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Clinical considerations for AOMs
Clinical Considerations for Antiobesity Medications: Matching the Right Medication to the Right Patient

Released: May 29, 2025

Expiration: May 28, 2026

Christopher Weber
Christopher Weber, MD, FAAP, FACP, CSCS, dABOM, FOMA
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Key Takeaways
  • Semaglutide and tirzepatide offer the most significant weight-loss benefit and have additional labeled indications, such as reducing risk of major adverse cardiovascular events (semaglutide) and treating moderate to severe obstructive sleep apnea (tirzepatide).
  • Older oral agents like extended-release phentermine/topiramate and bupropion/naltrexone remain valuable alternatives, especially when cost or patient preference limits the use of injectables.
  • Phenotype-based obesity care is an evolving field and shows promise in further personalizing care and optimizing patient outcomes.

As an obesity medicine specialist, I believe that the single most critical aspect of clinical decision-making involves selecting the right antiobesity medication (AOM) for the right patient. This is far from a 1-size-fits-all approach. And although the latest agents offer impressive efficacy, each patient brings a unique clinical picture, comorbidities, preferences, and barriers to care that should guide shared decision-making.

When there are no limiting factors, my first-line choices comprise the newer agents: semaglutide, a GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist. These agents consistently demonstrate significant weight loss in clinical trials. Of importance, they fundamentally alter how patients experience hunger and fullness, which can translate into meaningful behavior change and improved quality of life.

Comorbidities Steer the Choice
Comorbidities frequently guide which agent I recommend to patients. Semaglutide’s role in cardiovascular risk reduction as demonstrated in the SELECT trial is especially noteworthy. The trial specifically included patients with a BMI ≥27 kg/m2 and prior myocardial infarction, prior stroke, or symptomatic peripheral arterial disease. This is an important distinction when navigating health insurance approvals, as coverage may not extend to patients with broader cardiovascular histories such as those with stents or coronary bypass surgery. Despite this, I discuss semaglutide’s benefits with patients who are at elevated cardiovascular risk, even if they do not meet the strict trial criteria. Furthermore, the early onset of cardiovascular benefit that was observed before significant weight loss occurred suggests a potential direct cardioprotective effect. Based on these data, semaglutide has FDA approval to reduce the risk of major adverse cardiovascular events in patients with established cardiovascular disease and overweight/obesity, or type 2 diabetes.

Tirzepatide recently received FDA approval for obesity and moderate to severe obstructive sleep apnea (OSA) following the results of the SURMOUNT-OSA trial. Although health insurance companies may not cover tirzepatide for patients with mild OSA, I still discuss its potential benefits with them, especially in cases where cost is not a barrier. Of importance, this trial evaluated patients with and without positive airway pressure therapy, allowing for broader applicability in clinical practice.

In the realm of liver disease, the ESSENCE trial examined semaglutide in patients with metabolic dysfunction–associated steatohepatitis (MASH). Although FDA approval for this indication is pending, the trial demonstrated meaningful improvements in liver fibrosis and resolved steatohepatitis. For patients with known MASH, I often consider semaglutide because I anticipate a dual liver health and weight reduction benefit with its use.

Then there are patients with type 2 diabetes who benefit from these therapies because they improve glycemic control alongside weight loss. Although newer agents tend to provide more robust weight loss, older GLP-1 receptor agonists like liraglutide or dulaglutide (and particularly at its newer highest dose of 4.5 mg) remain viable treatment options, especially when cost or health insurance restrict patient access to newer therapies. The higher doses of liraglutide are approved by the FDA to treat obesity. I have also seen clinically meaningful weight loss with dulaglutide at this higher dose in select patients even though it is not an FDA-approved obesity treatment. 

By contrast, agents like exenatide or oral semaglutide tend to offer minimal weight loss benefit. However, the landscape may soon change. A higher-dose formulation of oral semaglutide is currently under FDA review, with trial data suggesting weight loss comparable to injectable semaglutide. If approved, this could be a major advancement for patients seeking an oral alternative with similar efficacy to its injectable counterpart.

Older Antiobesity Medications Are Still Valuable
Despite the prominence of novel AOMs, older oral agents still play an important role in clinical practice, especially when newer medications are inaccessible or contraindicated. For example, extended-release phentermine/topiramate remains an effective and affordable option. Weight loss with this agent approaches an average of approximately 7% to 11% depending on the dose, and it is typically well tolerated. Extended-release bupropion/naltrexone offers slightly less weight loss on average, but I have found that some patients—particularly those struggling with emotional or reward-based eating—respond very well to it. I also prescribe phentermine alone, which received FDA approval in 1959. Despite its age, it remains a reliable option when appropriately used and monitored.

An often overlooked option is orlistat, which is available by prescription or over-the-counter at a lower-dose weight–loss option. Although gastrointestinal adverse effects (ie, diarrhea) are common and often discourage its use, it has a niche role. For example, many of the newer agents cause constipation, so orlistat can help counterbalance this effect when used in combination. Although the over-the-counter dose is lower than its prescription version, patients may achieve therapeutic benefit with this lower dose and proper guidance.

Looking Ahead: Treatment Personalization and Emerging Therapies
As practice evolves toward phenotype-driven obesity care, specific eating behaviors and physiologic traits can be considered when choosing treatment. Some patients struggle with emotional or stress-related eating, whereas others must deal with early hunger and/or poor satiety. Although we do not yet have standardized protocols linking specific phenotypes to therapies, research is ongoing.

In the meantime, clinical judgment and conversations with patients should guide treatment decisions. Those who prefer to avoid injections may be better suited for oral agents even if they are less potent. In converse, patients wary of stimulants because of insomnia or cardiovascular sensitivity may prefer nonstimulant agents like extended-release bupropion/naltrexone. Factors such as dosing frequency, pill burden, convenience, and tolerance all influence the final choice.

There are 2 additional areas of research that deserve attention. First, a recent study suggests that semaglutide may provide benefit in patients with obesity and knee osteoarthritis, potentially via anti-inflammatory effects and weight loss. Second, there is growing interest in the use of GLP-1 receptor agonists for substance use disorders, where some data suggest reductions in craving and use. Although neither is yet an FDA-approved indication, these findings highlight the expanding AOM therapeutic landscape.

Your Thoughts
Have you had success with phenotype-based prescribing for patients with overweight or obesity? What factors do you most often consider when recommending an AOM for obesity treatment? You can get involved in the discussion by answering the poll question and posting a comment below.

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What factors do you most often consider when recommending AOMs for obesity? 

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