naltrexone sustained-release 8 mg plus bupropion sustained-

release 90 mg orally 2 tablets twice daily vs. placebo for 56 weeks

2 2

all patients received energy-reduced diet and intensive behavior modification in 28 group sessions

42% completed treatment

comparing naltrexone plus bupropion vs. placebo at week 56

weightloss in 9.3% vs. 5.1% (p < 0.001, NNT 24)

weightloss in patients completing treatment in 11.5% vs. 7.3% (p < 0.001, NNT 24)

weightloss 5% initial weight in 80.4% vs. 60.4% (p < 0.001, NNT 5)

weightloss 10% initial weight in 55.2% vs. 30.2% (p < 0.001, NNT 4)


14 de 22 07/02/2015 12:13 p. m.

Bupropion:

Human chorionic gonadotropin (HCG):

nausea most frequent adverse event in 34.1% vs. 10.5% (p < 0.001, NNH 4)

Reference - COR-BMOD trial (Obesity (Silver Spring) 2011 Jan;19(1):110 EBSCOhost Full Text)

combination of naltrexone and bupropion may increase weightloss (level 2 [mid-level] evidence)


419 obese persons aged 18-60 years randomized to 1 of 6 treatments for 24 weeks

placebo

naltrexone 48 mg/day

bupropion 400 mg/day

naltrexone 16 mg/day plus bupropion 400 mg/day



40.8% dropped out

mean weightloss at 24 weeks

0.9 kg (2 lbs) for placebo

1.1 kg (2.4 lbs) for naltrexone alone

2.6 kg (6 lbs) for bupropion alone

5.1 kg (11 lbs) for naltrexone 16 mg/day plus bupropion (p < 0.05 vs. naltrexone, vs. bupropion and vs. placebo)

5.1 kg (11 lbs) for naltrexone 32 mg/day plus bupropion (p < 0.05 vs. naltrexone, vs. bupropion and vs. placebo)

4 kg (9 lbs) for naltrexone 48 mg/day plus bupropion (p < 0.05 vs. naltrexone and vs. placebo)

Reference - J Clin Endocrinol Metab 2009 Dec;94(12):4898

naltrexone reported to reduce body mass index in 3-6 months in obese women with polycystic ovary syndrome

(level 3 [lacking direct] evidence)

based on case series

10 obese women aged 18-26 years with polycystic ovary syndrome were treated with naltrexone 25 mg/day for 15 days,

then dose increased to 50 mg/day for 6 months

all women lost weight during treatment (range 2-19 kg [4.4-41.8 lbs])

mean body mass index was

29.9 kg/m at baseline2

27 kg/m at 3 months (p < 0.0001 vs. baseline)2

26.1 kg/m at 6 months (p < 0.0001 vs. baseline)2

Reference - Fertil Steril 2002 May;77(5):936, commentary can be found in Fertil Steril 2003 Mar;79(3):659

bupropion may promote weightloss in overweight or obese women with binge eating disorder (level 2 [mid-level]

evidence)


61 overweight or obese women (mean body mass index [BMI] 35.8 kg/m ) with binge eating disorder were randomized to

bupropion 150 mg twice daily (once daily for first 3 days) vs. placebo for 8 weeks

2

54 women (89%) completed trial but all patients included in analyses with missing data replaced with baseline values

mean reduction in BMI 1.8% with bupropion vs. 0.6% with placebo (p = 0.002)

no significant differences in binge eating frequency or severity of food cravings or depression

Reference - J Clin Psychiatry 2013 Apr;74(4):400

addition of bupropion to zonisamide might promote weightloss in obese women (level 2 [mid-level] evidence)

based on small randomized trial without blinding

18 obese women (mean body mass index 36.8 kg/m ) randomized to zonisamide plus bupropion vs. zonisamide alone for 12

weeks

2

zonisamide started at 100 mg/day and gradually increased to 400 mg/day over 4 weeks

bupropion started at 100 mg/day and increased to 200 mg/day after 2 weeks

all women prescribed hypocaloric (500 kcal/day deficit), balanced diet

zonisamide plus bupropion associated with greater body weightloss compared to zonisamide alone (mean -7.2 kg [15.8 lbs]

vs. -2.9 kg [6.4 lbs], p = 0.003)

Reference - J Clin Psychiatry 2007 Aug;68(8):1226

no evidence to support use of HCG for treatment of obesity, weightloss, distribution of fat, or decreasing hunger and discomfort

associated with calorie-restricted diets (FDA DailyMed 2006 Mar)

HCG with Simeons diet not associated with weightloss in women with obesity (level 2 [mid-level] evidence)

based on systematic review

review of 24 studies (8 randomized trials and 16 cohort studies) evaluating HCG with Simeons diet in women with obesity


15 de 22 07/02/2015 12:13 p. m.

