Accepted Manuscript

Practical Use of Pharmacotherapy for Obesity

Leon I. Igel, MD, FACP, DABOM, Rekha B. Kumar, MD, MS, DABOM, Katherine H.
Saunders, MD, Louis J. Aronne, MD, FACP, DABOM, FTOS

PII: S0016-5085(17)30142-7
DOI: 10.1053/j.gastro.2016.12.049
Reference: YGAST 60969

To appear in: Gastroenterology

Accepted Date: 23 December 2016

Please cite this article as: Igel LI, Kumar RB, Saunders KH, Aronne LJ, Practical Use of
Pharmacotherapy for Obesity, Gastroenterology (2017), doi: 10.1053/j.gastro.2016.12.049.

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 ACCEPTED MANUSCRIPT

Title: Practical Use of Pharmacotherapy for Obesity

Authors:
Leon I. Igel, MD, FACP, DABOM
Assistant Professor of Clinical Medicine
Comprehensive Weight Control Center
Division of Endocrinology, Diabetes and Metabolism
Weill Cornell Medical College

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New York, NY, USA

Rekha B. Kumar, MD, MS, DABOM

Assistant Professor of Medicine

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Comprehensive Weight Control Center
Division of Endocrinology, Diabetes and Metabolism
Weill Cornell Medical College
New York, NY, USA

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Katherine H. Saunders, MD
Instructor of Medicine
Comprehensive Weight Control Center

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Division of Endocrinology, Diabetes and Metabolism
Weill Cornell Medical College
New York, NY, USA
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Louis J. Aronne, MD, FACP, DABOM, FTOS
Sanford I. Weill Professor of Metabolic Research
Comprehensive Weight Control Center
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Division of Endocrinology, Diabetes and Metabolism

Weill Cornell Medical College
New York, NY, USA
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Corresponding Author:
Leon I. Igel, MD, FACP, DABOM
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Assistant Professor of Clinical Medicine

Comprehensive Weight Control Center
Division of Endocrinology, Diabetes and Metabolism
Weill Cornell Medical College
1165 York Avenue
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New York, NY 10065

Phone: (646) 962-2111
Fax: (646) 962-0159
[email protected]
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Disclosures:
Leon I. Igel and Katherine H. Saunders have no conflicts of interest. Rekha B. Kumar is a speaker for
Jansen Pharmaceuticals and a shareholder in Zafgen and MYOS Corporation. Louis J. Aronne has
received research funding from Aspire Bariatrics, Eisai, and Takeda Pharmaceuticals. He declares
consultant/advisory board work with Jamieson Labs, Pfizer Inc, Novo Nordisk A/S, Eisai, VIVUS, GI
Dynamics, JOVIA Health, and Gelesis. He is a shareholder of Zafgen, Gelesis, MYOS Corporation, and
Jamieson Labs, and he is on the Board of Directors of MYOS Corporation and Jamieson Labs.
 ACCEPTED MANUSCRIPT

Abstract

Obesity management requires a multidisciplinary approach, as there are many factors that contribute to
the development of obesity as well as the preservation of excess weight once it has been gained. Diet,
exercise and behavior modification are key components of treatment. In addition to lifestyle changes,
weight gain secondary to medications is an important modifiable risk factor. Even after appropriate
lifestyle modification, and medication adjustments (where possible) to avoid agents that can contribute to
weight gain, many patients are still unable to achieve clinically meaningful weight loss. Pharmacotherapy

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for obesity management can fill an important role for these patients. This article will review: 1)
medications that can lead to weight gain and potential alternatives, 2) currently approved anti-obesity
medications and best practices to individualize the selection process, and 3) the use of testosterone in
men with hypogonadism and obesity.

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Keywords: Obesity, pharmacotherapy, weight management, testosterone

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Introduction:
Obesity management requires a multidisciplinary approach, as there are many factors that contribute to
the development of obesity and the preservation of excess weight. Diet, exercise and behavior
modification are key components of treatment. Weight gain secondary to medications is also an important
modifiable risk factor. Even after lifestyle modification and medication adjustments to avoid agents that
can contribute to weight gain, many patients are still unable to achieve clinically meaningful weight loss.
The body's physiologic and hormonal adaptations contribute to this difficulty, and hypogonadism is
1,2
frequently encountered. The 2013 AHA/ACC/TOS guidelines for the management of overweight and

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obesity in adults recommends consideration of weight-loss medication for individuals who fail to respond
2 2
to lifestyle interventions and have a BMI of ≥ 30 kg/m , or a BMI of ≥ 27 kg/m with weight-related
3
comorbidities. The Endocrine Society recently published the first guidelines on the pharmacological
4
treatment of obesity, including the management of drug-induced weight gain. The American Association

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of Clinical Endocrinologist and the American College of Endocrinology have also recently published their
5
guidelines to help guide decision making related to the care of patients with obesity. Now that there are
several options for anti-obesity pharmacotherapy, it is important to note nuances in mechanisms of action
and side effect profile in order to choose the best medication for each patient. This article will review: 1)

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medications that can lead to weight gain and potential alternatives, 2) currently approved anti-obesity
medications and best practices to individualize the selection process, and 3) the use of testosterone in
men with hypogonadism and obesity.

