Global Guidelines · Structured Recommendations · Algorithms
GLP-1 Receptor Agonists —
The Complete Guidelines Reference
Every major clinical practice guideline covering GLP-1 receptor agonists — from NICE NG28 and the ADA Standards through to ESC/EASD, EASO, KDIGO, and WHO frameworks — presented with full recommendation text, evidence grades, interactive accordions, prescribing algorithms, and a cross-guideline divergence analysis for UK clinicians.
Overview
The Global Guideline Landscape
Nine frameworks · 2023–2026 · Convergences and divergences
GLP-1 receptor agonists now appear in guidelines spanning endocrinology, cardiology, nephrology, hepatology, and obesity medicine — from nine separate organisations across three continents. While all guidelines endorse GLP-1 RAs for T2DM management, significant divergences exist in HbA1c thresholds, preferred agents, obesity indications, combination therapy sequencing, and the emphasis on cardiometabolic vs glycaemic goals. Understanding these differences is essential for UK clinicians consulting international literature or managing patients who have moved between healthcare systems.
9
Major guidelines covering GLP-1 RAs
2026
Most recent: NICE NG28 Feb 2026
3
Continents · UK · US · Europe · Global
5
Indication domains covered across guidelines
| Guideline | Org | Year | Scope | GLP-1 RA position | Preferred agents |
|---|---|---|---|---|---|
| NICE NG28 | NICE (UK) | Feb 2026 | T2DM adults | 2nd–3rd line · CV stream independent | Semaglutide, Tirzepatide |
| NICE TA875 | NICE (UK) | 2023 | Obesity | Weight management · BMI ≥30 | Semaglutide 2.4 mg |
| SfE Obesity | SfE (UK) | 2024 | Obesity · Endocrinology | Specialist-led · Tier 3 | Sema · Tirz when available |
| ADA Standards | ADA (US) | 2025 | Diabetes comprehensive | First-line with CV/CKD comorbidity | GLP-1 RA or SGLT2i first |
| AACE Consensus | AACE (US) | 2024 | T2DM · Obesity | First-line in obesity-T2DM | Tirzepatide · Semaglutide |
| AHA/ACC Obesity | AHA/ACC (US) | 2023 | CV prevention | CV risk reduction · SELECT evidence | Sema 2.4 mg for CVD+obesity |
| ADA/EASD Consensus | ADA/EASD (EU/US) | 2023 update | T2DM hyperglycaemia | Early use if CVD/CKD/HF risk | Sema preferred · Tirz strong option |
| ESC/EASD | ESC (Europe) | 2023 | CVD in diabetes | Class I recommendation · CVD+T2DM | Sema · Liraglutide · Dula |
| KDIGO CKD | KDIGO (Global) | 2024 | CKD + Diabetes | Standard care in T2DM+CKD | Semaglutide 1 mg (FLOW) |
NICE NG28 — February 2026
The definitive UK clinical guideline for T2DM management in adults. February 2026 update added tirzepatide alongside semaglutide as preferred GLP-1 RA, clarified HbA1c thresholds, and created a CV-independent prescribing stream for patients with established atherosclerotic CVD. Freely available on nice.org.uk.
NICE TA875 — Wegovy for Obesity (2023)
Technology appraisal recommending semaglutide 2.4 mg (Wegovy) for chronic weight management in adults with BMI ≥35 (or ≥30 with comorbidity) within an NHS specialist weight management service. Restricted to 2-year initial treatment period in primary care pathway; specialist services may extend based on clinical review.
SfE Obesity Guidelines — 2024
Society for Endocrinology guidance on pharmacological obesity management, emphasising multidisciplinary team approach, long-term treatment planning, and lean mass preservation. Explicitly recommends resistance exercise alongside GLP-1 RA therapy. Addresses sarcopenic obesity and MASH as special circumstances.
ADA Standards of Medical Care in Diabetes — 2025
The most widely referenced diabetes guideline globally, updated annually. The 2025 edition positions GLP-1 RAs and SGLT2 inhibitors as first-line additions to metformin in patients with established CVD, high CV risk, CKD, or obesity — regardless of HbA1c. Chapter 9 (Pharmacologic Approaches) and Chapter 10 (CV Disease) are most relevant.
AACE Comprehensive T2DM Management Algorithm — 2024
American Association of Clinical Endocrinology positions GLP-1 RAs or tirzepatide as first-line treatment in obese T2DM (BMI ≥30) — ahead of SGLT2i in this specific population. Tirzepatide is preferred over selective GLP-1 RAs for dual HbA1c and weight reduction goals. More aggressive in recommending early pharmacotherapy than NICE.
AHA/ACC Obesity & CV Disease Guideline — 2023
The American Heart Association/ACC Clinical Practice Guideline for Obesity and CVD (2023) was the first cardiology-led guideline to formally recommend pharmacological weight loss for CV risk reduction — pre-dating SELECT publication. Post-SELECT updates position semaglutide 2.4 mg as a Class IIa recommendation for CV risk reduction in patients with established CVD and obesity.
ADA/EASD Joint Consensus Report — T2DM Hyperglycaemia Management
The joint ADA/EASD consensus (Davies et al., updated 2022/2023) uses a person-centred framework with four decision cycles. GLP-1 RAs are recommended early — at the first intensification stage — in patients with CVD, CKD, HF, or weight management as a compelling need. Patient preferences and treatment burden are explicitly integrated into the algorithm.
ESC/EASD Guidelines on CVD in Diabetes — 2023
The European Society of Cardiology guidelines on cardiovascular disease in patients with diabetes give GLP-1 RAs and SGLT2 inhibitors Class I, Level A recommendations for patients with T2DM and established atherosclerotic CVD — independent of glycaemic control. These are cardiology-authored guidelines, giving them particular authority for the CV prevention indication.
WHO Essential Medicines & Diabetes Guidance
WHO has not yet issued a specific GLP-1 RA guideline but has published reports on access equity, essential medicines list considerations, and global diabetes management frameworks. Semaglutide underwent formal WHO Expert Committee review for EML listing (2025), citing SELECT and FLOW evidence — with major implications for global access and pricing negotiations. Refer to the WHO EML website for current listing status.
KDIGO Clinical Practice Guideline for Diabetes Management in CKD — 2024
The first KDIGO guideline dedicated specifically to diabetes management in CKD, incorporating FLOW trial data (2024). Provides detailed, eGFR-stratified recommendations for GLP-1 RA use across CKD stages G3a through G5, and addresses the combination of GLP-1 RA with SGLT2 inhibitor, RAAS blockade, and finerenone — the new four-pillar approach to cardiorenal protection in T2DM+CKD.