Simeons diet defined as fat-free diet consisting of 500 kcalories/ day plus HCG 125 units intramuscularly every day for 3.5 to

6 weeks

only 1 study demonstrated association between Simeons diet with HCG and weightloss

Reference - Br J Clin Pharmacol 1995 Sep;40(3):237 full-text

HCG not associated with weightloss in obese women (level 2 [mid-level] evidence)


40 women with BMI > 30 kg/m started diet (5,000 kilojoules [kJ]/day) and were randomized to HCG vs. placebo

intramuscularly 6 days/week for 6 weeks

2

no significant differences between groups in body weight, psychological profile or hunger levels

Reference - S Afr Med J 1990 Feb 17;77(4):185 PDF

WeightLoss Medications in Patients with Diabetes

orlistat (Xenical, Alli)

FDA approved for adjunctive therapy in addition to lifestyle changes (diet, exercise) in patients with

body mass index (BMI) > 30 kg/m2

BMI > 27 kg/m and diabetes, hypertension, or dyslipidemia2

dosing of orlistat (Xenical) 120 mg orally 3 times daily with fat-containing meals

orlistat may produce modest weightloss (2 kg [4.4 lbs]) over 12-57 weeks in patients with type 2 diabetes (level 2


addition of orlistat to oral antidiabetic agents may improve weightloss (level 2 [mid-level] evidence) and glycemic control

(level 3 [lacking direct] evidence)

some medications have evidence for efficacy in patients with type 2 diabetes, but are not FDA approved for this indication

fluoxetine may produce modest weightloss (5 kg [11 lbs]) over 8-52 weeks in patients with type 2 diabetes (level 2


addition of canagliflozin associated with weightloss in patients with type 2 diabetes inadequately controlled with metformin


exenatide, as a supplement to basal insulin or metformin, associated with weightloss in patients with type 2 diabetes (level 2


topiramate associated with weightloss and reductions in HbA1c in adults with type 2 diabetes controlled by metformin

combination phentermine and topiramate associated with weightloss in patients with prediabetes and/or metabolic syndrome

and may prevent type 2 diabetes

lorcaserin 10 mg once or twice daily may promote weightloss and improve glycemic control in adults with type 2 diabetes


see Weightloss medications in patients with diabetes for details

Psychotropic-induced weight gain

management of weight gain associated with antipsychotic medications

topiramate may reduce weight gain associated with atypical antipsychotics (level 2 [mid-level] evidence)

based on systematic review without meta-analysis

systematic review of 3 randomized trials comparing topiramate vs. placebo for antipsychotic-associated weight gain with

128 patients

Reference - Ann Pharmacother 2010 Apr;44(4):668

metformin prevents weight gain associated with atypical antipsychotics (level 1 [likely reliable] evidence)

based on systematic review

systematic review of 6 randomized trials comparing metformin vs. placebo for prevention of atypical antipsychotic-

associated weight gain with 336 participants

1 high-quality trial summarized below

metformin associated with reduction in

weight (weighted mean difference [WMD] -3.16 kg, 95% -4.8 to -1.53 kg) in analysis of 6 trials

body mass index (WMD 1.21 kg/m , 95% CI -1.84 to -0.59 kg/m ) in analysis of 6 trials2 2

waist circumference (WMD 1.99 cm, 95% CI -3.39 to -0.59) in analysis of 5 trials with 304 participants

no significant differences in risk of diabetes

Reference - J Clin Psychiatry 2010 Oct;71(10):1286

similar results in systematic review without meta-analysis of 8 randomized trials evaluating metformin for prevention of

atypical antipsychotic-associated weight gain with 449 patients (Ann Pharmacother 2010 Apr;44(4):668)

metformin may reduce weight gain in children and adolescents taking atypical antipsychotics


39 patients aged 10-17 years with weight increase > 10% during < 1 year of olanzapine, risperidone, or quetiapine

were randomized to metformin vs. placebo for 16 weeks


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Leptin:

weight stabilized in metformin group and increased by mean 0.31 kg/week in placebo group

Reference - Am J Psychiatry 2006 Dec;163(12):2072

metformin and/or lifestyle intervention is effective for prevention of antipsychotic-associated weight gain