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Medication-Induced Weight Gain
Medications can have unpredictable and variable effects on a patient’s weight, and it is important to
balance the benefits of any treatment against the probability of weight gain. Multiple medications are
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associated with weight gain, including select anti-diabetic, antihypertensive, antidepressant,
antipsychotic, anti-epileptic and antihistamine agents, as well as steroids, contraceptives and other
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hormonal agents.
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Weight gain is associated with several anti-diabetic therapies including insulin, thiazolidinediones (TZDs),
sulfonylureas, and meglitinides.7 Patients can gain as much as 10 kg in a relatively short period (3 to 6
8
months) after initiating treatment with these agents. Alternatively, there are anti-diabetic medications that
have proven to be weight-neutral or to promote weight loss. Metformin can lead to weight loss through
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9,10
multiple mechanisms. In addition to improving glycemic control, glucagon-like-peptide 1 (GLP-1)
agonists can lead to weight loss by decreasing appetite and enhancing satiety. Liraglutide was FDA-
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approved for chronic weight management in 2014 at a higher dose (3.0 mg daily) than what is available
for diabetes (1.8 mg daily). Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce glucose
11
reabsorption by the kidneys, leading to increased urinary glucose excretion. This may result in weight
loss as well as improved glucose control via direct caloric loss in the form of glycosuria. Both dipeptidyl
peptidase IV (DPP-4) inhibitors and α-glucosidase inhibitors (AGIs) appear to be weight-neutral or lead to
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12,13,14,15
minimal changes in weight. Pramlintide, the amylin analogue FDA-approved for use in
combination with insulin, can prevent weight gain or lead to weight loss by increasing satiety and
16,17
decreasing food intake. For patients with obesity and type 2 diabetes requiring insulin, the Endocrine
Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss
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promoting medication (metformin, GLP-1 agonist, or pramlintide) to mitigate associated weight gain due
4,6
to insulin use.
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With respect to antihypertensive agents, beta-adrenergic blockers (β-blockers) can promote weight gain
and prevent weight loss.18 In addition to potential adverse metabolic effects on lipids and/or insulin
sensitivity, β-blockers can decrease metabolic rate and may have other negative effects on energy
19
metabolism. β-blockers should be avoided if possible as first-line treatment for hypertension in patients
with overweight or obesity. However, not all β-blockers are associated with weight gain. Selective β-
blockers with a vasodilating component such as carvedilol and nebivolol are recommended when β-
4
blockers are required, for example in patients with coronary artery disease, heart failure or arrhythmias.
These agents appear to have less potential for weight gain and minimally affect lipid and glucose
20,21
metabolism. The α-adrenergic blockers (α-blockers) selectively block the postsynaptic α-adrenergic
receptor. Their use as a first-line antihypertensive treatment is not recommended following the ALLHAT
trial22 in which doxazosin was associated with a significantly increased risk for congestive heart failure
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compared to chlorthalidone. Doxazosin was also associated with significant weight gain, likely secondary
to extracellular fluid volume expansion.23 As a class, the α-blockers are also associated with asthenia,
23
which might contribute to weight gain by altering energy balance. Thus, in patients with weight
concerns, other antihypertensives would be preferable. Antihypertensive medications that are considered
weight-neutral include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers
(ARBs) and calcium channel blockers (CCBs). Angiotensin contributes to obesity-related hypertension, as
it is overexpressed in obesity. As a result, ACE inhibitors and ARBs are desirable options for the
treatment of patients with obesity. As many patients with obesity also have type 2 diabetes, these patients

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also benefit from the renal protection provided by these agents. Although thiazide diuretics are often
recommended as first-line agents for the treatment of hypertension, their dose-related side effects,
including dyslipidemia and insulin resistance, should be avoided in patients with obesity as they are at
6,24
higher risk for metabolic syndrome and type 2 diabetes.

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Weight gain in patients with psychiatric diagnoses is often multifactorial and a common adverse effect of
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many antidepressants and antipsychotics. Within classes of antidepressants, there is a range of weight
gain potential. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline have been

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25,26,27
associated with weight loss with short-term use and weight neutrality with long-term use. Within the
SSRI and tricyclic antidepressant (TCA) classes of drugs, paroxetine and amitriptyline respectively were
25,28
associated with the greatest risk for weight gain. Lithium, mirtazepine, and the MAO inhibitors are also
23
closely associated with weight gain. Bupropion is the only antidepressant that has been shown to

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27,29,30
consistently promote weight loss. Bupropion is a norepinephrine and dopamine reuptake inhibitor
approved for the treatment of depression and to assist with smoking cessation. Clinical trials found that it
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decreases body weight by suppressing appetite and reducing food cravings. It was approved by the
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FDA for chronic weight management in 2014 in combination with another medication, naltrexone, under
the brand name Contrave. As different classes of antidepressants are typically prescribed for different
types of depression, the few agents that are weight neutral and weight-loss-promoting are unfortunately
not appropriate for all patients with depression. For example, bupropion is activating and may exacerbate
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anxiety or be inappropriate for a patient with bipolar disorder. Therefore, the choice of agent must still be
guided by best practice for the individual patient's circumstance.6

With respect to the antipsychotics, there are few weight-neutral options. Lurasidone and ziprasidone
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32,33,34,35
appear to be the most weight-neutral in the class, with aripiprazole generally demonstrating a
36,37,38
lower risk for weight gain as well. Olanzapine, clozapine, quetiapine, and risperidone are
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consistently associated with weight gain, and studies demonstrate that patients may lose weight and
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develop improved glucose tolerance when switched from olanzapine to ziprasidone.

There is limited quality evidence to evaluate the weight impact of antihistamines, especially since many of
the trials examining antihistamine use are of short duration. It appears that the more potent the
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antihistamine, the greater the potential for weight gain. The most robust data on antagonism of
histamine H1 receptors are from studies of antipsychotic medications, which seem to induce at least part
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of their weight gain via antagonism of hypothalamic H1 receptors. The first generation (sedating)
antihistamines that act centrally are therefore more likely to promote weight gain than the 2nd and 3rd
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generational (non-sedating) antihistamines that do not cross the blood-brain barrier and are more
selective for peripheral H1 receptors. Alternatives to the use of antihistamines may include decongestants
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(such as pseudoephedrine), which are not associated with weight gain.

Anti-epileptic agents have a broad ranging effect on weight, with some medications associated with
substantial weight gain and others promoting weight loss. Topiramate and zonisamide are two agents that
27,43
have been consistently associated with weight loss. Topiramate monotherapy is FDA-approved for
both the treatment of migraines and the management of seizures, and was approved by the FDA for
chronic weight management in 2012 in combination with another medication, phentermine, under the
brand name Qsymia. Gabapentin, pregabalin, and valproic acid, are consistently associated with weight
44,45 46
gain, and carbamazepine is generally included in this category as well. Lamotrigine, levetiracetam
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and phenytoin are considered weight-neutral.
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It is difficult to categorize the weight impact of the hormonal contraceptives as a whole due to the large
variety of formulations. Different progestins have variable androgenic/anti-androgenic profiles, and
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estrogen doses vary considerably. In addition, quality studies assessing the weight impact of the
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contraceptives are limited, frequently due to lack of randomization or absence of a placebo group. A
recent Cochrane review of progestin-only contraceptives demonstrated evidence of weight gain
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associated with medroxyprogesterone acetate. There is no clear evidence of weight change associated
with combination (estrogen + progestin) oral contraceptive pills, although individual weight impact
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appears variable. There are, however, weight-neutral contraceptive options that minimize hormonal

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exposure, including barrier methods, copper IUDs, and surgical sterilization (including hysteroscopic
sterilization and tubal ligation) that can be utilized when appropriate. Whether hormonal IUDs are truly
weight neutral requires further investigation.50

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Oral glucocorticoids are often cited as the medication most likely to cause weight gain and impair glucose
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metabolism, but while this side effect is well known, the actual incidence is poorly defined. In addition,
8,52
viable alternatives are not always available. For dermatologic and pulmonary conditions, topical or
inhaled steroids may suffice while limiting systemic absorption and weight gain. For rheumatologic

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conditions, alternative classes of medications can also be considered such as non-steroidal anti-
inflammatory drugs (NSAIDs) or disease modifying anti-rheumatic drugs (DMARDs).