Comparison
Cross-Guideline Comparison
Key parameters compared across all 9 guidelines — at a glance
Parameter
🇬🇧 NICE NG28
🇺🇸 ADA 2025
🇪🇺 ADA/EASD
🇪🇺 ESC/EASD
Initial drug choice
Metformin first; GLP-1 RA at step 2–3 (or step 1 if CVD)
Metformin + GLP-1 RA/SGLT2i simultaneously if CVD/CKD/obesity
Person-centred; GLP-1 RA early if CVD/CKD/weight compelling
GLP-1 RA or SGLT2i first if established CVD (Class I)
HbA1c threshold
≥58 mmol/mol (7.5%) standard; ≥53 (7.0%) if CVD
No specific threshold if CVD/CKD — CV benefit is primary goal
Individualised — threshold secondary to CV/renal profile
No HbA1c threshold for CV indication — Class I regardless
Preferred GLP-1 RA (T2DM)
Semaglutide SC · Tirzepatide (both ★)
GLP-1 RA with proven CV benefit · Sema, Lira, Dula
Semaglutide preferred · Tirzepatide strong option
Sema, Liraglutide, Dulaglutide (Class I, Level A)
Obesity indication
NICE TA875: BMI ≥30 (Wegovy); Tier 3 specialist service
FDA approved; no specialist referral required in US
Part of T2DM weight management goals
Not primary scope — refers to obesity guidelines
CV without T2DM
Stream B: Wegovy (SELECT indication) via CV pathway
SELECT indication supported; incorporated into AHA guidance
Not T2DM guideline; refers to AHA/ACC
T2DM scope only; refers to AHA/ACC for non-diabetic
CKD recommendation
Sema with caution eGFR <15; FLOW data noted
GLP-1 RA recommended in CKD; Chapter 11 (CKD)
Recommends GLP-1 RA in CKD; KDIGO data cited
SGLT2i first in CKD; GLP-1 RA as add-on
Combination with SGLT2i
Both may be prescribed; not mandated in same step
Combination endorsed; both for CV+renal protection
Combination supported — complementary mechanisms
Both Class I if CVD+T2DM; sequential or concurrent
Heart failure
SGLT2i preferred for HFrEF; sema for HFpEF+obesity
SGLT2i Class I HFrEF; GLP-1 RA considered HFpEF
SGLT2i preferred HF; GLP-1 RA considered if obesity
SGLT2i Class I both HF types; GLP-1 RA not Class I for HF
Insulin combination
GLP-1 RA + basal insulin permitted; reduce insulin 20%
GLP-1 RA preferred over adding bolus insulin
GLP-1 RA preferred before insulin intensification
GLP-1 RA before insulin; reduce insulin if combined
T1DM
Not licensed; specialist use only off-label
Not approved; adjunctive use discussed in research context
Not endorsed; MODY must be excluded
Not within scope; T2DM guideline only
UK Guideline 1
NICE NG28 — Type 2 Diabetes in Adults
National Institute for Health and Care Excellence · February 2026 · Full recommendation set
🇬🇧
NICE — National Institute for Health and Care Excellence · United Kingdom
NG28 — Type 2 Diabetes in Adults: Management
The definitive UK clinical guideline for type 2 diabetes management in adults. NG28 sets prescribing thresholds, treatment algorithms, preferred agents, and monitoring standards that NHS clinicians are expected to follow. The February 2026 update was the most significant revision since 2022, incorporating tirzepatide, updated cardiovascular prescribing criteria, and expanded renal guidance post-FLOW trial.
2026
nice.org.uk ↗
EVIDENCE GRADES:
1++ High-quality meta-analysis / SR of RCTs
1+ Well-conducted RCTs
2++ High-quality systematic reviews of cohort studies
GPP Good practice point
Section 1 — Glycaemic Management & GLP-1 RA Prescribing
1++
NICE NG28 2026 — Comorbidity-led medicine selection
Do not apply the former later-line HbA1c-threshold model as a universal GLP-1 rule. The February 2026 pathway selects initial and further medicines according to ASCVD, early-onset T2DM, obesity, CKD, frailty, individualised glycaemic target and patient preference.
Current recommendation context: NICE NG28 was last updated 18 February 2026. Use its current visual summaries and prescribing guide because the medicine sequence varies by comorbidity and the benefit sought.
- For early-onset T2DM, NICE recommends metformin plus an SGLT-2 inhibitor and says to consider a GLP-1 receptor agonist or tirzepatide, with different stated benefits.
- For ASCVD, subcutaneous semaglutide up to 1 mg has a specific place in the pathway.
- Further treatment is tied to the individualised glycaemic target and whether treatment is being used for cardiovascular benefit.
- Always check current BNF, UK SmPC, MHRA safety updates and local formulary restrictions.
1++
NICE NG28 2026 — Product roles are not interchangeable
NICE does not simply co-designate semaglutide and tirzepatide as universal preferred agents. The recommendation depends on comorbidity, indication, benefit sought, authorised dose, stopping criteria and shared decision-making.
Why semaglutide and tirzepatide are preferred:
- Semaglutide SC (Ozempic) — SUSTAIN-7 demonstrated superiority over dulaglutide 1.5 mg on HbA1c (−0.40%) and weight (−3.5 kg). SELECT trial demonstrates CV superiority (HR 0.80) in obesity without T2DM.
- Tirzepatide (Mounjaro) — SURPASS-2 showed superiority over semaglutide 1 mg on HbA1c (−0.51%) and weight (−5.5 kg). NICE NG28 Feb 2026 added tirzepatide as co-preferred following technology appraisal completion.
- Both agents offer once-weekly SC dosing, improving adherence vs daily agents
- Dulaglutide (Trulicity) remains recommended as an alternative when semaglutide or tirzepatide is not tolerated or contraindicated
- Liraglutide (Victoza) is positioned as a third-line alternative given daily dosing and slightly inferior efficacy vs semaglutide
1++
NICE NG28 2026 — ASCVD pathway
For adults with T2DM and ASCVD, follow the current initial- and further-medicine recommendations. Subcutaneous semaglutide up to 1 mg has a specific NICE recommendation; do not generalise this to every GLP-1 medicine or dose.
This is the most significant change in NG28 February 2026. Previous versions specified HbA1c thresholds even for patients with CVD. The updated guidance explicitly decouples the CV indication from glycaemic control:
- Established ASCVD = prior MI, ischaemic stroke, TIA, coronary artery disease, PAD, or prior revascularisation
- GLP-1 RA preferred over SGLT2i when weight loss is a priority or SGLT2i is contraindicated/not tolerated
- SGLT2i preferred when heart failure (especially HFrEF) or CKD (eGFR ≥20) are present
- Both may be combined — NICE states this is clinically appropriate and not counted as a different treatment step
- For patients already at HbA1c target: this recommendation may mean adding a GLP-1 RA purely for CV protection — a paradigm shift in prescribing rationale
GPP
NG28 Rec 1.7.4 — Oral semaglutide (Rybelsus)
Consider oral semaglutide (Rybelsus 14 mg once daily) for people who prefer an oral route of administration and understand the fasting requirement. Oral semaglutide is less effective than subcutaneous semaglutide at equivalent doses but superior to DPP-4 inhibitors.
PIONEER-3 demonstrated oral semaglutide 14 mg was superior to sitagliptin 100 mg (HbA1c difference −0.5%; weight −2.5 kg extra). SOUL trial (2024) confirmed CV benefit (HR 0.86, p=0.039) extending the oral formulation's evidence base to cardiometabolic outcomes.
- Must be taken fasting (no food or drink other than water for 30 minutes after tablet)
- GI side effects are similar to SC formulation but may be marginally more frequent
- ~80–85% of the HbA1c benefit of SC sema 0.5 mg — suitable for patients who decline injections
- Not appropriate for patients who cannot reliably follow the fasting protocol
- Absorption affected by concurrent antacids or PPIs — take at least 30 minutes apart
1+
NG28 Rec 1.7.5 — GLP-1 RA with basal insulin
For people with type 2 diabetes on basal insulin who require further intensification, consider adding a GLP-1 receptor agonist in preference to adding prandial insulin, as GLP-1 RAs provide equivalent or superior HbA1c reduction with weight loss rather than weight gain.
Clinical rationale: Adding prandial (bolus) insulin to basal insulin (basal-bolus regimen) produces mean weight gain of +2–4 kg and significantly increases hypoglycaemia risk and injection frequency. Adding a GLP-1 RA to basal insulin (SURPASS-5 with tirzepatide: −2.6% HbA1c, −8.8 kg) provides comparable or superior glycaemic control with weight loss and no intrinsic hypoglycaemia risk.
