The World Health Organization's first-ever clinical guideline on the pharmacological treatment of obesity — a landmark shift recognising obesity as a chronic, relapsing disease requiring lifelong, person-centred care.
On 1 December 2025, the World Health Organization published its first-ever clinical guideline on the use of GLP-1 receptor agonist and GIP/GLP-1 dual agonist therapies for the treatment of obesity in adults. Published simultaneously in JAMA, this landmark document represents a critical paradigm shift in the global management of obesity.
The WHO guideline explicitly recognises obesity as a chronic, relapsing disease — moving away from historical framing as a "lifestyle condition." It emphasises that obesity requires lifelong care integrating behavioural, medical, surgical and preventive strategies. This is WHO's first clinical guidance that endorses pharmacotherapy as part of comprehensive obesity management.
The WHO Director-General, Dr Tedros Adhanom Ghebreyesus, framed the guideline as one component of a broader strategy built on three complementary pillars:
The guideline provides two conditional recommendations, graded using the GRADE methodology. Both are conditional due to limitations in long-term data, cost, system readiness, and equity implications.
In adults living with obesity (BMI ≥ 30 kg/m²), GLP-1 receptor agonists or GIP/GLP-1 dual agonists may be used as long-term treatment.
This recommendation is derived from clinical trials in which treatment durations ranged from 26 to 240 weeks, with a median follow-up of 52 weeks. Long-term use is defined as continuous treatment for at least 6 months.
Key outcomes evaluated included: weight change, quality of life, adverse events, major adverse cardiovascular events (MACE), and mortality.
This recommendation applies only to adults with obesity (BMI ≥ 30 kg/m²). It does not extend to people with a BMI between 27 and 30 kg/m² who have obesity-related diseases and disorders. Pregnant women are excluded.
Reasons for conditional (rather than strong) grading:
Intensive behavioural interventions, including structured interventions involving healthy diet and physical activity, may be offered to adults living with obesity who are prescribed GLP-1 therapies.
In the informing trials, intensive behavioural therapy comprised:
Although the evidence that IBT enhances GLP-1 effectiveness was limited, the WHO emphasised that counselling on behavioural and lifestyle changes should be provided as a first step to amplify and support optimal health outcomes. Follow-up durations in the evidence base ranged from 6 to 24 months, with no direct evidence for outcomes beyond 2 years.
The guideline was informed by three dedicated systematic literature reviews — one for each agent (liraglutide, semaglutide, tirzepatide) — conducted by a single review team. The GDG used the GRADE Evidence-to-Decision (EtD) framework for deliberations.
Eligible randomised controlled trials enrolled adults who were overweight or had obesity, regardless of cardiovascular or metabolic comorbidities. Comparisons were against lifestyle modification alone (with or without placebo) or alternative active drugs combined with lifestyle modification. Treatment duration required a minimum of 12 weeks.
The GDG agreed a priori that if full consensus could not be reached, a supermajority of 60% agreement would be required to proceed. For certain GRADE domains (desirable effects, undesirable effects, certainty of evidence, balance of effects), separate judgements were made for each agent.
The GDG reached consensus that the overall certainty of the evidence for the use of GLP-1 receptor agonists and GIP/GLP-1 dual agonists for obesity is moderate, based on the critical outcomes assessed across GRADE Evidence Profiles.
| Critical Outcome | Liraglutide vs Placebo | Semaglutide vs Placebo | Tirzepatide vs Placebo |
|---|---|---|---|
| Weight Change | ⊕⊕⊕ Moderate | ⊕⊕⊕⊕ Moderate–High | ⊕⊕⊕ Moderate |
| Adverse Events | ⊕⊕ Low | ⊕⊕ Very Low–Low | ⊕⊕ Low |
| Major Adverse CV Events | ⊕⊕ Low | ⊕⊕ Low | Insufficient data |
| Quality of Life | ⊕⊕ Low | ⊕⊕⊕ Low–Moderate | ⊕⊕ Low |
| Mortality | ⊕⊕ Low | ⊕⊕⊕ Low–Moderate | Insufficient data |
| Overall Agent Certainty | Moderate | Moderate | Low–Moderate |
The guideline specifically evaluates three agents with the strongest evidence base for the treatment of obesity. As of early 2025, 10 GLP-1–based therapies had received regulatory approval for obesity and/or diabetes treatment worldwide, with more than 40 compounds in development.
| Agent | Route / Frequency | Placebo-Corrected Weight Loss | ≥5% Weight Loss Threshold | Trial Duration |
|---|---|---|---|---|
| Liraglutide 3.0 mg | Daily SC injection | ~5% | Met in most trials | 52–56 weeks |
| Semaglutide 2.4 mg SC | Weekly SC injection | ~12% (total ~17.3% at 68w) | 69% of participants | 68 weeks |
| Oral Semaglutide 50 mg | Daily oral | ~13% | Met (no T2D only) | 68 weeks |
| Tirzepatide 5 mg | Weekly SC injection | ~13.7% | 72% of participants | 72 weeks |
| Tirzepatide 10 mg | Weekly SC injection | ~20% | >80% of participants | 72 weeks |
| Tirzepatide 15 mg | Weekly SC injection | ~22% | >85% of participants | 72 weeks |
The WHO guideline emphasises that obesity is a chronic disease requiring long-term management. Evidence from the STEP 1 extension trial showed that semaglutide 2.4 mg weekly produced an average weight loss of ~17.3% at 68 weeks, but approximately two-thirds of the weight lost was regained after treatment withdrawal — reinforcing the need for continued, lifelong therapy.