In summary, when possible, practitioners should utilize weight-neutral or weight loss-promoting

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medications. If there are no alternative medications, weight gain can be prevented or lessened by
selecting the lowest dose required to produce clinical efficacy for the shortest duration necessary.
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TABLE 1: Medications associated with weight gain, weight neutrality and weight loss
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Review of Anti-Obesity Medications

The goal of anti-obesity pharmacotherapy is not only to reduce weight, but more importantly to improve
the comorbid conditions associated with obesity, such as hyperglycemia, hyperlipidemia, and
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atherosclerotic heart disease. Before starting a medication for weight loss, it is important to discuss with
patients that obesity is a chronic disease that will require long-term treatment. It is helpful for patients to
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understand that the efficacy of the current medication options is generally 5%-10% body-weight loss in
the majority of successful patients, but that more weight loss can be achieved when several approaches
are utilized simultaneously. Prescribers should keep in mind that all anti-obesity pharmacotherapy is
classified as category X and female patients of reproductive potential should be counseled appropriately.
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Phentermine
Phentermine is an adrenergic agonist that promotes weight loss by activation of the sympathetic nervous
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system with a subsequent decrease in food intake and increase in resting energy expenditure. It was
approved by the FDA in 1959 and remains the most commonly prescribed anti-obesity medication. As
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there are no long-term safety trials of phentermine monotherapy, it was approved only for short-term use
(three months), but in clinical practice many practitioners prescribe it for a longer duration. Phentermine is
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a schedule IV medication.

In a 28-week, randomized, controlled trial comparing phentermine/topiramate extended release with

phentermine monotherapy and topiramate monotherapy in adults with obesity, phentermine alone (15 mg
daily) was associated with a 6.0 kg weight loss at 28 weeks, compared to a 1.5 kg weight loss with
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placebo. Forty-six percent of subjects in the phentermine group achieved ≥ 5% weight loss and 20.8%
achieved ≥ 10% weight loss, whereas 15.5% and 6.8% of placebo subjects achieved ≥ 5% weight loss
and ≥ 10% weight loss respectively.

The recommended dosage of phentermine is 15 to 37.5 mg orally once daily in the morning. Low-dose
phentermine recently received FDA approval (September 2016) under the brand name Lomaira as a
scored 8mg tablet that can be prescribed up to three times per day. The most common side effects of
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phentermine include dry mouth, difficulty sleeping, dizziness, and irritability and it should not be used with
MAO inhibitors or other sympathomimetic amines.

Appropriate candidates for phentermine include patients with obesity who need assistance with appetite
suppression. Due to the mild increase in heart rate and blood pressure that can accompany phentermine
use, this medication is generally used in younger patients without evidence of active or unstable coronary
disease, or uncontrolled hypertension. Patients who have anxiety or insomnia may feel their condition is
exacerbated by phentermine, and would not be ideal candidates.

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Orlistat (Xenical, Alli)
Orlistat was approved by the FDA for the treatment of obesity in 1999. Orlistat promotes weight loss by
inhibiting gastrointestinal lipases, thereby decreasing the absorption of fat from the gastrointestinal tract.

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Orlistat 120 mg taken 3 times per day decreases fat absorption by approximately 30%. Low-dose
orlistat (60 mg) 3 times daily is approved for over-the-counter use under the brand name Alli.

In the 4-year XENDOS trial, the orlistat-treated patients (taking 120 mg 3 times daily) had a significant

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weight loss of 5.8 kg compared to 3.0 kg with placebo, 52.8% of the orlistat patients lost ≥ 5% of initial
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body weight, and 26.2% lost ≥ 10% of their initial body weight.

Orlistat has gastrointestinal side effects including fecal urgency, oily stool, flatus with discharge, and fecal

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incontinence, but in clinical practice it may have a role in patients with obesity and constipation and/or
concomitant hypercholesterolemia that cannot be controlled by other means. The side effects of orlistat
can be ameliorated by following a balanced, reduced-calorie diet with no more than ~30% of calories from
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fat at any meal. The addition of a fiber supplement can also be helpful. As orlistat decreases the
absorption fat as well as fat-soluble vitamins (A, D, E, and K), patients should take a multivitamin
(separately from the medication) to ensure adequate nutrition.
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Phentermine/Topiramate Extended Release (Qsymia)

The combination of phentermine/topiramate extended-release (ER) was approved by the FDA in 2012 for
the treatment for obesity. Topiramate monotherapy is FDA-approved for epilepsy as well as migraine
prophylaxis, and has been found to decrease caloric intake, although the exact mechanism is unknown.
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The combination of phentermine plus topiramate extended-release leads to additive weight loss by
targeting different pathways simultaneously. Phentermine/topiramate is available in 4 doses: 3.75/23 mg
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7.5/46 mg, 11.25/69 mg, and 15/92 mg. Patients start at 3.75/23 mg daily in the morning and progress to
7.5/46 mg daily, with higher doses used if the medication is well-tolerated and additional weight loss is
desired, with the highest dose being 15mg/92mg daily. Phentermine/topiramate ER is a Schedule IV
compound.
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The efficacy of phentermine/topiramate ER on weight loss was assessed in two 1-year randomized,
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double-blind, placebo-controlled studies (EQUIP and CONQUER ) as well as a 56 week extension trial,
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SEQUEL. The CONQUER trial randomized 2487 patients with a mean BMI of 36.6 kg/m and
comorbidities including hypertension, dyslipidemia, diabetes, pre-diabetes, and/or abdominal obesity to
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either placebo, phentermine/topiramate ER 7.5/46 mg, or phentermine/topiramate ER 15/92 mg. Weight

loss of 7.8% and 9.8% was observed in the 7.5/46mg and the 15/92mg arms respectively, compared to
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1.2% with placebo. SEQUEL demonstrated persistent weight loss with phentermine/topiramate ER 1 year
after completion of the CONQUER study. At week 108, weight loss of 9.3% and 10.5% was observed in
the 7.5/46 mg and 15/92 mg arms respectively, compared to 1.8% with placebo.