- Mandatory dose reduction: Reduce basal insulin dose by 20% when initiating a GLP-1 RA to prevent hypoglycaemia
- Fixed-ratio combinations (IDegLira, IGlarLixi) are alternatives when simplifying the regimen is a priority
- Tirzepatide has the strongest evidence for add-on to glargine (SURPASS-5)
- Review prandial insulin doses if already on basal-bolus — GLP-1 RA may allow prandial dose reduction or cessation
1+
NG28 Rec 1.7.6 — BMI thresholds and ethnicity adjustments
When considering a GLP-1 receptor agonist for weight-related benefits, use a BMI threshold of 30 kg/m² for most adults, or 27.5 kg/m² for people of South Asian, Chinese, Black African, or African-Caribbean family origin, reflecting the lower BMI at which metabolic risk increases in these populations.
This recommendation codifies the ethnicity-adjusted BMI thresholds that have been recommended by NHS England since 2013 and are supported by WHO consultation data showing equivalent cardiometabolic risk occurs at lower BMI in South Asian and East Asian populations:
- South Asian (Indian, Pakistani, Bangladeshi, Sri Lankan): threshold BMI 27.5 kg/m² equivalent to 30 kg/m² in white European
- East Asian (Chinese, Japanese, Korean): similar adjustment to 27.5 kg/m²
- Black African / African-Caribbean: adjustment less established; use clinical judgement with BMI 27.5 as guide
- These thresholds apply to the weight management rationale for GLP-1 RA — the CV and renal indications apply regardless of BMI
Section 2 — Monitoring, Dose Titration & Treatment Review
GPP
NG28 Rec 1.7.7 — Dose titration protocol
Titrate GLP-1 receptor agonist doses according to the drug's Summary of Product Characteristics. Do not escalate doses faster than specified to minimise gastrointestinal adverse effects. Offer to slow titration if GI side effects are troublesome — patients who tolerate a slower titration schedule are more likely to persist with treatment.
Standard titration schedules (per SmPC):
- Semaglutide SC: 0.25 mg × 4 weeks → 0.5 mg × 4 weeks → 1 mg maintenance (T2DM); escalate to 2 mg if further HbA1c reduction needed. For obesity (Wegovy): → 1.7 → 2.4 mg over 16 weeks total
- Tirzepatide: 2.5 mg × 4 weeks → 5 mg × 4 weeks → escalate in 2.5 mg steps q4 weeks to max tolerated (up to 15 mg)
- Dulaglutide: 0.75 mg × 4 weeks → 1.5 mg → 3 mg → 4.5 mg (each step 4 weeks minimum)
- If GI side effects are severe at dose escalation: return to previous dose for an additional 4 weeks before retrying escalation
- Some patients may tolerate and prefer to remain at sub-maximal doses if adequate HbA1c control achieved
GPP
NG28 Rec 1.7.8 — Treatment review and non-response
Review the response to GLP-1 receptor agonist treatment at 6 months. Discontinue if HbA1c has not reduced by at least 11 mmol/mol (1.0%) from baseline or if the person has not lost at least 3% of body weight (where weight loss was a treatment goal), unless there is a compelling CV or renal reason to continue.
Interpreting the non-response threshold: The 11 mmol/mol (1.0%) HbA1c threshold at 6 months is a practical stopping rule for the glycaemic indication. However, the caveat — "unless there is a compelling CV or renal reason to continue" — is clinically critical and should not be overlooked:
- For patients with established CVD on semaglutide for SELECT indication: continue regardless of glycaemic response
- For patients with T2DM+CKD on semaglutide 1 mg for FLOW indication: continue for renal protection even if HbA1c change modest
- Weight loss threshold (3% at 6 months) applies when weight management is a stated goal — not when purely glycaemic or CV indication
- Poor HbA1c response may reflect inadequate dose titration — ensure patient is on maintenance dose before applying stopping rule
- Where response is partial but treatment is continued: document rationale explicitly in clinical records
1+
NG28 Rec 1.7.9 — Retinal screening before semaglutide (T2DM)
Before initiating semaglutide in people with type 2 diabetes, check the person's retinal screening status. If they have pre-existing retinopathy (particularly proliferative or pre-proliferative), refer to ophthalmology for assessment before starting treatment, because rapid HbA1c reduction may worsen retinal disease.
Basis: SUSTAIN-6 demonstrated a significant increase in retinopathy complications with semaglutide (HR 1.76, 3.0% vs 1.8%) — attributed to rapid HbA1c reduction in patients with pre-existing retinal disease. This is not a class-wide effect (not seen with liraglutide in LEADER or in SELECT, which enrolled people without diabetes).
- Check that retinal screening is up to date (within 12 months) before starting semaglutide in T2DM
- If retinal screening overdue — arrange urgent diabetic eye screening before initiating
- Pre-proliferative or proliferative retinopathy: ophthalmology review mandatory before prescribing
- Background retinopathy only: proceed with slower titration and retinal rescreen at 3–6 months post-initiation
- This caution applies specifically to semaglutide and is less well-characterised for tirzepatide (no equivalent trial signal)
NICE NG28 February 2026 — GLP-1 RA Decision Algorithm
UK Guideline 2
NICE TA875 — Semaglutide for Obesity
Technology Appraisal 875 · Wegovy · NHS specialist weight management pathway
⚖
NICE Technology Appraisal · United Kingdom
TA875 — Semaglutide 2.4 mg for Managing Overweight and Obesity
NICE's cost-effectiveness appraisal of semaglutide 2.4 mg (Wegovy) for chronic weight management in adults with obesity or overweight with weight-related comorbidities, within a specialist weight management service context. This TA sets the eligibility criteria for NHS access to Wegovy.
2023
NICE TA875 — Key Recommendations
A
TA875 Rec 1 — Eligibility criteria
Semaglutide 2.4 mg (Wegovy) is recommended as an option for managing excess weight, including obesity, in adults, only if they have a BMI of at least 35 kg/m² and at least 1 weight-related comorbidity, or a BMI of 30 to 34.9 kg/m² with a recent (within 2 years) referral from secondary care for a condition related to their weight.
Full eligibility (all must apply):
- BMI ≥35 with ≥1 weight-related comorbidity (T2DM, HTN, dyslipidaemia, OSA, CVD, MASH, OSA, depression related to obesity), OR BMI 30–34.9 with specialist referral for weight-related condition
- No contraindications to semaglutide
- Treatment provided within the context of a multidisciplinary tier 3 weight management service that includes lifestyle intervention, dietary support, and psychological support
- Prior unsuccessful attempt at a structured lifestyle programme
- Patient understands weight loss requires continued treatment and will regain weight if stopped
A
TA875 Rec 2 — Treatment duration and review
Treatment should be reviewed at 6 months. Stop semaglutide if the person has not lost at least 5% of their initial body weight since starting treatment. Treatment is recommended for a maximum of 2 years in most cases, with annual clinical review.
Important nuances on the 2-year limit:
- The 2-year limit applies to the initial NHS England primary care pathway commissioning — specialist weight management services (tier 3) can recommend continuation beyond 2 years for patients with high clinical need
- The STEP-4 withdrawal trial data (weight regain +6.9% on stopping) strongly suggests most patients will require indefinite therapy — this tension between the 2-year NHS limit and clinical evidence is ongoing
- NHS England is reviewing the 2-year restriction as of 2025 following clinical advocacy from obesity medicine societies
- Patients who lose ≥5% at 6 months should continue to 12 months, at which point efficacy and weight trajectory are reassessed
- Annual review must document continued benefit, tolerability, patient engagement with lifestyle programme, and clinical need for continuation
GPP
TA875 Rec 3 — South Asian ethnicity threshold
For people of South Asian, Chinese, Black African, or African-Caribbean family origin, use a lower BMI threshold (27.5 kg/m² instead of 30 kg/m²) to define eligibility for semaglutide 2.4 mg, reflecting the higher metabolic risk at lower BMI in these populations.