The GDG assessed the safety of each agent separately. GLP-1 therapies were generally well tolerated, with gastrointestinal side effects being the most frequently reported. No new long-term safety signals emerged from the systematic reviews.
| Safety Domain | Liraglutide 3.0 mg | Semaglutide 2.4 mg | Tirzepatide 10/15 mg |
|---|---|---|---|
| Overall AE Incidence | Highest among the three agents | Lower than liraglutide | Lower than liraglutide |
| Serious AEs | Similar to placebo | Similar to placebo | Similar to placebo |
| GI Tolerability | More GI AEs and higher discontinuation | Well-tolerated; dose-dependent GI effects | Well-tolerated; dose-dependent GI effects |
| Pancreatitis Risk | No increased risk vs placebo | No increased risk vs placebo | No increased risk vs placebo |
| Gallbladder Events | Elevated (~78% required cholecystectomy) | Elevated (2.6% vs 1.2% placebo) | Similar across dose groups and placebo |
| Hypoglycaemia Risk | Low (without concomitant insulin/SU) | Low (without concomitant insulin/SU) | Higher risk of severe hypoglycaemia (<54 mg/dL) |
The WHO guideline specifically highlights that the explosive global demand for GLP-1 therapies has fuelled the proliferation of falsified and substandard products, threatening patient safety. The guideline calls for regulated distribution, qualified prescriber requirements, strong regulatory oversight, patient education, and international cooperation to combat this growing problem.
The WHO guideline emphasises that effective implementation requires delivering GLP-1 therapies within a chronic care model supported by a fully capacitated health system. Medicines alone will not solve the global obesity burden.
GLP-1 receptor agonists and GIP/GLP-1 dual agonists should be delivered within a chronic care model that includes:
Treatment may be self-administered by patients in the community and does not require specific healthcare facility settings. This is a key enabler for scale-up, particularly in resource-limited settings. Patient education on injection technique, storage, and side-effect management is essential.
Countries expanding access to GLP-1 therapies must evaluate:
Equitable access is a central concern of the WHO guideline. The WHO Director-General explicitly warned that without concerted action, GLP-1 therapies could widen the gap between rich and poor, both between and within countries.
The guideline recommends that GLP-1 therapies should be incorporated into universal health coverage and primary care benefit packages. However, current global access and affordability remain far below population needs. Market competition as more biosimilars and novel agents enter the pipeline may help reduce prices over time.
Personalised periodic monitoring of treatment response and side effects is essential to ensure sustained adherence and achieve optimal health outcomes within the context of obesity chronic care programmes.
| Assessment | Timing | Rationale |
|---|---|---|
| Serum Creatinine & eGFR | At initiation, dose adjustment, and periodically | Evaluate kidney function; risk of AKI with GI fluid losses |
| HbA1c & Glycaemic Parameters | Baseline and serial monitoring | Assess glycaemic impact and hypoglycaemia risk |
| Body Weight & BMI | Each clinical encounter | Track treatment response and guide dose titration |
| GI Symptom Assessment | During titration and maintenance | Manage nausea, vomiting, and adherence barriers |
| Gallbladder Symptoms | Ongoing clinical vigilance | Cholelithiasis and cholecystitis risk |
| Nutritional Status | Periodic assessment | Monitor for nutritional deficiencies with reduced intake |
The WHO guideline notes that no other close diagnostic workup or monitoring is warranted beyond the assessments listed above. This is clinically relevant for implementation in resource-limited settings, keeping monitoring requirements proportionate and feasible.
The WHO has committed to continuously updating the guideline as new evidence emerges. Several key research gaps and policy development priorities have been identified for 2026 and beyond.
Prioritisation Framework: In early 2026, the WHO will develop an evidence-based, transparent, equitable prioritisation framework to identify which adults with obesity should be prioritised for GLP-1 treatment as supply and system capacity expand.
Paediatric Guideline: A separate guideline addressing the treatment of obesity in children and adolescents is forthcoming.
Continuous Updates: The guideline will be living — continuously updated in response to the evolving evidence base and emerging real-world data on safety, feasibility, effectiveness, and system-level requirements.
The therapeutic landscape is rapidly expanding. Beyond the three agents covered in this guideline, there are more than 40 novel compounds in clinical development, including: