In April 2026, the American College of Physicians published an updated clinical guideline covering pharmacologic treatments for overweight and obesity in outpatient settings. The guideline appears in the Annals of Internal Medicine and is described as a 'living' document, meaning it will be updated as new evidence emerges. It was written to help internal medicine physicians and other outpatient clinicians navigate a crowded field of weight-management medications.
The guideline used the GRADE system, a widely recognized framework that rates both the strength of a recommendation and the certainty of the underlying evidence. Recommendations can be 'strong' or 'conditional,' and evidence can be rated high, moderate, or low certainty. Understanding those labels matters when reading the findings, because not every drug on the list carries the same level of scientific confidence.
For readers curious about the peptide science behind these rankings, the document offers a clear hierarchy worth unpacking. Two peptide-based compounds sit at the very top of the list, while other agents follow at lower tiers with weaker supporting data.
What the guideline actually evaluated
The researchers focused on nonpregnant adults treated in outpatient settings, covering two overlapping groups. The first group consists of adults with a body mass index of 30 or above, which is the standard clinical threshold for obesity. The second group consists of adults with a body mass index between 27 and 30, which falls into the overweight range, but only when those individuals also have at least one related condition such as type 2 diabetes, abnormal cholesterol levels, high blood pressure, obstructive sleep apnea, or cardiovascular disease.
All recommendations in the guideline pair pharmacologic treatment with lifestyle modifications. The guideline does not suggest medication alone. Across every tier, the underlying assumption is that dietary change, physical activity, and behavioral support are also part of the plan. This framing reflects the current scientific consensus that medication works as an addition to lifestyle work, not a replacement for it.
First-line peptides and the evidence behind them
At the top of the list, the guideline places two peptide-based compounds: semaglutide and tirzepatide. Both receive a conditional recommendation supported by moderate-certainty evidence for adults with obesity. The same two compounds also lead the list for the overweight group with metabolic comorbidities.
Semaglutide is a glucagon-like peptide-1 receptor agonist, commonly abbreviated as a GLP-1 agonist. It mimics a gut hormone that influences appetite signaling, gastric emptying, and blood sugar regulation. Research across multiple trials has documented meaningful reductions in body weight when semaglutide is used alongside lifestyle changes, and the evidence pool is large enough that the GRADE reviewers rated it moderate certainty.
Tirzepatide adds a second mechanism. It acts on both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor, making it a dual agonist. Published trial data suggest the dual-receptor approach produces somewhat larger average weight reductions than single-agonist compounds, though head-to-head comparisons across all relevant outcomes are still accumulating. The guideline rates tirzepatide at moderate certainty as well, placing it alongside semaglutide rather than above or below it in the formal recommendation.
A conditional recommendation means the committee believes most patients would benefit, but that individual circumstances, including cost, access, contraindications, and personal preferences, should shape the final decision. It is a softer signal than a strong recommendation, which would imply the evidence is robust enough to apply broadly with little variation.
Second, third, and fourth-line options
Below the two leading peptides, the guideline lists additional agents, all rated at low certainty. For the obesity group, the second-line option is a combination of phentermine and topiramate, third is liraglutide, and fourth is a combination of naltrexone and bupropion. For the overweight group with comorbidities, liraglutide moves into the second-line position behind semaglutide and tirzepatide.
Liraglutide is also a GLP-1 receptor agonist and is the peptide most closely related to semaglutide on this list. It has a longer track record than its newer relatives but a smaller apparent effect size in the available trials. Its lower ranking reflects that evidence profile rather than a safety concern specific to liraglutide.
The non-peptide options, phentermine-topiramate and naltrexone-bupropion, carry additional caution flags. The guideline notes that phentermine-topiramate requires monthly pregnancy tests and is contraindicated in people with cardiovascular disease. Naltrexone-bupropion carries a warning related to suicidal ideation. These factors push those options further down the hierarchy for many patients.
What clinicians are asked to discuss with patients
A notable feature of the guideline is its explicit list of topics that clinicians and patients should cover before starting any medication or switching from one to another. The list includes benefits, harms, cost, access and availability, existing health conditions, weight loss goals, life expectancy, personal values and preferences, and any contraindications or warnings specific to the chosen compound.
This framing reflects a broader shift in clinical guidelines toward shared decision-making. Rather than prescribing a single path, the guideline acknowledges that the same drug may be right for one patient and wrong for another based on insurance coverage, side effect tolerance, or comorbidity profile. Cost and access appear prominently because semaglutide and tirzepatide, despite leading on evidence, are among the most expensive options and face supply constraints in some markets.
The inclusion of life expectancy as a discussion point is also notable. For some patients, long-term cardiovascular risk reduction may be the primary motivation for treatment, while for others, near-term quality of life or management of a specific comorbidity may matter more. The guideline does not resolve those trade-offs for clinicians but asks that they be named and considered explicitly.
Limitations of a living guideline
The document is labeled a living guideline deliberately. Evidence in this field is accumulating faster than traditional guideline cycles allow, and the authors built in a process for regular updates. Ratings that carry moderate certainty today may shift upward if longer-term cardiovascular or mortality data emerge, or they could be revised if safety signals appear in post-market surveillance.
It is also worth noting that GRADE moderate certainty does not mean the science is settled. It means the reviewers are reasonably confident that the true effect is close to the estimated effect, but acknowledges that future studies could change the picture. For semaglutide and tirzepatide, the evidence base is larger than for the lower-tier drugs, but much of it comes from trials of one to two years in duration. Decade-long safety and efficacy data do not yet exist for these compounds in the same volume they do for older medications.
The guideline also does not address all possible compounds studied in the weight-management literature, only those with sufficient trial data to evaluate through GRADE. Research into other peptide pathways, including agents targeting amylin, peptide YY, and growth hormone-related mechanisms, continues in academic and clinical settings but did not meet the inclusion criteria for this document.
Takeaways for the research-minded reader
For anyone following the peptide research space, the 2026 ACP guideline is a useful snapshot of where the mainstream clinical evidence stands. Two GLP-1-class peptides and one dual-agonist peptide now sit at the top of a formal, evidence-graded recommendation from one of the largest internal medicine organizations in the United States. That represents a meaningful shift from even a few years ago, when these compounds occupied a more experimental corner of the metabolic literature.
The guideline does not cover research peptides studied outside the clinical drug approval process, and it was written for licensed clinicians managing diagnosed conditions in outpatient care. Its scope is deliberately narrow. But the mechanisms it validates, GLP-1 receptor activation and dual incretin agonism, are the same mechanisms being examined in a wider body of basic and translational research exploring metabolic regulation, appetite signaling, and related physiology.
The literature in this area is moving quickly, and a living guideline that can update its rankings as new data arrive is a reasonable response to that pace of change.
