This is the second part of our two-part blog series covering The American Association of Clinical Endocrinology Consensus Statement: Algorithm for the Evaluation and Treatment of Adults with Obesity/Adiposity-Based Chronic Disease- 2025 Update (access the guidelines here). Last week, we discussed the initial evaluation and staging of those with excess weight. In today’s blog, we will dive into the treatment options.

The AACE guidelines promote different classes of medications based on obesity-related chronic disease (ORCD) severity, the first released guidelines that explicitly make this distinction. Medications are divided into first- and second-generation anti-obesity medication categories based on their expected weight-loss potential.

  • First-generation: Expected weight loss of ≥5% to 15%. The medications included in this categorization are phentermine monotherapy, phentermine/topiramate ER, naltrexone/bupropion ER, and liraglutide. Based on this criteria, orforglipron would also be included.
  • Second-generation: Expected weight loss of ≥15%. This includes semaglutide and tirzepatide. Once retatrutide is released (anticipated in late 2026 or early 2027), it will also be included in this category.

As discussed last week, AACE staging helps guide the aggressiveness of pharmacotherapy. It preferentially supports the use of second-generation anti-obesity medications in patients with more severe stage 3 disease. Importantly, this does not preclude the use of these medications in earlier stages (stage 1 or 2), but rather emphasizes prioritizing more aggressive treatment in those with severe disease complications. This aligns with broader medical practice, where treatment intensity is escalated based on disease severity. First-generation agents remain appropriate for stages 1 and 2, particularly given their lower cost and greater accessibility. Understandably, limitations related to cost, insurance coverage, tolerability, and patient preference may necessitate deviation from these guidelines.

In addition to AACE staging, treatment selection can be guided by clinical trial data demonstrating benefits for specific ORCD conditions, independent of weight loss, highlighting a patient-centered, individualized approach. The table below summarizes these findings, categorizing medications as first, second, or third-line based on evidence supporting their use in specific adiposity-based chronic disease (ABCD) conditions.

While there are clear patterns across therapies, it is important to recognize that even when trials have not directly evaluated specific indications, weight loss itself is generally associated with improvements across many conditions. In addition, many first and second-generation medications have secondary benefits (including off-label) that may treat concurrent comorbidities, which should be considered:

  • Binge eating syndrome and food cravings: Topiramate, phentermine/ topiramate, liraglutide, and semaglutide
  • Migraines: Topiramate
  • Alcohol use dependence: Naltrexone
  • Smoking cessation: Bupropion

Now, let’s get into the individual medications themselves. I have summarized these in prior blogs (linked below), but provide a brief synopsis below:

  • Orlistat: Approved in 1999, this medication inhibits pancreatic lipase, reducing fat absorption by approximately 30%. It has been shown to reduce the incidence of diabetes and improve LDL-C levels, independent of weight loss. Adverse effects are primarily gastrointestinal, including fecal urgency, incontinence, and abdominal discomfort. It can impair the absorption of fat-soluble vitamins, potentially leading to deficiencies. Additionally, it may cause oxalate nephropathy and should be avoided in patients with malabsorption disorders.
  • Phentermine: This is one of the most commonly prescribed anti-obesity medications, and has been available since 1959. It is contraindicated in patients with a history of coronary artery disease, stroke, congestive heart failure, uncontrolled hypertension, glaucoma, hyperthyroidism, arrhythmias, or substance use disorder.
  • Phentermine/topiramate: This combination was approved in 2012, with FDA indications expanded to include patients as young as 12 years in 2022. In addition to known teratogenicity (topiramate), potential adverse effects of topiramate include calcium phosphate nephrolithiasis in those with a history of kidney stones, and thus should be avoided in this population, drowsiness, dysgeusia, and paresthesia. Phentermine-related contraindications and side effects, discussed above, also apply. Importantly, the combination of phentermine and topiramate extended-release has been shown to reduce blood pressure in contrast to phentermine monotherapy, improve obstructive sleep apnea, and decrease progression from prediabetes to type 2 diabetes.
  • Naltrexone/bupropion ER: Approved in 2014 for weight management in adults, this combination includes bupropion, which can be stimulating and should be used cautiously in patients with anxiety and avoided in those with uncontrolled hypertension. Bupropion is also contraindicated in individuals with seizure disorders or conditions that lower the seizure threshold, whereas naltrexone is contraindicated in chronic opioid use. This combination medication should not be taken with high-fat meals, as this can increase systemic absorption. Similar to phentermine/topiramate, dose reduction is required in patients with advanced hepatic or renal impairment.
  • Liraglutide: Approved in 2020 for chronic weight management, it was the first GLP-1 receptor agonist approved for obesity. Its relatively short half-life of approximately 13 hours (compared with 183 hours for semaglutide) necessitates daily dosing. It is approved for patients aged 12 years and older for obesity. As with other GLP-1 receptor agonists, common adverse effects include nausea, constipation, and diarrhea, particularly during dose escalation. To improve tolerability, initiate therapy at a low dose and titrate gradually, encourage smaller, more frequent meals, and advise patients to stop eating when full.
  • Semaglutide: In 2021, semaglutide was approved for obesity management, and in 2022, its indication was expanded to include adolescents aged 12 years and older. More recently (2026), an oral formulation was approved for obesity. It also has FDA approval for the treatment of metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis and for secondary prevention of major adverse cardiovascular events. Clinical trials have demonstrated additional benefits, including improvements in osteoarthritis symptoms, reduced progression to type 2 diabetes, and improved outcomes in patients with heart failure with preserved ejection fraction.
  • Tirzepatide: The first dual incretin (GLP-1 and GIP) therapy, approved in 2022 for obesity management. A recent blog reviewed the latest trials and improvements in secondary conditions, so those details will not be repeated here.
  • Cellulose and citric acid hydrogel (Plenity® and Epitomee®): FDA-cleared, volume-occupying device promotes satiety by expanding in the stomach. Plenity® previously exited the market but has recently returned as a non-prescription option, while Epitomee® is FDA-approved but not yet commercially available. Weight loss with these devices has been associated with improvements in triglycerides and reductions in blood pressure.
  • Setmelanotide: This medication is approved for a limited number of genetic causes of obesity in patients as young as 2 years, including Bardet–Biedl syndrome and deficiencies or mutations in POMC, proprotein convertase 1, and the leptin receptor. It was more recently approved for acquired hypothalamic obesity in patients aged 4 years and older. Adverse effects include hyperpigmentation, spontaneous erections, increased sexual arousal, and suicidal ideation.

Metabolic and bariatric surgery was also briefly discussed. This topic has been covered extensively in other blogs, but remember that indications include a BMI ≥35 kg/m² for all individuals and a BMI 30-34.9 kg/m² with cardiometabolic disease such as diabetes.

During treatment, clinical response, both from anthropopathic measurements as well as ORCD clinical improvements, should be monitored, with therapy intensity adjusted accordingly. Given that most ORCD require a weight reduction of at least 5% to clinically improve outcomes, if treatment has not led to at least 5% weight reduction by the 3-month mark, a change in pharmacologic treatment is indicated. In contrast, weight loss of more than 15% improves and may even put into remission many ORCD.

Lots of information and great tables are included in the guidelines. We touched the surface on what I felt was the highest yield for ABOM exam purposes, but again, I would encourage you to take the time to go through these guidelines cover to cover. Not only will this be useful in broadening understanding of these medications for the exam, but it will also provide numerous clinical pearls that will improve the quality of care provided to patients.

Sample Question:

A primary care clinic is implementing additional anthropometric measurements as part of routine vital signs to better assess cardiometabolic risk in patients with overweight and obesity. In addition to height, weight, and blood pressure, the clinic plans to incorporate the waist-to-height ratio into standard screening. Which of the following waist-to-height ratio thresholds is most appropriate for identifying increased cardiometabolic risk?

A. 0.3 for Asian patients

B. 0.5 for all populations

C. 0.7 for Caucasians

D. 1 for all populations

Next Week: Medullary Thyroid Carcinoma

Upcoming: Monthly Knowledge Check. This is a review checklist of must-know items for ABOM exams based on the previous four blog topics. In addition, this will include a brief explanation of the correct answers to previous sample questions.

For more practice questions, check out the following:

  • Obesity Medicine Board Review Questions (2026)
  • Obesity Medicine Practice Tests (2026)

(Copyright 2026) Obesity Medicine Board Review Questions, LLC: obesitymedicinereview.com

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Copyediting by Kelly Smith

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