Frances is a 49-year-old woman with a body mass index (BMI) of 34 kg/m². She has tried numerous diets and exercise plans to lose weight but is frustrated by a lack of significant progress. She tried Weight Watchers® and saw a dietitian for 6 months but didn't lose any weight. She has a history of prediabetes, hypertension, kidney stones, and chronic back pain.

Tom, a 34-year-old man, has a history of depression, gastroesophageal reflux disease, and a bout of acute pancreatitis, as well as lifelong obesity. He has tried aggressively for the past 2 years to lose weight, working with a dietitian, a personal trainer, and a group support program. He eats a low-fat diet and exercises regularly, but his appetite and cravings have increased significantly over the past several months. He has lost and kept off 40 pounds, lowering his BMI to 33 kg/m², but has been unable to lose any more weight.

What are the most appropriate medication treatment options for patients like these? Read on as we discuss appropriate use of each of the four agents approved for long-term treatment and an additional medication approved for short-term use—including how to use medications in specific patient cases.

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Obesity is a chronic medical condition that requires a comprehensive approach for successful management. Although behavioral change is central and all affected patients should receive counseling on nutrition and physical activity, those who do not respond may benefit from US Food and Drug Administration (FDA)-approved anti-obesity medications.

Available agents are able to help patients achieve, on average, 5%-15% weight loss, which usually leads to significant improvements in many obesity-associated comorbid conditions, including hyperglycemia and diabetes, hyperlipidemia, hypertension, and others.

Pharmacotherapy is indicated in all patients with a BMI ≥ 30 kg/m² as well as those with a BMI ≥ 27 kg/m² who have at least one obesity-related comorbidity (eg, diabetes, hypertension, hyperlipidemia). Medication, however, should only be seen as an adjunct to behavioral counseling—not a substitute.

It is important to emphasize that the benefits of medication are typically lost if the treatment is discontinued. Patients who respond to treatment should continue the medication, and that includes both those with a goal of continued weight loss and those who need to maintain lost weight. Although short-term medications may be useful in some cases, those approved for long-term use will primarily be discussed in this slideshow.

Unfortunately, exceedingly few patients with clear indications for pharmacotherapy are taking anti-obesity medications, as demonstrated on the graph.^[1] Only about 1% of patients for whom they are indicated are prescribed these medications.

Several stimulant-type medications have been approved for decades for short-term use. The most commonly used, by far, is phentermine, which is a sympathomimetic amine that suppresses appetite. This schedule IV drug was approved for short-term (less than 12 weeks) use in 1959. While average weight loss with phentermine is approximately 5% of body weight, no data on long-term maintenance of this weight loss have been published.

The most relevant potential contraindications include pregnancy, nursing, monoamine oxidase inhibitor use, glaucoma, drug abuse history, hyperthyroidism, uncontrolled hypertension, and history of coronary artery disease.^[2]

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Orlistat is the only peripherally acting agent. It is a pancreatic lipase inhibitor that reduces the absorption of ingested fat. Orlistat is dosed thrice daily with meals. It was initially approved by the FDA in 1999 and is now approved for over-the-counter use at half-dose (60 mg), branded as alli®. The XENDOS trial^[3] showed that orlistat plus intensive behavioral counseling led to twice the weight loss (23 lb) of that achieved with counseling plus placebo (12 lb) among 3305 individuals over the period of 1 year. Progression to type 2 diabetes was reduced by 45% in patients with baseline impaired glucose tolerance and 37% overall in the orlistat group compared with the placebo group.

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Since 2012, four new medications have been approved by the FDA. These medications have robust evidence for efficacy and safety. In contrast to the older appetite-suppressant medications (eg, phentermine), these agents have demonstrated long-term efficacy and safety and have been formally approved for long-term administration.

In contrast to peripherally acting medications, which do not affect appetite, these medications are centrally acting, leading to decreased appetite or increased satiety. This is particularly important because studies (and clinical and personal experiences) show that weight loss tends to increase appetite.^[5]

The combination of phentermine and extended-release topiramate takes advantage of the additive weight-loss effects of these agents. While both phentermine and topiramate, on their own, lead to relatively small weight losses, the combination leads to particularly impressive weight loss, even at low doses. In the SEQUEL trial,^[6] patients treated with the combination lost more than 10% of starting body weight, on average, compared with less than 2% weight loss in the placebo group. Treated patients had improved cardiometabolic markers and many were able to reduce or discontinue blood pressure or diabetes medications. Progression to type 2 diabetes was reduced by 76% compared with placebo in patients treated with the highest dose of the medication.^[6] In the EQUIP trial,^[7] patients with severe obesity (BMI ≥ 35 kg/m²) who completed 1 year of treatment with phentermine-topiramate ER 15 mg/92 mg lost 14.4% of body weight compared with 2.1% in the placebo group. Patients with extreme obesity (BMI > 45 kg/m²), a population that is rarely included in studies of nonsurgical weight loss interventions, showed even greater benefits, with more than 50% of patients who completed the trial losing more than 15% of initial body weight and 28% of patients losing more than 20% of initial body weight.^[8]

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For weight loss treatment, start with 3.75 mg phentermine/23 mg topiramate ER and escalate to 7.5/46 mg after 2 weeks. Response should be evaluated after 12 weeks, and treatment should either be escalated to a higher dose or discontinued if patients do not achieve at least a 3% weight loss.

