Obesity Pharmacotherapy

Obesity Pharmacotherapy

Donna H. Ryan

Rekha Kumar


With nearly 40% of US adults having a BMI ≥30 kg/m2, and unsuccessful following lifestyle modification changes alone, many of these individuals would benefit from intensifying therapy with an antiobesity medication (AOM)1 to help them adhere to lifestyle changes in order to lose enough weight to achieve health benefits and to sustain weight loss. On the other hand, some medications promote unintentional weight gain and providers also need to avoid prescribing certain drugs which would worsen obesity.

Since 2012, four new medications have been approved by the US Food and Drug Administration (US FDA) with an indication for chronic weight management, although one was voluntarily withdrawn in February 2020. In addition, one capsule that is considered a device was marketed in 2020. Moreover, there are several companies with active obesity drug discovery programs and promising compounds in development that appear to produce twice the amount of weight loss achievable with current medications. Thus, we are entering a period where prescribers have access to safe and increasingly effective tools to help patients with complications of excess abnormal body fat to regularly achieve enough weight loss to prevent and control obesity-driven chronic diseases. This chapter will review current best practices and context regarding using medications for patients with obesity (including avoiding medications that promote weight gain), the safety and efficacy of currently available medications (both with a weight management indication and those commonly used “off-label” to aid weight management), and the most promising AOMs on the horizon.


In the National Institutes of Health (NIH)-supported Obesity Guidelines released in 2014,2 obesity pharmacotherapy was allowed for individuals who are unresponsive to lifestyle interventions after 6 months of treatment, have a BMI of ≥30 kg/m2, or a BMI of ≥27 kg/m2 with a weight-induced comorbidity where weight-loss medication may be added to the treatment plan. At the time those recommendations were drafted, orlistat was the only medication available for obesity management. In 2015, the US Endocrine Society produced the first guidelines3 that recommended pharmacologic treatment of obesity. These evidence statements and recommendations were based on a systematic evidence review encompassing all available approved AOMs. This guidance was also notable for including recommendations for management of drug-induced weight gain.3 The Endocrine Society guidelines review the existing evidence for the FDA-approved medicines for weight management, and the recommendations contained in them are not just permissive of medication use (as in earlier guidelines), but also directive of medication use to help patients achieve weight loss in order to attain health benefits.3 Taking this a step further, the AACE/ACE Guidelines4 from 2016 indicate that initial pharmacotherapy added to lifestyle intervention is appropriate if patients present with one or more severe comorbidities and would benefit from weight loss of 10% or more.4,5

As shown in Table 8.1, there are currently four medications approved for chronic weight management by the US FDA in addition to phentermine and a few related compounds which are approved for short-term use. Although their abuse potential is low, some of these medications are scheduled by the US Drug Enforcement Agency and regulated by the states. Of note is the fact that three medications have been approved since 2012 and are approved for long-term use (reinforcing the concept that obesity is a chronic disease). The mechanism of action of FDA-approved AOMs is also shown in Table 8.1. These medications (except orlistat) work biologically to suppress appetite, affecting hunger, satiety, and response to highly rewarding foods, thus making it easier for patients to follow their dietary intentions to restrict caloric intake. The rationale for using medications to aid in weight loss and weight loss maintenance is based on an advanced understanding of the biologic regulation of body weight and food intake. Knowledge has emerged regarding the biologic basis of eating, e.g., the gut-brain axis of the homeostatic regulation of hunger and satiety, and of the reward circuitry that governs the response to foods of high hedonic value.6 Patients who struggle losing weight with lifestyle alone do not have weak “will power.” Rather, the biologic forces opposing weight loss are very powerful. Furthermore, once weight loss occurs, metabolic adaptations reduce metabolism, adding to the forces opposing weight loss and driving regain.