The most common side effects of phentermine/topiramate ER include paresthesias, dizziness, dysguesia,
insomnia, constipation and dry mouth. The medication should be discontinued or the dose should be
escalated if 3% weight loss is not achieved after 12 weeks at 7.5/46 mg daily. In addition, if 5% weight
loss is not achieved after 12 weeks on the maximum dose (15/92 mg daily), the medication should be
discontinued. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers
and women of reproductive potential about the possible increased risk of orofacial clefts in infants
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exposed to topiramate during the first trimester of pregnancy.
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The ideal patient to prescribe phentermine/topiramate ER is someone who could benefit from the appetite
suppressant effects of the agent. Due to the phentermine component, this medication should not be
prescribed to patients with a history of cardiovascular disease or other conditions that could be
exacerbated by a stimulant. Patients who have weight gain partially attributable to antidepressants,
specifically SSRIs/SNRIs, are reasonable candidates for phentermine/topiramate ER, as the EQUIP,
CONQUER and SEQUEL trials all included patients with histories of depression on these medications.

Lorcaserin (Belviq)

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Lorcaserin was approved by the FDA in 2012 for the treatment for obesity. Lorcaserin selectively
activates the central serotonin (5-HT)2C receptor, and has a much greater affinity for this receptor as
compared to the 5-HT2A and 5-HT2B receptors. By binding to the 5-HT2C receptors on anorexigenic pro-
opiomelanocortin (POMC) neurons in the hypothalamus, lorcaserin reduces appetite, and has been

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designed to avoid cardiac valvular effects mediated through the 5-HT2B receptor. There has been no
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evidence of an increased risk of valvulopathy with lorcaserin over 2 years, and long-term data are
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expected from a 5-year cardiovascular outcome study. The recommended treatment dose of lorcaserin
is 10 mg twice daily. There is also a recently-approved once-daily 20 mg extended release tablet.

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Lorcaserin is listed as a Schedule IV substance. It should be discontinued if ≥ 5% weight loss is not
achieved after 12 weeks.

Three phase III randomized, double-blind, placebo-controlled trials (BLOOM,62 BLOSSOM64 and BLOOM-

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DM ) evaluated the effects of lorcaserin on weight. The BLOOM trial included 3182 adults with
overweight or obesity who received lorcaserin 10 mg twice daily or placebo for 52 weeks, in conjunction
with diet and exercise. At week 52, patients in the placebo group continued to receive placebo, but
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patients in the lorcaserin group were randomly reassigned to receive either lorcaserin or placebo for an
additional 52 weeks. At 1 year, the average weight loss in the lorcaserin arm was 5.81% compared to
2.16% with placebo, and 47.5% of the subjects taking lorcaserin had lost ≥ 5% body weight as compared
to 20.3% in the placebo group. Patients who lost ≥ 5% body weight at 52 weeks and were maintained on
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lorcaserin treatment in year 2 were able to maintain their weight loss better than those switched to
placebo. The BLOOM-DM study was conducted in patients with obesity and type 2 diabetes. At 52
weeks, 37.5% of patients treated with lorcaserin 10 mg twice daily had lost ≥ 5% body weight, which was
more than twice the percentage in the placebo group. There was a hemoglobin A1c (HbA1c) reduction of
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0.9% in those on lorcaserin as compared to a 0.4% reduction in the placebo group.
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The most common side effects of lorcaserin include headache, dizziness, fatigue, nausea, dry mouth, and
constipation. There is a theoretical interaction with other serotonergic drugs such as SSRIs. Although no
incidents were reported in Phase III studies, co-administration may lead to the development of serotonin
syndrome.
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Ideal candidates for use of lorcaserin are often patients who describe inadequate meal satiety. Lorcaserin
has a generally mild side effect profile and evidence of greater HbA1c reduction than expected for the
degree of weight loss achieved with lorcaserin use, so it may be a reasonable therapy in patients with
diabetes and cardiometabolic disease who might not be appropriate to receive stimulant-based
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medications for weight loss. Lorcaserin should be used with caution in patients on other serotonin
modulating medications, and in patients with known cardiac valvular disease pending the results of the 5-
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year cardiovascular outcome study.

Naltrexone/Bupropion Extended Release (Contrave)

Naltrexone/bupropion was FDA approved for the treatment of obesity in 2014. Bupropion is a dopamine
and norepinephrine reuptake inhibitor that is FDA-approved as an antidepressant and to assist with
smoking cessation. Inhibiting reuptake of dopamine and norepinephrine modulates the central reward
pathways triggered by food. Naltrexone is an opioid antagonist that is FDA-approved for the treatment of
alcohol and opioid dependence. Naltrexone antagonizes an inhibitory feedback loop that would otherwise
limit bupropion’s anorectic properties, and the combination of naltrexone/bupropion has been shown
activate POMC neurons in the arcuate nucleus of the hypothalamus. This promotes release of alpha-
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melanocyte–stimulating hormone, an anorectic neuropeptide involved in body weight regulation. Each
tablet of naltrexone/bupropion contains 8 mg of extended-release naltrexone and 90 mg of extended-
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release bupropion. Initial prescription should be for one tablet daily in the morning with instructions to
increase by one tablet a week to a maximum dose of two tablets twice daily (32/360 mg). The medication
should be discontinued if a patient has achieved ≤ 5% weight loss at 16 weeks (after 12 weeks at the
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maintenance dose).