(level 1 [likely reliable] evidence)

based on randomized trial

128 patients aged 18-45 years with antipsychotic-associated weight gain were randomized to 1 of 4 treatment groups

and followed for 12 weeks

inclusion criteria

treatment with single atypical antipsychotic drug for first episode of schizophrenia

weight gain > 10% pretreatment body weight within 1 year of treatment

stable psychiatric improvement

treatment groups

metformin 750 mg/day

lifestyle intervention (with educational, dietary and exercise components) plus placebo

metformin plus lifestyle intervention

placebo only

metformin plus lifestyle intervention group showed significantly greater weightloss and reduction in body mass index

(BMI) vs. other groups at 12 weeks

Weight and BMI Changes by Type of Intervention:

Group Mean Weight Change Mean BMI Change

Metformin and lifestyle intervention -4.7 kg (10.4 lbs) -1.8 kg/m

Metformin only -3.2 kg (7 lbs) (p = 0.02)* -1.2 kg/m (p = 0.01)*

Placebo and lifestyle intervention -1.4 kg (3.1 lbs) (p = 0.01)* -0.5 kg/m (p < 0.001)*

Placebo only +3.1 kg (6.8 lbs) (p < 0.001)* +1.2 kg/m (p < 0.001)*

Abbreviation: BMI, body mass index.

* p value vs. metformin plus lifestyle intervention

2

2

2

2

metformin group showed significantly greater weightloss (p = 0.004) and BMI reduction (p = 0.006) compared to

lifestyle intervention plus placebo group

Reference - JAMA 2008 Jan 9;299(2):185, commentary can be found in JAMA 2008 Apr 23;299(16):1898, ACP J Club

2008 Aug 19;149(2):5 EBSCOhost Full Text

Investigational Drugs

products to treat obesity need to demonstrate at least 5% average weightloss over placebo for FDA approval

recombinant leptin in addition to mild calorie restriction not associated with significant weightloss in overweight

and obese patients (level 2 [mid-level] evidence)


284 overweight and obese adults were randomized to 1 of 3 treatment groups or 1 of 3 matching placebo groups for 12

weeks

recombinant leptin 10 mg subcutaneously once daily in morning

recombinant leptin 10 mg subcutaneously once daily in evening

recombinant leptin 10 mg subcutaneously twice daily

all patients instructed to decrease energy intake by 2,100 kilojoules [kJ]/day (500 kcal/day) for duration of trial

no significant differences between treatment groups and placebo groups for absolute change in weightloss (p = 0.68)

Reference - Diabetes Obes Metab 2005 Nov;7(6):755 EBSCOhost Full Text

leptin associated with weightloss at 2 months in overweight men (level 2 [mid-level] evidence)


24 men aged 24-41 years with body mass index 25-32 kg/m randomized to pegylated human recombinant leptin 80 mg

subcutaneously vs. placebo weekly for 46 days

2

all patients were instructed to maintain very low-energy diet of 2,100 kJ/day (500 kcal/day)

mean body weight change from baseline -14.6 kg (-32 lbs) with leptin vs. -11.8 kg (-26 lbs) with placebo at end of treatment

(p = 0.027), significant differences maintained at 57 days

Reference - Am J Clin Nutr 2003 Apr;77(4):771 full-text


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Betahistine:

Other investigational drugs:

leptin does not appear to reduce body weight in obese men (level 2 [mid-level] evidence)


30 obese men (mean body mass index 33.9 kg/m ) randomized to pegylated recombinant human leptin 20 mg

subcutaneously vs. placebo weekly for 12 weeks

2

all patients were prescribed a hypocaloric diet (500 kcal/day or 2 megajoules [MJ]/day deficit)

mean body weight change from baseline -4.3 kg (-9.5 lbs) with leptin vs. -6.4 kg (-14.1 lbs) with placebo (not significant)

Reference - J Clin Endocrinol Metab 2000 Nov;85(11):4003, editorial can be found in J Clin Endocrinol Metab 2000

Nov;85(11):4000

leptin reported effective for weight regain in case series of 4 patients with congenital leptin deficiency (Arq Bras Endocrinol

Metabol 2010 Nov;54(8):690 full-text)

betahistine might be associated with weightloss in women < 50 years old (level 2 [mid-level] evidence)

based on subgroup analysis of randomized trial

281 obese patients randomized to betahistine (varying doses) vs. placebo for 12 weeks

betahistine not associated with significant weightloss overall

among subgroup of non-Hispanic white women < 50 years old, mean weightloss was 4.24 kg (9 lbs) in 23 participants taking

betahistine 48 mg vs. 1.65 kg (4 lbs) in 25 participants taking placebo (p = 0.005)

Reference - Int J Obes (Lond) 2008 Oct;32(10):1559 EBSCOhost Full Text

betahistine hydrochloride does not appear to reduce food intake in women (level 3 [lacking direct] evidence)

based on small randomized trial without clinical outcomes

76 women with BMI 30-40 kg/m randomized to betahistine hydrochloride (48 mg, 96 mg, or 144 mg) vs. placebo for 24

hours

2

no significant between group difference in food intake, hunger, fullness, or desire to eat

Reference - Am J Clin Nutr 2010 Dec;92(6):1290

botulinum toxin A intragastric injections do not appear to promote weightloss in obese adults (level 2 [mid-level]

evidence)

based on 2 small randomized trials

60 obese adults (mean age 49 years) randomized to gastric antral injections of botulinum toxin A (100 units vs. 300 units vs.