This codifies the ethnicity-adjusted threshold into NHS commissioning. In practice, many specialist services have been applying this adjustment based on NICE's general guidance on ethnicity-adjusted BMI thresholds since 2013. The TA875 incorporation provides clear commissioning authority for accessing Wegovy at BMI ≥27.5 in South Asian patients with weight-related comorbidities.
UK Guideline 3
SfE — Society for Endocrinology
Obesity & Metabolic Disease Guidelines · 2024 · UK Specialist Perspective
🏥
Society for Endocrinology · United Kingdom
Pharmacological Management of Obesity in Adults — Clinical Guidance 2024
The SfE guidance addresses pharmacological obesity management from a specialist endocrinology perspective, complementing NICE TA875 with clinical depth on agent selection, lean mass preservation, MASH co-management, sarcopenic obesity, and long-term treatment planning in complex patients. It reflects the expertise of UK endocrinologists managing the most challenging obesity cases.
2024
SfE Key Recommendations
1+
SfE Rec 1 — Agent selection hierarchy
For weight management, use the medicine's marketing authorisation together with the relevant NICE technology appraisal and NHS commissioning criteria. Tirzepatide is covered by TA1026 and semaglutide by TA875; neither is a universal agent of choice for every adult with obesity.
The SfE takes a more pragmatic approach than NICE TA875, acknowledging that tirzepatide (Mounjaro) is likely to receive obesity licensure in the UK during 2025 and recommending clinicians plan for this. The hierarchy for specialist services:
- Tirzepatide 15 mg (Mounjaro) — maximum weight loss; UK-licensed for both T2DM and weight management (Mounjaro); NICE TA criteria apply for NHS access
- Semaglutide 2.4 mg (Wegovy) — NICE TA875-approved standard; excellent CV evidence (SELECT); oral Wegovy tablet MHRA-authorised June 2026
- Liraglutide 3 mg (Saxenda) — daily injection; lower efficacy; use if weekly agents not tolerated
- Orforglipron (oral non-peptide) — Phase 3 programme ongoing; anticipated regulatory filing 2025–2026
1+
SfE Rec 2 — Lean mass preservation
All patients commenced on GLP-1 receptor agonists for obesity management should receive structured advice on resistance exercise and adequate dietary protein intake (minimum 1.2 g/kg ideal body weight/day) to mitigate lean body mass loss, which accounts for 35–40% of GLP-1 RA-induced weight reduction.
The SfE is the only UK guideline to explicitly quantify the lean mass concern and provide specific protein intake recommendations:
- GLP-1 RAs produce approximately 35–40% of weight loss from lean body mass (muscle, bone, organ mass)
- In older adults (≥65), sarcopenic obesity patients, and those with low baseline muscle mass, this may precipitate or worsen sarcopenia
- Resistance exercise (3×/week, progressive load) is the most evidence-based intervention to preserve muscle during weight loss
- Dietary protein: minimum 1.2 g/kg IBW/day; 1.5 g/kg IBW/day in older adults or those with pre-existing low muscle mass
- Refer to physiotherapy or exercise specialist for structured programme alongside pharmacotherapy
- Consider DEXA body composition assessment at baseline and 12 months in high-risk patients (older adults, low BMI at baseline, known sarcopenia)
GPP
SfE Rec 3 — MASH in obesity management
In patients with confirmed MASH and concurrent obesity or T2DM, tirzepatide or semaglutide should be prescribed via their licensed obesity or T2DM indication, with liver-specific monitoring (LFTs 3-monthly, elastography at 12–18 months). Hepatology MDT involvement is recommended when fibrosis stage F2 or above is confirmed.
SfE addresses MASH more explicitly than NICE, reflecting the specialist endocrinology caseload where T2DM + obesity + fatty liver disease commonly co-exist:
- Tirzepatide preferred for MASH based on SYNERGY-NASH data (74% MASH resolution at 15 mg vs 10% placebo)
- Semaglutide is an acceptable alternative pending a Phase 3 MASH biopsy trial
- Arrange baseline liver elastography (FibroScan) and FIB-4 score before initiating in suspected MASH
- Reassess at 12–18 months with repeat elastography — document fibrosis stage change
- If concurrent use with resmetirom (Rezdiffra) is being considered — hepatology review mandatory (no combination trial data yet)
GPP
SfE Rec 4 — Long-term therapy and stopping criteria
GLP-1 RA therapy for obesity should be considered a long-term (potentially lifelong) treatment. The NICE TA875 2-year limit reflects commissioning constraints rather than clinical evidence and should not be used as a clinical stopping criterion. Clinicians should advocate for individual patients requiring continuation beyond 2 years through appropriate clinical review processes.
The SfE explicitly acknowledges and challenges the NICE TA875 2-year treatment limit, reflecting the clinical reality demonstrated by STEP-4 (complete weight regain after withdrawal):
- Obesity is a chronic relapsing disease — treating it with a time-limited course of pharmacotherapy is analagous to treating hypertension for 2 years
- NHS England is reviewing the 2-year restriction as of 2025 in response to clinical advocacy
- Where continuation beyond 2 years is clinically indicated: document clinical need; involve specialist service; use the annual review process to support continuation
- Clinical stopping criteria (not time-based): <5% weight loss at 6 months; intolerable side effects; contraindication development; patient preference after informed discussion
UK Guideline 4
NHS England — Commissioning Pathways
Tier 3 Weight Management · CV Prevention · Formulary Policy · 2025
🏴
NHS England · Commissioning & Formulary Policy
GLP-1 RA Commissioning Pathways — England 2025
NHS England operates distinct commissioning pathways for GLP-1 RAs depending on indication. Understanding which pathway applies determines prescriber type, eligibility criteria, monitoring requirements, and treatment duration limits. These are not clinical guidelines but have direct legal and financial implications for NHS prescribing.
2025
Three NHS England GLP-1 RA Commissioning Pathways
Pathway 1 — T2DM (Primary Care)
Prescribing via NHS Primary Care / GP practice. Agent: Ozempic (Sema SC), Mounjaro (Tirzepatide), Trulicity (Dulaglutide), Rybelsus (Oral Sema). Governed by NICE NG28 criteria.
Prescriber: GP or Practice Nurse (with training)
Pathway 2 — Obesity (Tier 2/3)
Prescribing via NHS Specialist Weight Management Service (Tier 2 or Tier 3). Agent: Wegovy (Sema 2.4 mg). Governed by NICE TA875. Requires MDT assessment and lifestyle programme engagement.
Prescriber: Specialist service clinician
Pathway 3 — CV Prevention (SELECT)
NHS England CV Prevention Programme — Wegovy for established CVD + obesity (no T2DM). SELECT indication. Piloted in selected ICBs from 2024; national rollout 2025. Cardiology or primary care with CV training.
Prescriber: Cardiology / Trained GP (pilot areas)
NHS Formulary Status & Supply — April 2026
Authorisation, NICE recommendation and local NHS availability are separate decisions. Mounjaro has been UK-authorised for weight management since November 2023 and NICE TA1026 recommends it for defined eligible groups with phased implementation. Wegovy access follows its relevant technology appraisal and commissioning pathway. Check current NHS England implementation guidance, local formulary and supply information before prescribing.
US Guideline 1
ADA Standards — Medical Care in Diabetes 2025
American Diabetes Association · Annual update · Most widely cited diabetes guideline globally
🇺🇸
American Diabetes Association (ADA) · United States
Standards of Medical Care in Diabetes — 2025
The ADA Standards of Care is the most widely referenced diabetes guideline globally, updated annually with 16 sections covering all aspects of diabetes management. Chapter 9 (Pharmacologic Approaches) and Chapter 10 (CVD and Risk Management) contain the primary GLP-1 RA recommendations. The ADA uses an evidence grading system (A, B, C, E) reflecting quality of supporting evidence.