Four 56-week multicenter, randomized, double-blind, placebo-controlled trials (Contrave Obesity

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Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes ) were conducted to evaluate the
effect of naltrexone/bupropion in conjunction with lifestyle modification in a cohort of 4536 patients with

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overweight or obesity. The COR-I, COR-II, and COR-BMOD trials enrolled patients with BMI ≥ 30 kg/m²
or BMI ≥ 27 kg/m² and at least one weight-related comorbidity. The COR-Diabetes trial enrolled patients
with BMI ≥ 27 kg/m² with type 2 diabetes with or without hypertension and/or dyslipidemia. In the 56-week
COR-I trial, weight loss of 6.1% was observed in patients assigned to naltrexone/bupropion 360/32 mg

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compared to 1.3% with placebo, and 48% of treatment group patients lost greater than 5% bodyweight
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from baseline, as compared to 16% of placebo patients. In the COR-Diabetes trial, 44.5% of patients
receiving naltrexone/bupropion lost ≥ 5% of their body weight after 56 weeks vs. 18.9% of patients on
placebo. Patients using naltrexone/bupropion demonstrated a 0.6% reduction in HbA1c from baseline,

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compared to a 0.1% reduction in placebo.

The most common side effects of naltrexone/bupropion include nausea, constipation, headache,
dizziness, insomnia, and dry mouth. Medication interactions include MAO inhibitors and opioids.

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Naltrexone/bupropion should be avoided in patients with uncontrolled hypertension, uncontrolled pain,
history of seizures, or any condition that predisposes to seizure such as anorexia or bulimia nervosa,
abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs. Bupropion carries
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a black box warning related to a potential increase in suicidal thoughts in young adults within the first few
months of treatment initiation, so patients should be monitored closely for any mood changes (although
no evidence of suicidality was reported in phase III studies).
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Ideal candidates for naltrexone/bupropion may include patients that have concomitant depression, since
the bupropion component can assist in the treatment of this condition. Patients who are trying to quit
smoking or reduce alcohol intake are also good candidates. In clinical practice, patients who describe
cravings for food and/or addictive behaviors related to food have done well on this medication. Compared
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to the other three anti-obesity medications approved since 2012, naltrexone/bupropion is neither a
controlled substance nor an injectable agent.
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Liraglutide 3.0 (Saxenda)

Liraglutide 3.0 mg was approved by the FDA for the treatment of obesity in 2014. Liraglutide is a GLP-1
receptor agonist that is also FDA approved for the treatment of type 2 diabetes in doses up to 1.8 mg as
the brand name Victoza. Peripheral administration of liraglutide results in uptake in brain regions
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regulating appetite, including the hypothalamus. A study involving individuals with obesity and without
diabetes demonstrated that liraglutide 3.0 mg/day decreased food intake as well as subjective hunger,
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and delayed gastric emptying. Liraglutide is initiated at a dose of 0.6 mg daily, with instructions to
increase by 0.6 mg weekly to a maximum dose of 3.0 mg daily. In case of nausea or other gastrointestinal
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symptom, the dose should be reduced to the previous tolerable dose.

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Two Phase III trials, SCALE Obesity and Prediabetes and SCALE Diabetes, evaluated the efficacy of
liraglutide 3.0 mg in subjects with overweight/obesity and either normoglycemia/prediabetes or diabetes
respectively. Both 56-week, randomized, double-blind, placebo-controlled trials demonstrated significant
weight loss (8.0% in the liraglutide arm of SCALE Obesity and Prediabetes compared to 2.6% with
placebo, and 6.0% in the liraglutide arm of SCALE Diabetes compared to 2.0% with placebo). The
76
efficacy of liraglutide after diet-induced weight loss was examined in the SCALE Maintenance study.
Four hundred and twenty-two overweight and obese subjects who lost ≥ 5% of their initial body weight on
a low calorie diet were randomly assigned to liraglutide 3.0 mg daily or placebo for 56 weeks. Mean
weight loss on the initial diet was 6.0%. By the end of the study, participants in the liraglutide group lost
76
an additional 6.2% compared to 0.2% with placebo.
 ACCEPTED MANUSCRIPT

The most common side effects of liraglutide include nausea, vomiting, diarrhea, constipation, dyspepsia
and abdominal pain. There is also evidence of a mild increase in heart rate with liraglutide use.77
Liraglutide carries a black box warning related to an association with medullary thyroid cancer in rodents,
although the relevance to humans has not been determined. Nonetheless, liraglutide is contraindicated in
patients who have had medullary thyroid cancer or who have a family history multiple endocrine
73
neoplasia type 2 (MEN 2). Concomitant use of liraglutide with insulin or insulin secretagogues increases
the risk of hypoglycemia. The medication should be discontinued if a patient has not achieved 4% weight
loss at 16 weeks.

PT
Ideal patients for liraglutide include patients with overweight or obesity who report inadequate meal
satiety, and/or have type 2 diabetes, prediabetes or impaired glucose tolerance. Unlike the other anti-
obesity medications, liraglutide does not appear to alter the neurotransmitters involved in mood

RI
regulation, and therefore is a good choice in patients requiring use of concomitant psychiatric
medications. Liraglutide is not appropriate for patients with an aversion to needles, since it requires a
daily subcutaneous injection.

SC
78
Table 2: Summary of pharmacotherapy for obesity

Use of testosterone in men with obesity and hypogonadism

Men with obesity frequently have low total testosterone levels, with some studies reporting greater than

U
50% having testosterone levels below 300 ng/dl (normal total testosterone range for adult men is 300 to
79,80
800 ng/dL in most laboratories). Obesity-related decreases in testosterone are frequently attributable
81
to low concentrations of sex hormone binding globulin (SHBG). Men with obesity and hypogonadism
AN
who have low total testosterone solely due to low SHBG have normal free testosterone levels. However,
81,82
a subset of men with obesity will also have frankly low free testosterone levels. When this occurs, it is
thought to be due to increased aromatization of testosterone to estradiol in adipose tissue, with
subsequent estradiol-mediated negative feedback suppressing pituitary luteinizing hormone (LH)
M

81,83,84
secretion. Therefore, when evaluating low total testosterone clinically in a man with obesity, the
measurement of morning serum free testosterone is essential.