500 units) vs. placebo and followed for 24 weeks

no significant difference among groups in body weight change, satiation, caloric intake, gastrointestinal symptoms, or

psychological eating behaviors at 16 weeks

Reference - Clin Gastroenterol Hepatol 2013 Feb;11(2):145

10 obese women (body mass index [BMI] 30-35 kg/m ) were randomized to botulinum toxin A via endoscopic intragastric

injections vs. normal saline injections and followed for 6 months

2

no significant weight reduction from baseline in either group

no significant difference in early satiety between groups

Reference - Obes Surg 2007 Jun;17(6):732, correction can be found in Obes Surg 2007 Jul;17(7):996

tesofensine associated with greater mean weightloss compared to placebo (level 2 [mid-level] evidence)


203 obese patients (BMI 30 to 40 kg/m ) randomized to tesofensine 0.25 mg vs. 0.5 mg vs. 1 mg vs. placebo once daily

for 24 weeks

2

all patients prescribed energy restricted diet

trial had 2-week run-in and 8 weeks of follow-up

79% completed trial

mean weightloss from baseline (all p < 0.0001 vs. placebo)

2.2 kg (5 lbs) with placebo

6.7 kg (15 lbs) with tesofensine 0.25 mg

11.3 kg (25 lbs) with tesofensine 0.5 mg

12.8 kg (28 lbs) with tesofensine 1 mg

tesofensine not associated with significant increase in systolic or diastolic blood pressure

most common adverse events with tesofensine included dry mouth, nausea, constipation, hard stools, diarrhea, and

insomnia

Reference - Lancet 2008 Nov 29;372(9653):1906, commentary can be found in Lancet 2009 Feb 28;373(9665):719

Nonprescription WeightLoss Supplements

orlistat (Alli) is only FDA approved nonprescription weightloss aid

insufficient evidence to support use of other dietary supplements for weightloss; no weight-loss supplements meet criteria for


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Guidelines:

United States guidelines:

Review articles:

recommended use

FDA warnings relatively frequent regarding nonprescription weightloss aids; 2009 Mar 20 warning lists 72 products containing

undeclared active pharmaceutical agents

ephedra products banned in United States and Canada; ephedra-like products (such as ma huang and Metabolife 356) not

recommended due to safety concerns

"ephedra-free" products may contain ephedrine-like substances and use names like bitter orange, country mallow, or heartleaf

caffeine not recommended in high doses sometimes included in weight-loss products

green tea associated with weightloss (level 2 [mid-level] evidence), but may contain high caffeine doses and hepatotoxicity has

been reported

other products possibly associated with short-term weightloss (level 2 [mid-level] evidence)

chitosan, but effect minimal and unlikely to be of clinical significance

conjugated linoleic acid (CLA), but evidence inconsistent

chromium picolinate, but effect minimal and unlikely to be of clinical significance

glucomannan

Cissus quadrangularis formulation (Cylaris) containing green tea extract

white bean (Phaseolus vulgaris) extract

other products with no evidence of efficacy

dehydroepiandrosterone (DHEA)

garcinia

guar gum

multiple other substances (such as garcinia cambogia)

see Weightloss nonprescription medications and supplements for details

Antiobesity Agents Withdrawn from Market

aminorex was amphetamine-based anorectic withdrawn from European market in 1960s

benfluorex (an anorectic agent which was approved in Europe for use in overweight patients with diabetes) withdrawn from

European market in 2009 due to risk of heart valve disease

ephedra products banned in United States in 2004 and Canada in 2002; ephedra-like products (such as ma huang and Metabolife

356) not recommended due to safety concerns

phentermine/fenfluramine (phen-fen) and dexfenfluramine (Redux) were effective regimens for promoting weightloss but

fenfluramine and dexfenfluramine were withdrawn from market in 1997 due to associations with valvular heart disease and

pulmonary hypertension

phenylpropanolamine (stimulant) removed from United States market in 2000 due to association with hemorrhagic stroke

rimonabant (Acomplia, Zimulti) effective for weightloss, authorized in Europe in 2006, not FDA approved, and withdrawn from