TABLE 8.1 Current Antiobesity Medications Approved in the United States and How They Worka






  • Sympathomimetic amine; norepinephrine release and to lesser extent releases other monoamines

Approved 1959

  • Yes


  • Pancreatic lipase inhibitor; blocks absorption of 30% of ingested dietary fat

Approved 1999

OTC Approved 2007

  • No

Phentermine/Topiramate ER

  • Sympathomimetic

  • Anticonvulsant (GABA receptor modulator carbonic anhydrase inhibitor, glutamate antagonist)

Approved 2012

  • Yes

Naltrexone SR/Bupropion SR

  • Opioid receptor antagonist

  • Dopamine/norepinephrine reuptake inhibitor

Approved 2014

  • No

Liraglutide 3.0 mg

  • GLP-1 receptor agonist

Approved 2014

  • No

GABA, gamma aminobutyric acid.

aInformation from product labels of prescribing information, except where noted.

Even with our most intensive lifestyle interventions, some patients are unsuccessful at achieving adequate weight loss. In the “gold standard” Look AHEAD intensive lifestyle intervention, despite a minimum of 24 counseling sessions in the first year and the use of meal replacements, 30% of patients did not achieve 5% weight loss from baseline.7 Furthermore, weight regain occurred even though intervention continued through year 4. At that time, there was only 3.6% difference in weight between the intensive lifestyle intervention group and control.8 Clearly, HCPs cannot duplicate this degree of intensity of effort at the intervention deployed in Look
AHEAD. In primary care efforts at lifestyle intervention, average weight loss is on the order of 0.9 to 2.0 kg in 6 months.9 For the many patients who are unable to achieve and sustain weight loss with lifestyle intervention alone, AOMs are needed to help achieve enough weight loss to produce improved health benefits. Additionally, for patients with more severe complications of obesity, such as type 2 diabetes (T2D) or obstructive sleep apnea, weight loss of >10% is needed to maximize health benefits. Despite the limitations of lifestyle intervention for weight loss, high-intensity behavioral treatment of obesity (≥14 visits in the first 6 months, followed by at least monthly contact for maintenance of weight loss) is recommended as a standard of care for treatment of obesity and should produce a 5% to 10% weight loss during the first 6 months of treatment. Several randomized trials using different medications have reported that the combination of intensive behavioral treatment and pharmacotherapy is additive in terms of weight loss.

How much weight does a patient need to lose? Health benefits can be achieved without normalizing body weight or achieving a BMI <25 or <30 kg/m2. One begins to see improvement in glycemic measures, triglycerides, and HDL-cholesterol with small amounts of weight loss (3% to 5%), but there appears to be a further dose response benefit with greater levels of weight loss.2 Modest weight loss (5% to 10%) is also associated with improvement in systolic and diastolic blood pressure.2 There are graded improvements in measures of quality of life, depression, mobility, sexual dysfunction, and urinary stress incontinence that are demonstrable with modest weight loss (5% to 10%) and continue to improve with further weight loss.10 Additionally, for patients with higher BMI levels (≥40 kg/m2), the ability to lose the same proportion of weight with lifestyle intervention is equal to that of those with lower BMI levels, and there is equal benefit in terms of risk factor improvement with modest weight loss.10 For some comorbid conditions, more weight loss is needed, i.e., 10% to 15%, to translate into clinical improvement. This is observed for obstructive sleep apnea and nonalcoholic steatohepatitis.10

Table 8.2 shows the proportion of patients who achieved 5% or 10% weight loss at 1 year in the clinical studies which were performed for FDA approval. All medications are included except phentermine. There are no long-term studies with phentermine, and its efficacy is discussed below. It should be noted that in all cases there is a greater proportion of medication-treated subjects who achieve the 5% and 10% benchmark, compared to placebo. Also noteworthy is the wide range of success that is achieved with placebo alone. This is because the components, delivery, and intensity of the lifestyle intervention varied between the studies.