Testosterone deficiency in males is associated with energy imbalance, impaired glucose control, reduced
D

85
insulin sensitivity, dyslipidemia, increased abdominal fat mass, and a reduction in lean body mass.
Testosterone replacement in men with obesity and hypogonadism has demonstrated favorable
86,87,88
TE

results. In these studies, testosterone replacement has been associated with weight loss, as well as
improvements in fasting plasma glucose, insulin resistance (HOMA-IR), triglyceride levels, treadmill
duration, high-density lipoprotein cholesterol, lean body mass and waist circumference, among other
89,90
metabolic and body composition parameters.
EP

We suggest consideration of testosterone assessment in patients with signs and symptoms that could
indicate hypogonadism including decreases in energy, libido, muscle mass, and body hair, as well as hot
flashes, gynecomastia, and infertility. This assessment should include a morning total testosterone
concentration drawn between 8 AM and 10 AM, as well as a free testosterone level by equilibrium dialysis
C

and a SHBG level in patients with obesity. If the testosterone levels are subnormal, they should be
repeated, and serum luteinizing hormone (LH) and follicle stimulating (FSH) concentrations should be
AC

measured to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism. If

testosterone levels are low in men with concomitantly low LH/FSH, indicative of secondary
hypogonadism, further evaluation to identify the etiology of hypothalamic and/or pituitary dysfunction may
include measurements of serum prolactin and iron saturation, pituitary function testing, and magnetic
91
resonance imaging of the sella turcica. In patients with obesity, treatment with testosterone replacement
therapy should be considered when the AM free testosterone by equilibrium dialysis if frankly low on at
least 2 separate assessments, and the above hypogonadism workup has been completed to rule out an
etiology of hypogonadism unrelated to obesity.

Currently the most common method of testosterone replacement is as a topical preparation. Transdermal
testosterone preparations (gel, patch) have been favored to intramuscular injections due to the relative
stability of testosterone levels from day-to-day, and the ability to avoid the discomfort of intramuscular
 ACCEPTED MANUSCRIPT

injections. Testosterone injections offer the benefit of avoiding daily administration and may be
advantageous in patients with reduced personal disease-management skills or resources. Implantable
testosterone pellets also offer a longer-term alternative, but require a procedure for implantation. Gel
preparations dry quickly when applied to the skin surface, but can be inadvertently transferable to other
individuals via prolonged skin contact. In addition, absorption from gels can be variable, providing
inconsistent testosterone replacement in some patients. Testosterone patches minimize this issue, but
come with their own limitations including potential skin irritation at the site of patch placement and issues
91
with patch adherence. In general, the transdermal testosterone preparations also cost more than the

PT
injectable options. Consequently, the method of testosterone replacement should be individualized for
each patient. We suggest transdermal testosterone preparations for most hypogonadal men because
they usually produce normal serum testosterone concentrations, and patients typically find them the most
convenient. After treatment is initiated, patients should be monitored to determine that normal serum

RI
testosterone concentrations are being achieved. Testosterone levels should be tested 2 to 3 months after
treatment initiation, and/or after any dose change. Once stable levels are confirmed on a given dose,
monitoring every 6 to 12 months is typically sufficient. The timing of testosterone measurements will vary
depending on the preparation. For patients receiving testosterone injections, levels should be measured

SC
midway between injections, targeting a midnormal value (500-600 ng/dL). For patients receiving
transdermal preparations, levels can be measured at any time, with the understanding that peak values
occur 6 to 8 hours after application of the patch, and that testosterone concentrations can vary
substantially with gel use, although not in a predictable way.91

Table 3: Testosterone Replacement Therapy

U
91
AN
92,93,94
Data regarding the safety of testosterone therapy have been conflicting. Based on available data,
the FDA in 2015 required a labeling change to inform both health care professionals and patients of a
possible increased risk of heart attack and stroke with the use of testosterone preparations to treat age-
M

95
related hypogonadism. There is also some evidence suggesting that testosterone injections are
associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with
96
gels. Safety concerns regarding testosterone injections may be related to the increased time spent in
both the supratherapeutic and subtherapeutic range in between injections as compared to patients
D

96,97
receiving transdermal testosterone preparations. However, these safety concerns may be unfounded,
and it may be that the increased cardiovascular risk demonstrated in the aforementioned studies is
TE

related to the high-risk patient populations that received therapy, and a lack of appropriate comparator
98,99,100,101
groups. Multiple associations, societies, and agencies, supported by an array of testosterone
102,103,104,105,106,107,108,109,110
safety data, as well as data demonstrating the cardiometabolic benefits of
88,111,112
testosterone replacement therapy, support the use of testosterone in appropriately selected
113
patients. Long-term cardiovascular outcomes remain unclear, and additional prospective trials of
EP

testosterone replacement therapy are needed to help answer this lingering question.

Conclusions
While lifestyle modification is the cornerstone of obesity management, long-term weight loss is frequently
C

difficult to achieve solely with diet and exercise as the body’s counter-regulatory neurohormonal axis
adapts to maintain excess body weight. A careful review of a patient's medications to identify those that
AC

may be contributing to weight gain (or limiting weight loss) is also essential. Consideration of weight-
neutral and weight loss-promoting alternatives may assist a patient's weight loss efforts. Successful use
of pharmacotherapy for obesity requires tailoring treatment to each patient’s unique behaviors and
comorbidities. When choosing an anti-obesity medication, it is essential to consider medication
interactions, contraindications, and risk of potential adverse effects. Weight loss maintenance requires a
long-term approach with chronic treatment and follow-up to prevent relapse. Although there are now
several anti-obesity medications, the percentage of patients receiving pharmacotherapy for the treatment
of obesity is still quite small due to the paucity of physicians trained in the field, lack of reimbursement for
114
weight management office visits, and poor insurance coverage of weight loss medications. These are
all areas that need improvement in order to better treat obesity as a chronic disease.
 ACCEPTED MANUSCRIPT

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testosterone therapy prescription in men. PLoS ONE. 2014;9:e85805.
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Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial
infarction, and stroke in men with low testosterone levels. JAMA. 310:1829–1836.
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FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone
due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with
use. March 3rd, 2015. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm.
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Layton JB, Meier CR, Sharpless JL, et al. Comparative Safety of Testosterone Dosage Forms. JAMA
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Dobs AS, Meikle AW, Arver S, et al. Pharmacokinetics, efficacy, and safety of a permeation-enhanced
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treatment of hypogonadal men. J Clin Endocrinol Metab. 1999 Oct;84(10):3469–3478.
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Dohle GR, Arver S, Bettocchi C, et al. Guidelines on male hypogonadism. 2015. http://uroweb.org/wp-
content/uploads/EAU-Guidelines-Male-Hypogonadism-2015.pdf.
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Goodman N, Guay A, Dandona P, et al. American Association of Clinical Endocrinologists and

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American College of Endocrinology position statement on the association of testosterone and
cardiovascular risk. Endocr Pract. 2015;21:1066–1073.
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Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: testosterone replacement
therapy in the aging male. Maturitas. 2016;84:94–99.

