AGA releases first guideline ranking most effective anti-obesity medications
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The AGA has released its first guideline endorsing the use of four medications for obesity management, when paired with lifestyle interventions, for patients who have failed to lose weight with diet and exercise alone.
The new guideline also ranked its recommended four “anti-obesity medications” in order of effectiveness: semaglutide 2.4 mg (Wegovy, Novo Nordisk), extended-release phentermine-topiramate (Qsymia, Vivus), liraglutide 3 mg (Saxenda, Novo Nordisk) and extended-release naltrexone-bupropion (Contrave, Currax Pharmaceuticals).
“Obesity is a chronic condition that requires a multidisciplinary approach, starting with lifestyle interventions,” Perica Davitkov, MD, guideline author and associate program director of gastroenterology fellowship training at Case Western Reserve University, told Healio. “However, in the long term, the majority of adults with obesity will not respond adequately to lifestyle interventions alone. Therefore, they should be offered one of the four suggested medications to treat obesity.”
Spurred on by the significant increase in obesity prevalence and obesity-related complications, “some of which are managed in gastroenterology clinics and as a sequela of the prior AGA guidelines on endoscopic placement of intragastric balloons for treatment of obesity,” Davitkov noted that the AGA has prioritized development of guidelines on FDA-approved medications for obesity management.
However, not all FDA-approved medications received the AGA endorsement. The AGA recommended against the use of orlistat because of its moderate potential benefit for weight loss and higher incidence of treatment discontinuation due to side effects. The AGA also acknowledged a “knowledge gap” on the use of Gelesis100 oral superabsorbent hydrogel, recommending that it only be used in the context of a clinical trial.
Semaglutide
With the strongest total body weight loss percentage (10.8%) among the included agents, coupled with a low risk for adverse events and treatment discontinuation, semaglutide 2.4 mg “may be prioritized over other approved [anti-obesity medications] for the long-term treatment of obesity for most patients,” according to the AGA.
Already approved for the treatment of type 2 diabetes mellitus, semaglutide has demonstrated glucoregulatory and cardioprotective benefits that would further promote its use. However, the guideline also made note of the possibility of delayed gastric emptying with the use of this drug, with side effects of nausea and vomiting.
The AGA guideline panel made a conditional recommendation for the use of semaglutide due to potential varying weight loss in patients with type 2 diabetes.
Phentermine-topiramate
As the second most effective anti-obesity agent, with a total body weight loss percentage of 8.5%, extended-release phentermine-topiramate received a conditional AGA recommendation with a moderate certainty of evidence.
As topiramate has demonstrated efficacy in treating migraine headaches, the AGA noted that this combination can be preferentially used for patients with comorbid migraines. However, the AGA guideline panel cautioned that this combination “should be avoided in patients with a history of cardiovascular disease and uncontrolled hypertension.”
Additionally, since topiramate is teratogenic, women of reproductive age should be advised to use contraception consistently while receiving the medication. The panel also noted that patient blood pressure and heart rate should be checked periodically.
Although phentermine monotherapy has been approved by the FDA and remains one of the most prescribed anti-obesity medications in U.S., its approval is only for short-term use and lacks high-quality data for the efficacy and safety of long-term monotherapy.
“Based on lower-certainty evidence, phentermine and diethylpropion monotherapy along with lifestyle interventions are also suggested for use in treatment of obesity,” Davitkov said. “[However,] these medications are approved by the FDA for short-term use (12 weeks), and longer use will be off-label.”
Liraglutide
Like semaglutide, liraglutide 3 mg has been approved for the treatment of type 2 diabetes mellitus and has been shown to reduce morbidity and mortality in patients with type 2 diabetes at risk for cardiovascular disease.
With an effective total body weight loss of 4.8%, the AGA panel determined the drug to have a moderate weight loss benefit and small magnitude for potential adverse effects, consisting mostly of nausea and vomiting. However, the guideline did note that liraglutide has been linked to an increased risk for pancreatitis and gallbladder disease.
Naltrexone-bupropion
With the lowest total body weight loss percentage (3%), extended-release naltrexone-bupropion was determined to hold moderate benefit for weight loss with a small magnitude for adverse events. Additionally, the AGA noted that naltrexone-bupropion may be considered for the treatment of overweight or obesity in patients attempting smoking cessation as well as in patients with depression.
However, the AGA guideline panel cautioned that this combination “should be avoided in patients with seizure disorders and used with caution in patients at risk of seizures,” and should not be used concomitantly with opiates. The panel also noted that patient blood pressure and heart rate should be checked periodically, especially during the initial 12 weeks of treatment.
“Shared decision-making, including patients’ values and preferences, is important to consider when deciding which medications should be used,” Davitkov said. “Also, this decision should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs and access to the therapy.”
He noted that “this guideline is the first since diabetes drugs were approved for obesity treatment and provides clear information for doctors and their adult patients who struggle to lose weight or keep it off with lifestyle changes alone.”
Perspective
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Derrick Cetin, DO
This is not the first organization to release guidelines on anti-obesity medications (AOMs). The Obesity Medicine Association, American College of Clinical Endocrinology and The Obesity Society also have released guidelines on the use of AOMs. The AGA went a step further and released guidelines on four anti-obesity medications, ranking them in order of efficacy. I agree with the AGA recommendation that GLP-1 receptor agonists, extended-release phentermine-topiramate, liraglutide and extended-release naltrexone-bupropion are the most effective anti-obesity medications available as of this release. The placebo-subtracted percent weight loss of 10.8, 8.5, 4.8, and 3, respectively, are similar to data from published studies.
It is important to be aware of new anti-obesity medications that are available, as patients may bring them up during an appointment. They can be an important adjunct to lifestyle interventions to promote weight loss, maintain weight loss, and control hunger and cravings when on a calorie-restricted diet.
What we find in the field of obesity medicine is that not every patient who takes an anti-obesity medication is going to lose as much weight as described in the aforementioned studies. Certain individuals have better outcomes to treatment: Some people lose weight and others may gain weight. So, we have to look at individual responsiveness to a given anti-obesity medication, beyond the weight loss reported in studies.
In my practice, I find it helpful to look at four different phenotypes, as shown in studies, to better individualize treatment. Some patients may have a hungry gut, some may have a hungry brain, others may have emotional/stress eating and others may have low metabolism. Some of the new medications — like semaglutide or liraglutide — can be very effective for an individual with a hungry gut, as the medication slows stomach emptying and sends signals to the part of the brain that regulates hunger and metabolism. The extended form of phentermine-topiramate can address a hungry brain, while others, such as naltrexone-bupropion, can be more effective for an individual who has emotional stress eating. Selecting an anti-obesity medication based on a specific phenotype may lead to better individual response to treatment. In obesity medicine, this is called precision medicine.
I would like to emphasize that obesity is a complex, heterogeneous disease. Treatment should be individualized and is best provided by a multidisciplinary team approach.
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