2025
ADA EVIDENCE GRADES:
A Clear evidence from well-conducted RCTs
B Supportive evidence from RCTs / cohort studies
C Poorly controlled / observational evidence
E Expert consensus / clinical experience
Chapter 9 — Pharmacologic Approaches to Glycaemic Treatment
A
ADA 9.1 — First-line addition with compelling comorbidities
For people with type 2 diabetes and established cardiovascular disease, CKD, or heart failure, a GLP-1 receptor agonist or SGLT2 inhibitor with proven cardiovascular benefit should be used as part of the glucose-lowering regimen, independent of HbA1c and regardless of metformin use. (Level A)
The most clinically important divergence from NICE: The ADA 2025 positions GLP-1 RAs as potentially first-line (before metformin) in patients with compelling comorbidities. Metformin is no longer mandatory before GLP-1 RA initiation in the ADA framework when CVD, CKD, or obesity drives the clinical decision.
- The evidence base: LEADER (HR 0.87), SUSTAIN-6 (HR 0.74), REWIND (HR 0.88), SELECT (HR 0.80), FLOW (HR 0.76)
- The ADA explicitly states: "these agents are recommended for persons with these comorbidities to reduce cardiovascular risk regardless of whether additional glucose lowering is needed"
- GLP-1 RA preferred over SGLT2i when: obesity and weight loss is a priority; CKD eGFR too low for SGLT2i; patient preference
- SGLT2i preferred over GLP-1 RA when: HFrEF; volume overload; CKD protection primary (noting FLOW now shifts some balance back to GLP-1 RA)
- Metformin remains appropriate for most patients as foundational therapy — the ADA does not abandon metformin, but removes its requirement as a prerequisite
A
ADA 9.2 — Agent selection when weight loss is a goal
For people with type 2 diabetes who need glucose lowering and for whom weight loss is an important treatment goal, a GLP-1 receptor agonist with significant weight-loss efficacy (preferably semaglutide or tirzepatide) is recommended. (Level A)
The ADA 2025 specifically names tirzepatide and semaglutide as the preferred agents when weight loss is a primary goal — the first ADA edition to explicitly rank agents within the GLP-1 RA class:
- Tirzepatide: SURPASS-2 (−11.2 kg vs sema 1 mg); SURMOUNT-1 (−20.9% in obesity); greatest weight loss of any approved agent
- Semaglutide SC: STEP-1 (−14.9%); SELECT (−9.4% in established CVD); well-established safety and CV evidence
- Dulaglutide and liraglutide: less weight loss; appropriate alternatives if sema/tirz not tolerated
- Oral semaglutide: less weight loss than SC formulation; acceptable for injection-averse patients
A
ADA 9.3 — Obesity pharmacotherapy in diabetes
For adults with type 2 diabetes and overweight or obesity, pharmacotherapy for weight management (semaglutide 2.4 mg or tirzepatide 15 mg) should be offered in conjunction with lifestyle intervention to improve glycaemic control and reduce cardiovascular risk factors. (Level A)
The ADA 2025 explicitly endorses obesity-dose pharmacotherapy (semaglutide 2.4 mg, tirzepatide 15 mg) in people with T2DM where weight management is a goal — unlike NICE NG28 which has separate T2DM and obesity pathways. In the US, there is no equivalent to the NHS Tier 3 requirement — obesity pharmacotherapy can be prescribed by any physician:
- Semaglutide 2.4 mg (Wegovy) licensed for obesity in US since 2021; also approved for CV risk reduction (SELECT indication)
- Tirzepatide 15 mg (Zepbound) licensed for obesity in US since 2023
- No requirement for specialist referral or prior 6-month lifestyle programme in US (contrast with NICE TA875)
- BMI threshold: FDA approval for BMI ≥30 or ≥27 with comorbidity — same as EU/UK but without Tier 3 service requirement
Chapter 10 — Cardiovascular Disease and Risk Management
A
ADA 10.1 — GLP-1 RA for established ASCVD
In people with type 2 diabetes and established atherosclerotic cardiovascular disease, or high cardiovascular risk, a GLP-1 receptor agonist with demonstrated cardiovascular benefit should be prescribed to reduce the risk of major adverse cardiovascular events. (Level A)
The ADA defines "demonstrated CV benefit" narrowly — limited to agents with positive MACE superiority in CVOTs:
- Class I recommendation (preferred): Semaglutide SC (SUSTAIN-6 + SELECT), Liraglutide (LEADER), Dulaglutide (REWIND)
- Not preferred for CV indication: Exenatide XR (EXSCEL — non-inferior only), Lixisenatide (ELIXA — neutral)
- For patients without T2DM but with CVD and obesity: SELECT indication for semaglutide 2.4 mg — ADA Chapter 10 explicitly endorses this
- "High CV risk" defined as: age ≥55 + ≥2 of: coronary/carotid/lower extremity stenosis ≥50%, LVH, eGFR <60, or albuminuria
A
ADA 10.2 — Heart failure considerations
In people with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF) and obesity, semaglutide 2.4 mg may be considered to improve quality of life and functional capacity. For heart failure with reduced ejection fraction (HFrEF), SGLT2 inhibitors remain the preferred agent. (Level B)
The ADA 2025 is the first major guideline to formally incorporate STEP-HFpEF data into its recommendations:
- STEP-HFpEF (n=529): KCCQ-CSS +7.8 pts, 6MWD +21.5 m, weight −13.3% at 52 weeks
- STEP-HFpEF-DM (T2DM cohort): comparable improvements across both endpoints
- HFpEF mechanism: weight-mediated preload reduction + anti-inflammatory effects + epicardial adipose tissue reduction
- For HFrEF (EF <40%): SGLT2i (empagliflozin, dapagliflozin) have Class I evidence; GLP-1 RA not contraindicated but no powered HFrEF outcomes trial
- ADA caution: mild chronotropic effect of GLP-1 RAs (+2–4 bpm) is generally well-tolerated but monitor in severe HFrEF
ADA 2025 — T2DM Pharmacotherapy Framework (Simplified)
US Guideline 2
AACE — Comprehensive T2DM Management Algorithm
American Association of Clinical Endocrinology · 2024 Update · Most aggressive GLP-1 RA positioning
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American Association of Clinical Endocrinology (AACE)
Comprehensive Type 2 Diabetes Management Algorithm — 2024 Update
The AACE algorithm is produced by US endocrinology specialists and takes the most aggressive stance on early, high-efficacy therapy of all major guidelines. It positions tirzepatide as the preferred first-line agent in obese T2DM (BMI ≥30) and uses a complication-centric model that prioritises cardiometabolic risk reduction from treatment initiation.