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Agency of European Medicine. No consistent evidence of an increased risk of heart problems with
testosterone medicines (EMA/706140). November 21st, 2014.
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Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J
Med. 2016;374:611–624.
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Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced
incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36:2706–2715.
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Anderson JL, May HT, Lappé DL, et al. Impact of testosterone replacement therapy on myocardial
infarction, stroke, and death in men with low testosterone concentrations in an integrated health care
system. Am J Cardiol. 2016;117:794–799.
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replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol.
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Sharma R, Oni OA, Chen G, et al. Association between testosterone replacement therapy and the
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incidence of deep vein thrombosis and pulmonary embolism: a retrospective cohort study of the Veterans
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medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13:1327–1351.
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Albert SG, Morley JE. Testosterone therapy, association with age, initiation and mode of therapy with
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ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin
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Thomas CE, Mauer EA, Shukla AP, et al. Low adoption of weight loss medications: A comparison of
prescribing patterns of antiobesity pharmacotherapies and SGLT2s.Obesity (Silver Spring). 2016
Sep;24(9):1955-61.
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TABLE 1: Medications associated with weight gain, weight neutrality and weight loss
Weight gain Weight neutral / Less weight gain Weight loss
ANTI-DIABETICS Insulin α-glucosidase inhibitors GLP-1 agonists
Meglitinides Bromocriptine Metformin
Sulfonylureas Colesevelam Pramlintide
Thiazolidinediones DPP-4 inhibitors SGLT2 inhibitors
ANTIHYPERTENSIVES α-adrenergic blockers ACE inhibitors
β-adrenergic blockers ARBs
(atenolol, metoprolol, β-adrenergic blockers (carvedilol,

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nadolol, propranolol) nebivolol)
Calcium channel blockers
Thiazides
ANTIDEPRESSANTS Lithium SSRIs (fluoxetine, sertraline) Bupropion

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MAOIs
Mirtazapine
SSRIs (paroxetine)
Tricyclic antidepressants

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(amitriptyline, doxepin,
imipramine, nortriptyline)
ANTIPSYCHOTICS Clozapine Aripiprazole
Olanzapine Lurasidone
Quetiapine Ziprasidone

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Risperidone

ANTI-EPILEPTICS Carbamazepine Lamotrigine Topiramate

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Gabapentin Levetiracetam Zonisamide
Pregabalin Phenytoin
Valproic acid
CONTRACEPTIVES Medroxyprogesterone Barrier methods
acetate IUDs
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Surgical sterilization (hysteroscopic

sterilization, tubal ligation)
ANTIHISTAMINES 1st generation 2nd and 3rd generation
antihistamines antihistamines
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Alternatives: decongestants
STEROIDS Glucocorticoids Inhaled steroids
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Topical steroids

Alternatives: NSAIDs, DMARDs

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose co-transporter 2; ACE,
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angiotensin-converting enzyme; ARB, Angiotensin II receptor blockers; MAOI, monoamine oxidase inhibitor; SSRI,
selective serotonin reuptake inhibitor; IUD, intrauterine device; NSAID, non-steroidal anti-inflammatory drug; DMARD,
disease modifying antirheumatic drug
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Adapted from:

Saunders KH, Igel LI, Shukla AP, et al. Drug-induced weight gain: Rethinking our choices. J Fam Pract. 2016
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November;65(11):780-782,784-786,788

Apovian CM, Aronne L, Powell AG. Clinical management of obesity. West Islip (NY): Professional Communications,
Inc; 2015. p. 148–50
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Table 2. Summary of Pharmacotherapy for Obesity

Medication Mechanism of Action Trial Trial Arms Weight Loss (%) Good Candidates Poor Candidates
& Typical Dosage
*
Phentermine Adrenergic agonist Aronne LJ, et al. [56] 7.5 mg daily 5.45% Younger patients who Patients with uncontrolled
(Schedule IV controlled 28 weeks need assistance with hypertension, active or
substance) 15 mg daily 6.06%* appetite suppression unstable coronary disease,
hyperthyroidism, glaucoma,
Typical Dosing: Placebo 1.71% anxiety, insomnia, or

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8 mg - 37.5mg QAM patients who are generally
*Topiramate ER sensitive to stimulants;
and Phen/Top ER Patients with a history of

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arms excluded drug abuse or recent MAOI
use
*
Orlistat Lipase inhibitor XENDOS [58] 120 mg TID 9.6% (week 52) Patients with Patients with malabsorption

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*
208 weeks 5.25% (week 208) hypercholesterolemia syndromes, or other
and/or constipation gastrointestinal conditions
Placebo 5.61% (week 52) who can limit their that predispose to GI
Typical Dosing: 2.71% (week 208) intake of dietary fat upset/diarrhea; Patients

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60 - 120mg TID with who cannot modify the fat
meals content of their diets

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*
Phentermine/topiramate Adrenergic EQUIP [59] 15/92 mg daily 10.9% Younger patients who Patients with uncontrolled
Extended Release agonist/neurostabilizer 56 weeks need assistance with hypertension, active or
*
(Schedule IV controlled 3.75/23 mg daily 5.1% appetite suppression unstable coronary disease,
substance) hyperthyroidism, glaucoma,

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Placebo 1.6% anxiety, insomnia, or
*
Typical Dose Titration: CONQUER [60] 15/92 mg daily 9.8% patients who are generally
3.75/23 mg daily for 2 56 weeks sensitive to stimulants;

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weeks, increasing to 7.5/46 mg daily 7.8% Patients with a history of
7.5/46 mg daily, with drug abuse or recent MAOI

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further dose escalation Placebo 1.2% use; Patients with a history
*
as needed/tolerated SEQUEL [61] 15/92 mg daily 10.5% of nephrolithiasis
thereafter (11.25/69 mg, 108 weeks
*
then 15/92 mg) (52-week extension of 7.5/46 mg daily 9.3%
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CONQUER trial)
Placebo 1.8%
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data from weeks 0-108