Europe in 2008 due to psychiatric adverse effects

sibutramine (Meridia) withdrawn in United States and Europe due to increased risk of heart attack and stroke

see Weightloss medications withdrawn from market for details

Guidelines and Resources

National Heart Lung and Blood Institute (NHLBI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

guideline on identification, evaluation and treatment of overweight and obese adults can be found in Arch Intern Med 1998 Sep

28;158(17):1855

Academy of Nutrition and Dietetics (AND) position statement on weight management can be found in J Am Diet Assoc 2009

Feb;109(2):330

see Obesity for many additional guidelines

review can be found in J Obes 2011;2011:179674 EBSCOhost Full Text full-text

review can be found in Endocrinol Metab Clin North Am 2008 Dec;37(4):923

review can be found in Med Clin North Am 2007 Nov;91(6):1225

review of pharmacotherapy for weightloss in adults can be found in BMJ 2014 Jun 6;348:g3526

review of drug treatments for obesity (orlistat, sibutramine, and rimonabant) can be found in Lancet 2007 Jan 6;369(9555):71,

commentary can be found in Lancet 2007 Apr 7;369(9568):1163

review of medications currently approved by United States Food and Drug administration for long-term treatment of obesity

(orlistat, lorcaserin, and phentermine plus topiramate-extended release) can be found in JAMA 2014 Jan 1;311(1):74

review of diet, drugs and surgery for weightloss can be found in Treat Guidel Med Lett 2011 Apr;9(104):17


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Recommendation grading systems used:

DynaMed editorial process:

Special acknowledgements:

How to cite:

You are viewing a DynaMed summary. Use of DynaMed indicates acceptance of DynaMed Terms of Use. Limitations of DynaMed are

contained in the DynaMed Terms of Use.

Please give us your feedback by e-mailing DynaMed at: [email protected]

evidence-based review of pharmacological and surgical treatment of obesity can be found in AHRQ Evidence Report 2004

Jul:103 PDF, summary can be found in Am Fam Physician 2004 Dec 1;70(11):2225

supporting systematic review of pharmacologic treatment can be found in Ann Intern Med 2005 Apr 5;142(7):532

EBSCOhost Full Text full-text, commentary can be found in ACP J Club 2005 Sep-Oct;143(2):50 EBSCOhost Full Text

review of drug therapy can be found in N Engl J Med 2002 Feb 21;346(8):591, summary can be found in Am Fam Physician 2002

Apr 15;65(8):1675, commentary can be found in N Engl J Med 2002 Jun 27;346(26):2092

review of drug therapy can be found in J Clin Endocrinol Metab 2003 Jun;88(6):2462 (Am Fam Physician 2004 Feb 15;69(4):948)

review of drug therapy can be found in J Clin Endocrinol Metab 2004 Jun;89(6):2616 (Am Fam Physician 2005 Feb 1;71(3):597)

review of long-term drug therapy for obesity can be found in Arch Intern Med 2001 Aug 13/27;161(15):1814, commentary can

be found in Arch Intern Med 2002 May 13;162(9):1070

review with emphasis on drug therapy can be found in Am Fam Physician 2000 Apr 1;61(7):2131

review of drug-induced fibrotic valvular heart disease can be found in Lancet 2009 Aug 15;374(9689):577

review of weightloss maintenance can be found in Am Fam Physician 2010 Sep 15;82(6):630 EBSCOhost Full Text

Patient Information

handout on weightloss medicines from American Academy of Family Physicians or in Spanish

handout with emphasis on drug therapy can be found in Am Fam Physician 2000 Apr 1;61(7):2143

References

National Heart, Lung, and Blood Institute (NHLBI) grading system for evidence

Evidence A - randomized controlled trials, rich body of data

Evidence B - randomized controlled trials, limited body of data

Evidence C - nonrandomized trials and observational studies

Evidence D - expert panel consensus judgement

Reference - NHLBI and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) guideline on identification,

evaluation and treatment of overweight and obese adults (Arch Intern Med 1998 Sep 28;158(17):1855)

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The participating members of the DynaMed Editorial Team have declared that they have no financial or other competing interests

related to this topic.

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otherwise indicated.

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Pieter Cohen, MD (Assistant Professor of Medicine, Harvard Medical School; Somerville Hospital Primary Care; Cambridge Health

Alliance; Massachusetts, United States) provides peer review.

Fatima Cody Stanford, MD, MPH (Fellow of Obesity Medicine and Nutrition, Massachusetts General Hospital; Harvard Medical

School; Massachusetts, United States) provides peer review.

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