Lorcaserin is a selective serotonin 2c (5HT-2c) receptor agonist, which specifically stimulates the 5HT-2c receptors in the appetite center of the brain. As opposed to earlier serotonin agonists that were used off-label for weight loss, lorcaserin primarily stimulates the 2c subtype rather than other serotonin receptors in the brain and body, thereby leading to fewer adverse effects.

On average, treatment with lorcaserin leads to a nearly 8% body weight loss in patients completing 1 year of treatment.^[10] Several intermediate cardiovascular risk factors, including blood pressure, heart rate, lipids, and glycemic control, improve with the weight loss. Patients with type 2 diabetes had 0.9% glycated hemoglobin (A1c) improvement, which is more than expected from moderate weight loss alone and on par with many type 2 diabetes medications.

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Dosing of lorcaserin is 10 mg twice daily and does not require titration. Patients who respond to lorcaserin usually do so relatively quickly. Therefore, response to treatment should be evaluated 12 weeks after initiation. If patients lose 5% or more weight from baseline, they will probably continue losing weight, so the medication should generally be continued. In contrast, if patients do not lose at least 5% of initial body weight after 12 weeks, then the treatment should generally be discontinued because there is low likelihood of further weight loss.

Bupropion, a dopamine and norepinephrine reuptake inhibitor, has been approved by the FDA for treatment of depression and smoking cessation. Naltrexone is an opioid receptor antagonist used in the treatment of addictions. Alone, neither agent is effective for weight loss, but the combination can produce impressive weight loss. Patients feel diminished appetite and fewer cravings. In clinical trials, weight loss exceeded 8% of baseline body weight, compared with < 2% with placebo, and cardiometabolic parameters improved. When combined with intensive lifestyle intervention, naltrexone SR-bupropion SR use led to 12% weight loss, compared with 7% weight loss in the counseling-plus-placebo group. Patients with type 2 diabetes lost about 6% of body weight and had significantly improved glycemic control, including lowering of A1c by 0.6%, compared with 0.1% with placebo. Measures of food cravings were also improved across the clinical trials, which may be related to the effects of naltrexone and/or bupropion in the mesocorticolimbic dopamine system and other brain areas related to reward-driven behaviors.^[11]

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Treatment is initiated with one pill (8 mg naltrexone/90 mg bupropion) daily for the first week, followed by weekly escalation to a target dose of four pills (32/360 mg), administered as two pills twice daily, by week 4. Response should be evaluated after 12 weeks on the target dose (which is typically 16 weeks from initiation, accounting for the titration schedule), and treatment may be discontinued if patients do not achieve at least 5% weight loss. Those who lose at least 5% of their starting body weight by week 16 have average 1-year weight loss exceeding 13%.^[11]

Liraglutide 3.0 mg is the most recently approved medication for chronic weight management. It was approved for a primary indication of obesity treatment in December 2014. Liraglutide is a glucagon-like peptide 1 receptor agonist that was initially approved in 2010 for diabetes treatment, at a maximum dose of 1.8 mg. Liraglutide requires injectable administration through a small needle delivered subcutaneously to the abdomen, arm, or thigh. Treatment with liraglutide led to approximately 9% weight loss, compared with 3% with placebo, and most patients maintained that loss through 3 years. In patients with prediabetes at baseline, 71% treated with liraglutide no longer had prediabetes at the end of 1 year, compared with 37% in the placebo group. After 3 years, there was nearly an 80% lower progression to diabetes compared with placebo. In a unique trial assessing weight maintenance, participants initially engaged in a medically monitored diet and lost approximately 6% of body weight within 12 weeks. They were randomly assigned to either liraglutide 3.0 mg or placebo and followed for 1 year to evaluate weight loss maintenance. The liraglutide group lost an additional 7% of body weight and was much less likely to regain lost weight.^[12]

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Initiation of treatment includes weekly titration by 0.6 mg/week administered subcutaneously over 5 weeks, to the target dose of 3.0 mg. Response to treatment should be evaluated after 16 weeks and treatment should be stopped if patients do not achieve at least 4% weight loss.

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Answer: Liraglutide 3.0 mg

This patient is an ideal candidate for liraglutide 3.0 mg, as it would probably improve her weight and glycemic control. Liraglutide has been shown to decrease the progression to diabetes by nearly 80% compared with placebo.

Orlistat and phentermine-topiramate ER are not ideal options, as they may increase the likelihood of kidney stone recurrence.

Naltrexone SR-bupropion SR is not ideal, as it is contraindicated with the use of opioid medications. It could be used intermittently when the patient is not using an opioid (with 7-10 days in between use to avoid concomitant administration), or the patient could be advised to switch to a non-opioid pain medication.

Lorcaserin is not contraindicated but is not an ideal choice because she is taking a serotonergic agent.

Because this patient is interested in long-term weight management support and is not likely to become pregnant, given her age, the use of a long-term medication is preferred to a short-term one.

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Answer: Naltrexone SR/bupropion SR

Naltrexone SR/bupropion SR is a particularly useful option for this patient. It would probably help him to reduce his weight even further. In addition, although it is not approved for depression or smoking cessation per se, a benefit is likely given the effect of bupropion on depression and smoking cessation.

Orlistat is not an ideal option, as this peripherally acting medication probably would not help him to reduce his food intake and manage his increased appetite.

Phentermine is likewise not an ideal option, as it is only approved for short-term use, and this patient likely will need long-term treatment.

Lorcaserin is not contraindicated, but it is not an ideal choice because the patient is taking a serotonergic agent.

Liraglutide is contraindicated in patients with history of pancreatitis.