In terms of context, the studies that led to the approval of AOMs were all conducted along with a lifestyle intervention of diet and physical activity counseling. In any study where the medication was stopped, weight regain was demonstrated. Therefore, the labels state they are “indicated as an adjunct to reduced calorie diet and increased physical activity for chronic weight management in adults.” As discussed later, the medication could be given after patients lose weight on a strict diet to produce more weight loss and advance maintenance. Furthermore, this chapter will later discuss the use of medications in the setting of bariatric procedures, where AOMs are used as an adjunct to the surgical procedure to treat insufficient weight loss or weight regain or to improve weight-related comorbidities.


Qualifications for Prescription

The FDA labels for AOMs provide the indications of BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with a weight-related comorbidity. It is not necessary for patients to fail a weight loss attempt while under the care of an HCP for the patient to be prescribed a medication; the history of failure to maintain successful weight loss is enough. For patients with more severe complications (T2D, hypertension, and sleep apnea), practitioners should be more proactive about using medications and follow the AACE recommendations.4,5 Those patients would benefit from 10% or more loss and should be prescribed medications to augment the weight loss effort.

Choosing an Individual Medication

The Endocrine Society guideline3 indicates that contraindications and warnings should be the first step to match the patient to the medication profile, excluding medications from consideration if they are contraindicated or associated with serious warnings. See Table 8.3
for a description of contraindications and safety issues with AOMs. Choosing a medication requires matching the patient profile to the medication profile. If patients describe difficulty controlling their appetite, then common sense dictates that one of the medications that affect appetite should be chosen, rather than orlistat. Also, one should consider dual benefits: orlistat can enforce a low-fat diet and lower plasma LDL cholesterol.15 Liraglutide 3.0 mg can lower glycemic measures and, at a dose of 1.8 mg in patients with T2D, is associated with reduction in cardiovascular events in addition to affecting appetite and body weight.16 See Table 8.4 for a description of dual benefits of AOMs.

TABLE 8.2 Antiobesity Medications Approved in the United States: Dosing and Route of Administration; Efficacy (Proportion of Treated Individuals Who Achieve >5% and >10% During Phase 3 Clinical Trials)a






  • 8 mg up to tid, before meals


  • 15 mg, 30 mg, or 37.5 mg once daily

In a 6-month study11

Phentermine 7 mg = 43.3%

Phentermine 15 mg = 46.2%

Placebo = 15.5%

Not described


  • 120 mg tid, before meals


  • 60 mg tid before meals

  • Oral

In five studies, Orlistat = 35.5%-54.8%


Placebo = 16%-27.4%

In five studies, Orlistat = 16.4%-25.8%


Placebo = 3.8%-9.9%

Phentermine/Topiramate ER (Phen/TPM)

  • 7.5 mg/46 mg qid

  • 15 mg/92 mg qid, indicated as rescue

  • Oral, once daily dosing (requires titration)

In two studies, Phen/TPM (3 doses) = 45% − 70%;

vs. Placebo = 17% − 21%

Difference from placebo = 27.6% − 49.4%

In two studies, Phen/TPM (3 doses) = 19% − 48%;

vs. Placebo = 7%

Difference from placebo = 11.4% − 40.3%

Naltrexone SR/Bupropion SR (NB)

  • 32 mg/360 mg

  • Oral; bid dosing (requires titration)

In three studies, NB = 44.2% − 62.3%;


Placebo = 17% − 43%

Difference from placebo = 14% − 25%

In three studies, NB = 15% − 35%;


Placebo = 5% − 21%

Difference from placebo = 10% − 14%


  • 3.0 mg

  • Injection; once daily dosing (requires titration)

In two studies, Liraglutide = 62%12 and 49%13;


Placebo = 34.4%12 and 16.4%13

Difference from placebo = 32.6%14 and 22.6%12

In two studies, Liraglutide = 22.4%13 and 33.9%12;


Placebo = 5.5%13 and 15.4%12

Difference from placebo = 16.9%12 and 18.5%14

aInformation from product labels of prescribing information, except where noted.

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Aug 25, 2021 | Posted by in GENERAL | Comments Off on Obesity Pharmacotherapy

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