*
Lorcaserin Serotonin (5-HT)2C BLOOM [62] 10 mg BID 5.8% Patients who report Patients on other serotonin
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(Schedule IV controlled receptor agonist 52 weeks inadequate meal modulating medications,

substance) Placebo 2.2% satiety and patients with known
*
BLOSSOM [64] 10 mg BID 5.8% cardiac valvular disease
52 weeks
*
Typical Dosing: 10 mg daily 4.7%
10 mg BID or 20mg XR
daily Placebo 2.8%
*
BLOOM-DM [65] 10 mg BID 4.5%
52 weeks
*
10 mg daily 5.0%

Placebo 1.5%
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*
Naltrexone/Bupropion Opioid receptor COR-I [68] 16/180 mg BID 6.1% Patients who describe Patients with uncontrolled
Extended Release antagonist/dopamine 56 weeks cravings for food hypertension, uncontrolled
*
and norepinephrine 8/180 mg BID 5.0% and/or addictive pain, recent MAOI use,
reuptake inhibitor behaviors related to history of seizures, or any
Placebo 1.3% food, patients who condition that predisposes
*
COR-II [69] 16/180 mg BID 6.4% are trying to quit to seizure such as:
56 weeks smoking, reduce anorexia/bulimia nervosa,
Typical Dose titration: Placebo 1.2% alcohol intake, and/or abrupt discontinuation of
*
Week 1: 8/90 mg QAM COR-BMOD [70] 16/180 mg BID 9.3% have concomitant alcohol, benzodiazepines,

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Week 2: 8/90 mg BID 56 weeks depression barbiturates or antiepileptic
Week 3:16/180 mg Placebo 5.1% drugs
*
QAM, 8/90 mg QPM COR-DIABETES [71] 16/180 mg BID 5.0%

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Week 4 (and beyond): 56 weeks
16/180 mg BID Placebo 1.8%
*
Liraglutide 3.0 mg GLP-1 receptor agonist SCALE Obesity and 3.0 mg daily 8.0% Patients who report Patients with an aversion to

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Prediabetes [74] inadequate meal needles, history of
56 weeks Placebo 2.6% satiety, and/or have pancreatitis, personal or
type 2 diabetes, family history of medullary
Typical Dose Titration: prediabetes or thyroid carcinoma, or

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*
Week 1: 0.6 mg daily SCALE Diabetes [75] 3.0 mg daily 6% impaired glucose multiple endocrine
Week 2: 1.2 mg daily 56 weeks tolerance; Patients neoplasia syndrome type 2

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*
Week 3: 1.8 mg daily 1.8 mg daily 4.7% requiring use of
Week 4: 2.4 mg daily concomitant
Week 5 (and beyond): Placebo 2.0% psychiatric
*
3.0 mg daily SCALE Maintenance 3.0 mg daily 6.2% medications

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[76]
56 weeks (after initial Placebo 0.2%
≥ 5% weight loss with

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LCD)

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BID twice daily; TID thrice daily; QAM every morning; GI gastrointestinal; QPM every evening; LCD low calorie diet
*
p < 0.001 vs. placebo
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Adapted from: Saunders KH, Kumar RB, Igel LI, Aronne LJ. Pharmacologic Approaches to Weight Management: Recent Gains and Shortfalls in Combating Obesity. Curr
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Atheroscler Rep. 2016 Jul;18(7):36.

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Table 3: Testosterone Replacement Therapy
Testosterone Preparation Name Dosage Supplied Typical Dose Application Site Advantages Disadvantages
Formulation (Brand Name) Range
Long-acting injections Testosterone 200 mg/mL 100-200 mg every Thighs for intramuscular Relatively Requires intramuscular
enanthate 2 weeks or 50- self-injection, gluteal inexpensive; injection; fluctuating
(Delatestryl) 100 mg weekly administration when flexible/infrequent serum testosterone
injected by another dosing; no risk of levels with peaks and
Testosterone 100 mg/mL 100-200 mg every person transference valleys

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cypionate 200 mg/mL 2 weeks or 50-
(Depo-Testosterone) 100 mg weekly
Extra-long-acting Testosterone 250 mg/mL 750 mg initially, Gluteal intramuscular Few yearly injections Injection-associated
injections undecanoate (Aveed) followed by 750 injection only and less fluctuation in pulmonary oil

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mg after 4 weeks, testosterone levels; microembolism (POME);
followed by 750 no risk of transference restricted access in
mg every 10 United States

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weeks
Transdermal AndroGel 1% 25 mg in 2.5 g 50 to 100 mg/day Skin of the back, Easy application; Potential for transfer to
gels/pumps/solutions - Gel packets packet, 50 mg in 5 g abdomen, upper thighs good skin tolerability partner or child by skin-
packet and upper arms to-skin contact; can be

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more expensive than
AndroGel 1.62% 20.25 mg in 1.25 g 20.25 to 81 Skin of the back, other formulations

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- Gel packets packet, 40.5 mg in mg/day abdomen, upper thighs
- Metered-dose pump 2.5 g packet, 20.25 and upper arms
mg per pump

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Axiron 2% solution 30 mg per actuation 30 to 120 mg/day Apply using applicator to
- metered-dose pump skin of axilla

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Fortesta 2% gel 10 mg per actuation 10 to 70 mg/day Skin of front and inner
- Metered-dose pump thighs

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Testim 1% gel 50 mg in 5 g packet 50 to 100 mg/day Skin of the back,
- Gel packets abdomen, upper thighs
and upper arms
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Testogel 1% gel 50 mg in 5 g packet 50 to 100 mg/day Skin of the back,
- Gel packets abdomen, upper thighs
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and upper arms

Transdermal patches Testosterone 24-hour 2 mg/24-hr patch 2 to 6 mg per day Dry, intact skin of back, Easy application; no Skin rash/irritation at site
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patch (Androderm) abdomen, upper thighs or risk of transference of application; poor

4 mg/24-hr patch upper arms adherence of patch
Subcutaneous implants Testosterone pellets 75 mg pellets 150 to 450 mg Subcutaneous implant Long-lasting therapy; Incision required for
(pellets) (Testopel) every 3 to 6 under skin in the hips less fluctuation in insertion; pellet
months testosterone levels; extrusion; infection at
no risk of transference site of pellet insertion
Buccal tablets Buccal testosterone 30 mg per tablet 30 mg twice daily Buccal application No risk of skin-to-skin Poor adherence; gum
system (Striant) transference irritation; changes in
taste of food

Adapted from: Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
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