ACP: tirzepatide, semaglutide first-line

The American College of Physicians published a living clinical practice guideline on 16 June 2026 in the Annals of Internal Medicine, ranking tirzepatide and semaglutide as first-line pharmacologic treatments for adults with obesity or overweight plus weight-related comorbidities^[1]. The guideline covers 13 drugs, grades the evidence behind each, and assigns a tiered treatment sequence. It is the first major US physician-society guideline to place GLP-1 and dual GIP/GLP-1 agonists at the top of a formal recommendation hierarchy for obesity.

What the guideline recommends

For adults with a BMI of 30 or higher, ACP conditionally recommends starting pharmacologic treatment alongside lifestyle modifications. The guideline places semaglutide and tirzepatide first, supported by moderate-certainty evidence from the meta-analysis published alongside it. Phentermine-topiramate sits second, liraglutide third, and naltrexone-bupropion fourth, all three supported by low-certainty evidence^[1].

For adults with a BMI between 27 and 30 who also have type 2 diabetes, dyslipidaemia, hypertension, obstructive sleep apnoea, or cardiovascular disease, the guideline again places semaglutide and tirzepatide first, with liraglutide as a second option^[1].

Both recommendations are graded as conditional rather than strong, meaning ACP acknowledges that individual patient values, costs, and access should influence the choice. The guideline explicitly asks clinicians to discuss benefits, harms, costs, and availability before prescribing. It also flags specific clinical considerations: pregnancy is a contraindication for several of the listed drugs, cardiovascular history should inform which agents are appropriate, and psychiatric monitoring is warranted with naltrexone-bupropion.

How this fits with the companion reviews

The guideline does not stand alone. ACP published it as a package alongside two systematic reviews in the same issue of Annals. The first is a meta-analysis of benefits and harms pooling 69 randomised controlled trials and 112,511 participants across 13 drugs. That review supplied the efficacy rankings that informed the tiered recommendation: semaglutide and tirzepatide produced the greatest weight loss relative to placebo, with semaglutide also showing a probable reduction in all-cause mortality and major adverse cardiovascular events from the SELECT trial data.

The second is a cost-effectiveness systematic review that rated tirzepatide as potentially high-value but flagged poor study quality across all published obesity drug cost models. Together, the three papers form the evidence base behind the tiered recommendations.

What the guideline does not cover

The scope is adults in outpatient settings. It excludes pregnant adults, inpatient settings, and bariatric surgery comparisons. It does not cover investigational agents that lacked sufficient Phase 3 data at the October 2025 search cut-off, including retatrutide and orforglipron. It does not address paediatric obesity, which falls under separate guidelines. And it does not tell clinicians which specific drug within the first-line tier to choose: the ranking puts semaglutide and tirzepatide side by side without favouring one over the other.

Cost is acknowledged but not resolved. The guideline references the companion cost-effectiveness review but does not set price thresholds or formulary recommendations. In practice, access to tirzepatide and semaglutide varies widely by insurance plan, employer coverage decisions, and country. The branded products, Mounjaro and Zepbound for tirzepatide and Wegovy for semaglutide, carry list prices that put them out of reach for many uninsured patients^[3]. ACP leaves the cost conversation to the prescriber-patient discussion rather than embedding it in the recommendation grading.

Long-term cardiovascular outcomes data remain thin for most drugs in the guideline. Semaglutide is the only agent with a completed large-scale cardiovascular outcomes trial (SELECT) reporting a mortality benefit. For tirzepatide, the dedicated MACE outcomes trial in obesity without diabetes has not yet read out^[2]. The guideline acknowledges this gap without resolving it.

Why a living guideline

ACP calls this a "living" guideline, meaning it will be updated as new evidence accumulates rather than waiting for a scheduled revision cycle. That design matters here because several late-stage obesity drugs (retatrutide, orforglipron, semaglutide-cagrilintide) are expected to report Phase 3 results through 2027, and tirzepatide's own cardiovascular outcomes data should arrive before 2029. A static guideline published today would be outdated within a year^[1].

For readers tracking the incretin class, this guideline is the reference framework US internists will use when prescribing. The tirzepatide and semaglutide pages on this site cover the trial evidence, regulatory status, and safety profiles behind the first-line recommendation. The guideline itself is indexed at PubMed under PMID 42296496^[1]. Outside the US, prescribing frameworks differ: the EMA authorises Mounjaro for both diabetes and weight management under a single brand^[3], and the UK's NICE has its own technology appraisals (TA924 for diabetes, TA1026 for obesity) governing NHS access. This ACP guideline applies to US outpatient practice specifically, but the underlying evidence base is the same international trial programme.