2024
AACE Key Recommendations — 2024
A
AACE Rec 1 — Tirzepatide as preferred first-line in obesity-T2DM
For adults with type 2 diabetes and obesity (BMI ≥30 kg/m²), tirzepatide is the preferred pharmacological agent, offering superior HbA1c reduction (up to −2.58%) and weight loss (up to −22%) compared with all other approved agents. Initiate at 2.5 mg SC weekly and titrate to maximum tolerated dose. (Grade A)
AACE goes further than any other guideline in placing tirzepatide as the primary first-line choice in the obesity + T2DM phenotype — ahead of both SGLT2 inhibitors and selective GLP-1 RAs:
- Rationale: SURPASS-2 showed superiority over semaglutide 1 mg on all endpoints; SURMOUNT-1 showed −20.9% weight in obesity; SURMOUNT-2 showed −13.4% in T2DM + obesity at 15 mg
- AACE explicitly frames obesity-T2DM as requiring maximum efficacy from first treatment decision — not stepwise escalation
- Target dose: 15 mg SC weekly for maximum cardiometabolic benefit
- US context: tirzepatide 15 mg (Mounjaro for T2DM; Zepbound for obesity) is available without specialist referral — unlike UK Tier 3 pathway
- AACE positions SGLT2i as preferred when HF or CKD are primary concerns; GLP-1 RA/tirzepatide when weight + HbA1c are primary
A
AACE Rec 2 — Complication-centric model
Treatment selection should be guided primarily by the presence and severity of diabetes complications and comorbidities (atherosclerotic CVD, CKD, HF, MASH, obesity), not by HbA1c level alone. GLP-1 RAs are first-line in the presence of ASCVD, obesity, or MASH — regardless of current HbA1c. (Grade A)
The AACE complication-centric model predates and influenced the ADA/EASD consensus approach. It explicitly rejects HbA1c as the primary driver of treatment decisions in complex patients:
- ASCVD present → GLP-1 RA with proven CV benefit (sema, lira, dula, or tirz via CV proxy data)
- Obesity (BMI ≥30) → Tirzepatide or semaglutide as primary agent
- MASH → GLP-1 RA preferred (tirzepatide based on SYNERGY-NASH; sema based on LEAN)
- CKD (eGFR ≥25 + UACR ≥100) → GLP-1 RA + SGLT2i combination; sema 1 mg preferred per FLOW
- HF → SGLT2i first; GLP-1 RA if HFpEF + obesity
- HbA1c level only becomes primary driver when none of the above comorbidities are present
B
AACE Rec 3 — HbA1c target individualisation
HbA1c targets should be individualised: ≤6.5% (48 mmol/mol) is achievable and recommended in most non-elderly adults without significant hypoglycaemia risk using GLP-1 RAs or tirzepatide. Less stringent targets (≤7.5–8.0%) are appropriate in elderly, frail, or high hypoglycaemia-risk patients. (Grade B)
AACE recommends a more aggressive HbA1c target (≤6.5% / 48 mmol/mol) than NICE NG28 (which targets <53 mmol/mol / 7.0% in most patients) when using GLP-1 RAs or tirzepatide — justified by these agents' capacity to achieve normoglycaemia without intrinsic hypoglycaemia risk:
- SURPASS-2: 27% of tirzepatide 15 mg patients achieved HbA1c ≤5.7% (normal range)
- The ability to target near-normoglycaemia without hypoglycaemia is a unique property of GLP-1 RAs and tirzepatide
- NICE NG28 UK context: targets are more conservative (≤48 mmol/mol, 6.5% for most; ≤53, 7.0% if on agents with hypoglycaemia risk)
- Older adults (≥75), frailty: AACE recommends ≤7.5–8.0% to avoid hypoglycaemia — aligned with NICE's frailty-adjusted approach
US Guideline 3
AHA/ACC — Obesity & CV Risk Guideline
American Heart Association / American College of Cardiology · 2023 · SELECT evidence incorporated
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American Heart Association / American College of Cardiology
AHA/ACC Guideline for the Diagnosis and Management of Obesity in Adults — 2023
The first major cardiology society guideline specifically addressing obesity management — including pharmacotherapy — from a cardiovascular risk perspective. The 2023 guideline predated SELECT by months; subsequent focused updates (2024) incorporated SELECT data to give semaglutide 2.4 mg Class IIa recommendation for CV risk reduction in non-diabetic obesity with established CVD.
2023–24
AHA/ACC Key Recommendations
IIa/A
AHA/ACC Rec 1 — Semaglutide for CV risk reduction in obesity
In adults with overweight or obesity (BMI ≥27 kg/m²) and established cardiovascular disease but without diabetes, semaglutide 2.4 mg weekly can be useful to reduce the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. (Class IIa, Level of Evidence A — based on SELECT trial)
This recommendation is the formal cardiology endorsement of the SELECT indication — and the first Class IIa recommendation for a weight-management pharmacotherapy in a cardiovascular guideline:
- SELECT (NEJM 2023, n=17,604): HR 0.80 (95% CI 0.72–0.90, p<0.001) for primary 3-point MACE
- NNT approximately 67 over 40 months to prevent one MACE event
- The Class IIa (not Class I) reflects that SELECT is a single trial — replication in independent cohorts would support upgrading to Class I
- Importantly, this recommendation applies to patients without diabetes — a genuinely new clinical territory for cardiovascular pharmacotherapy
- 73% reduction in new-onset T2DM in SELECT: AHA/ACC notes this as an additional benefit supporting the cardiometabolic medicine rationale
I/A
AHA/ACC Rec 2 — Obesity as a CV risk factor requiring treatment
Obesity should be recognised and treated as a chronic disease associated with increased cardiovascular risk. Weight loss of ≥5–10% achieved through lifestyle, pharmacotherapy, or bariatric surgery reduces cardiovascular risk factors. GLP-1 receptor agonists are recommended components of evidence-based obesity treatment when lifestyle changes are insufficient. (Class I, Level A)
This overarching Class I recommendation elevates GLP-1 RA-based obesity treatment to cardiological standard of care — a significant departure from historical cardiology guidelines that focused on lifestyle alone for obesity:
- GLP-1 RAs recommended alongside lifestyle, not instead of it — the combination produces greater and more sustained weight loss
- AHA/ACC notes that weight loss of ≥10% produces clinically meaningful reductions in SBP (−6 mmHg), LDL (−5%), triglycerides (−15%), HbA1c (−1%), and CRP (−40%)
- The CLASS of recommendation (Class I) for obesity treatment as CV prevention is transformative — elevating weight management from "lifestyle advice" to evidence-based cardiovascular medicine
- This recommendation is expected to influence insurance coverage decisions in the US and ICS commissioning decisions in England
European Guideline 1
ADA/EASD Consensus — Hyperglycaemia Management in T2DM
Joint ADA / European Association for the Study of Diabetes · Person-centred framework · 2022–2023 update
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American Diabetes Association / European Association for the Study of Diabetes — Joint
Management of Hyperglycaemia in Type 2 Diabetes — Consensus Report
The ADA/EASD consensus report represents the most widely implemented international diabetes treatment framework, used across Europe and globally. It employs a four-cycle, person-centred approach to treatment decisions, integrating patient preferences, health priorities, and comorbidities before defaulting to HbA1c as the primary driver. The 2022 report was updated in 2023 to incorporate SURPASS-2 tirzepatide data and FLOW trial implications.
2022–23
The Four-Cycle ADA/EASD Decision Framework
①
Assess
Patient health status, priorities, preferences, and comorbidities
②
Agree
Jointly agree on treatment goals considering what matters most to the person
③
Advise
Provide evidence-based advice on treatment options aligned with goals
④
Assist & Arrange
Support implementation; arrange follow-up and monitoring; revisit regularly
ADA/EASD Consensus — GLP-1 RA Recommendations
A
ADA/EASD Rec 1 — Compelling need for weight loss
When weight loss is a compelling treatment priority — which it should be considered in most people with T2DM and overweight or obesity — a GLP-1 receptor agonist with high weight-loss efficacy (semaglutide or tirzepatide) is recommended at the first intensification step, independent of baseline HbA1c.
The ADA/EASD consensus introduced the concept of "compelling needs" — clinical priorities beyond HbA1c that should drive treatment selection:
- Compelling need: Weight management → GLP-1 RA or tirzepatide (sema or tirz preferred; lira, dula as alternatives)
- Compelling need: CV risk reduction (ASCVD) → GLP-1 RA with proven CV benefit or SGLT2i
- Compelling need: HF or CKD protection → SGLT2i preferred; GLP-1 RA additive
- Compelling need: Minimise hypoglycaemia → GLP-1 RA (glucose-dependent; no intrinsic hypo risk)
- Compelling need: Minimise cost → Generic metformin + SU or TZD (not GLP-1 RA class)
- GLP-1 RAs directly address multiple compelling needs simultaneously — the only class offering weight loss, CV protection, and near-absent hypoglycaemia risk in one agent
A
ADA/EASD Rec 2 — ASCVD or high CV risk
For people with type 2 diabetes and established atherosclerotic CVD or indicators of high CV risk, a GLP-1 receptor agonist with demonstrated cardiovascular benefit should be offered as part of the glucose-lowering regimen. This recommendation applies regardless of baseline HbA1c and independent of current glycaemic control.
The ADA/EASD consensus aligns with NICE NG28 and ESC/EASD on the CV-independent prescribing principle, but frames it within the compelling needs model:
- Established ASCVD: GLP-1 RA with proven MACE benefit — sema (SUSTAIN-6 + SELECT), lira (LEADER), dula (REWIND)
- Indicators of high CV risk (not established ASCVD): GLP-1 RA appropriate but evidence weaker — REWIND (69% primary prevention) most applicable
- Tirzepatide in ASCVD: SURPASS-CVOT data support use; select sema when strongest CV evidence is the priority
- Patient preference, tolerability, and access should be discussed alongside the evidence when selecting between sema and tirz for the CV indication
B
ADA/EASD Rec 3 — Person-centred agent selection
When selecting between GLP-1 receptor agonists, consider: injection frequency preference (daily vs weekly), oral vs subcutaneous preference, expected weight loss magnitude, CV outcome evidence strength, renal function, retinopathy history, and cost. Patient engagement in this decision improves long-term adherence.
The ADA/EASD is distinctive in its emphasis on treatment burden and patient engagement as equally important as clinical efficacy in treatment selection:
- Injection frequency: once-weekly (sema SC, tirz, dula) preferred over once-daily (lira) or twice-daily (exenatide IR) for most patients
- Oral preference: oral sema 14 mg — accept ~15% lower efficacy vs SC for meaningful convenience improvement
- Weight loss priority: tirzepatide > sema 2.4 mg > sema 1 mg > lira > dula > exenatide
- CV evidence strength: sema (strongest — SUSTAIN-6 + SELECT) > lira (LEADER) > dula (REWIND)
- Cost: significant variation; generic alternatives may be preferred in cost-constrained settings
- Shared decision making documentation should include the specific reasons for agent choice
European Guideline 2
ESC/EASD — CVD in Diabetes Guidelines
European Society of Cardiology · 2023 · Class I Level A recommendations for GLP-1 RAs
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European Society of Cardiology / European Association for the Study of Diabetes
ESC Guidelines on Cardiovascular Disease in Patients with Diabetes — 2023
The ESC guidelines represent the European cardiological standard for managing cardiovascular disease in patients with diabetes. They carry particular clinical authority for the CV indication — being written by cardiologists rather than diabetologists — and give GLP-1 RAs their strongest international recommendation level (Class I, Level A) for patients with T2DM and established ASCVD.
2023
ESC/EASD Key Recommendations
I/A
ESC Rec 1 — GLP-1 RA in T2DM + established ASCVD
In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, a GLP-1 receptor agonist with proven cardiovascular benefit (semaglutide, liraglutide, or dulaglutide) is recommended to reduce cardiovascular events, independent of glycaemic status. (Class I, Level of Evidence A)
Class I, Level A is the highest recommendation level in ESC guidelines — equivalent to "must do" based on multiple high-quality RCTs. This places GLP-1 RAs in established ASCVD+T2DM at the same evidence level as ACE inhibitors post-MI and statins in secondary prevention:
- Evidence base: LEADER (HR 0.87), SUSTAIN-6 (HR 0.74), REWIND (HR 0.88) — three independent large RCTs with MACE superiority
- AMPLITUDE-O (efpeglenatide, HR 0.73) also cited as supportive although agent not widely available
- "Proven cardiovascular benefit" definition: MACE superiority demonstrated in a dedicated CVOT — excludes exenatide XR (EXSCEL non-inferior only) and lixisenatide (ELIXA neutral)
- The guideline explicitly states: "The cardiovascular benefit of GLP-1 RAs in T2DM is likely a class effect of certain agents but not all agents in the class"
- In clinical practice: the ESC recommendation means European cardiologists should prescribe semaglutide, liraglutide, or dulaglutide to all T2DM patients with established ASCVD — regardless of whether a diabetologist is also managing their diabetes
IIa/B
ESC Rec 2 — GLP-1 RA in T2DM + high CV risk (no established disease)
In patients with type 2 diabetes and multiple cardiovascular risk factors but no established atherosclerotic CVD, a GLP-1 receptor agonist with proven cardiovascular benefit may be considered to reduce the risk of future cardiovascular events. (Class IIa, Level B)
The step down to Class IIa for primary prevention reflects the weaker (but still positive) evidence:
- REWIND (dulaglutide) is the primary evidence source — 69% of participants had no established CVD at baseline; HR 0.88 for MACE across the whole trial
- The REWIND primary prevention subgroup (HR 0.98, wider CI) did not individually show significant benefit — the overall trial benefit drove the recommendation
- "High CV risk" in ESC context: age ≥50 + ≥2 risk factors; or evidence of end-organ damage (LVH, eGFR <60, microalbuminuria)
- ESC recommends SGLT2i as an equally valid alternative for primary prevention in high-risk T2DM patients
I/A
ESC Rec 3 — Prefer GLP-1 RA over adding insulin
When treatment intensification is required in people with type 2 diabetes and cardiovascular disease, a GLP-1 receptor agonist is recommended in preference to adding insulin, as GLP-1 RAs provide cardiovascular benefit, weight loss, and reduced hypoglycaemia risk compared with insulin intensification. (Class I, Level A)
The ESC makes an unusually strong statement against insulin intensification as the default next step in T2DM+CVD — a position that reflects the accumulated CVOT evidence and the mechanistic advantages of GLP-1 RAs:
- Insulin has no proven CV benefit in T2DM outcomes trials (ORIGIN: HR 1.02 for MACE with insulin glargine)
- Insulin carries significant hypoglycaemia risk — hypoglycaemia activates sympathetic nervous system, may trigger acute CV events
- GLP-1 RA intensification produces CV benefit, weight loss, and near-absent hypoglycaemia risk
- When insulin is eventually needed (e.g. markedly elevated HbA1c): prefer basal insulin + GLP-1 RA combination over basal-bolus to maintain GLP-1 RA benefits
- Fixed-ratio combinations (IDegLira, IGlarLixi) offer simplified combination therapy when both are required
1+
ESC Rec 4 — GLP-1 RA and SGLT2i combination
In people with type 2 diabetes and established ASCVD with both cardiovascular and renal risk, combining a GLP-1 receptor agonist and an SGLT2 inhibitor is recommended, as these agents have complementary mechanisms and additive cardiovascular and renal benefits. (Class I, Level B)
The ESC 2023 is one of the first guidelines to explicitly Class I-recommend the GLP-1 RA + SGLT2i combination:
- Complementary mechanisms: SGLT2i reduces volume overload and provides direct HF/renal protection; GLP-1 RA reduces weight, postprandial glucose, and CV events via different pathways
- No dedicated RCT of the combination exists (single agent vs combination) — recommendation based on mechanistic complementarity and subgroup analyses
- FLOW (NEJM 2024): renal benefit of sema 1 mg was consistent in those on background SGLT2i (HR 0.78) — providing the first direct evidence that both together are better than either alone for renal outcomes
- Cost and tolerability must be considered — the combination requires two medications and monitoring for both GI and renal side effects
European Guideline 3
EASO — European Obesity Guidelines
European Association for the Study of Obesity · 2024 · GLP-1 RA in obesity management
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European Association for the Study of Obesity (EASO)
EASO Clinical Practice Recommendations for Obesity Management — 2024
EASO 2024 recommendations frame obesity as a chronic, relapsing disease requiring long-term pharmacotherapy — explicitly rejecting time-limited prescribing. They strongly endorse semaglutide 2.4 mg and tirzepatide 15 mg as the most effective pharmacological agents, with lean mass preservation and mental health monitoring as specific concerns.
2024
EASO Key Recommendations
A
EASO Rec 1 — GLP-1 RA as standard pharmacotherapy for obesity
GLP-1 receptor agonists — specifically semaglutide 2.4 mg and tirzepatide 15 mg — are recommended as first-line pharmacotherapy for adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with weight-related complications, producing 10–22% weight loss when combined with lifestyle intervention. (Grade A)
EASO sets the most permissive access criteria of any major guideline — no specialist referral requirement, no prior lifestyle programme duration, no time limit:
- Semaglutide 2.4 mg: STEP-1 (−14.9% body weight), STEP-2 T2DM (−9.6%), SELECT CV evidence — preferred where CV protection is a co-goal
- Tirzepatide 15 mg: SURMOUNT-1 (−20.9%), SURMOUNT-3 (−26.6% combined with lifestyle) — preferred where maximum weight loss is the goal
- EASO does not mandate specialist referral — prescribing should be available in primary care across Europe (contrast with UK Tier 3 requirement)
- Access equity is an explicit EASO concern: the guideline calls for reimbursement of obesity pharmacotherapy as standard of care in all European healthcare systems
A
EASO Rec 2 — Long-term / lifelong treatment
Pharmacotherapy for obesity should be considered long-term or indefinite treatment, analogous to antihypertensive or lipid-lowering therapy. Time-limited prescribing (e.g. 2-year restrictions) is not supported by clinical evidence and results in weight regain that negates the achieved health benefits. (Grade A)
EASO is the most explicit of all guidelines in challenging time-limited obesity pharmacotherapy policies:
- STEP-4 withdrawal data: +6.9% body weight regain within 48 weeks of stopping semaglutide; risk factors completely reverted
- SURMOUNT-4 (tirzepatide withdrawal): comparable weight regain pattern after discontinuation
- EASO formally states: "Policies limiting obesity pharmacotherapy to 2 years are not consistent with the chronic disease model and should be revised"
- Addressed directly at European national health systems that limit reimbursement duration
- In the UK context: NICE TA875 2-year limit is specifically challenged by this recommendation; SfE guidance takes the same position
GPP
EASO Rec 3 — Mental health screening
Before initiating GLP-1 receptor agonists for obesity management, screen for active eating disorders (anorexia nervosa, bulimia), severe depression, or suicidal ideation. Monitor mental health during treatment — appetite suppression and rapid weight change may affect body image and psychological wellbeing in vulnerable patients. (Good Practice Point)
EASO is the only major guideline to specifically address the mental health interface with GLP-1 RA obesity treatment:
- GLP-1 RAs reduce hedonic eating and food reward salience — potentially beneficial in binge eating disorder, but may reinforce restrictive behaviours in AN
- FDA pharmacovigilance review (2023): no confirmed causal link between GLP-1 RAs and suicidal ideation; but active monitoring is warranted
- Use PHQ-9 or GAD-7 as baseline screening tools where routine mental health assessment is not in place
- Active anorexia nervosa or ARFID: contraindication to GLP-1 RA for obesity
- Binge eating disorder: GLP-1 RA may be beneficial — coordinate with psychiatry/psychology team
- Monitor for signs of food restriction that exceeds intended weight management — particularly in younger patients and those with prior eating disorder history
Global Guideline 1
WHO — Global Diabetes & Obesity Frameworks
World Health Organization · Essential Medicines List · Global Access Agenda · 2024–2026
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World Health Organization (WHO) · Geneva
Global Diabetes Framework · Essential Medicines Review · Obesity Policy 2024
The WHO has not issued a dedicated GLP-1 RA clinical guideline but has engaged extensively with the class through the Essential Medicines List review process and global diabetes and obesity programme reports. Its stance emphasises access equity, cost barriers in LMICs, and the transformative potential of generic/small-molecule GLP-1 RAs for global health. The EML semaglutide decision (expected 2025–2026) may be the most consequential regulatory action for global access.
2024–26
The WHO's approach to GLP-1 RAs is primarily through its Essential Medicines List (EML) — the list of medications considered essential for basic healthcare systems globally. EML listing triggers: mandated procurement by WHO member states' public health programmes; TRIPS agreement flexibilities for generic manufacturing; and pricing negotiations that can reduce drug costs by 60–90%.
WHO EML — Current Status (April 2026)
Semaglutide is under formal WHO Expert Committee on Selection and Use of Essential Medicines review for EML listing. The application cites: SELECT CV evidence (20% MACE reduction), FLOW renal evidence (24% renal composite reduction), and the global burden of T2DM and cardiovascular disease in LMICs. The 2025 Expert Committee reviewed the semaglutide EML application — see WHO EML website for current listing decision. If listed: estimated 60–80% price reduction through generic competition within 5 years.
WHO Obesity Policy — Global Action Plan
WHO's Global Action Plan on Physical Activity and the Ending Childhood Obesity programme do not specifically address pharmacotherapy but the WHO Technical Report on obesity (2024) acknowledges GLP-1 RAs as transformative pharmacological tools — while noting that access inequity means >90% of current GLP-1 RA prescribing occurs in high-income countries. WHO calls for technology transfer and compulsory licensing mechanisms to ensure equitable access in LMICs.
WHO — The Access Transformation Horizon
The WHO's most significant impact on GLP-1 RA prescribing may come not from clinical guidelines but from access policy. Semaglutide's composition-of-matter patents expire in the UK in 2031 (earlier in some markets). Multiple biosimilar programmes (Mylan/Viatris, Biocon, Sun Pharma, multiple Chinese manufacturers) are underway. If oral non-peptide GLP-1 RAs (orforglipron, danuglipron) achieve approval, their small-molecule nature allows generic rather than biosimilar development — potentially enabling 90%+ cost reduction and placing GLP-1 RAs within reach of LMIC healthcare systems where the global burden of T2DM and obesity is greatest. The WHO EML review process for semaglutide (2025) is expected to catalyse this transition — check WHO EML for current status.
Global Guideline 2
KDIGO — Diabetes Management in CKD
Kidney Disease: Improving Global Outcomes · 2024 · First CKD-dedicated GLP-1 RA guidance
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Kidney Disease: Improving Global Outcomes (KDIGO) — International
Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease — 2024 Update
KDIGO 2024 is the first comprehensive guideline dedicated specifically to diabetes management in CKD, incorporating the landmark FLOW trial data (semaglutide 1 mg reducing renal composite by 24% in T2DM+CKD). It introduces the four-pillar model of cardiorenal protection — RAAS blockade + SGLT2i + GLP-1 RA + finerenone — and provides detailed eGFR-stratified prescribing recommendations for all major agents.
2024
KDIGO 2024 — Four-Pillar Cardiorenal Protection Model
🏗
Pillar 1
RAAS Blockade
ACEi or ARB · BP target <130/80 · Reduces proteinuria
🔌
Pillar 2
SGLT2 Inhibitor
Empagliflozin · Dapagliflozin · eGFR ≥20 required
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Pillar 3 ★ NEW
GLP-1 RA
Sema 1 mg · FLOW: −24% renal composite · eGFR ≥15
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Pillar 4
Finerenone
Non-steroidal MRA · FIDELIO-DKD · eGFR ≥25
KDIGO 2024 — GLP-1 RA Recommendations in CKD
1A
KDIGO Rec 1 — Semaglutide in T2DM + CKD (FLOW indication)
We recommend semaglutide 1 mg SC weekly for adults with type 2 diabetes and CKD (eGFR 25–75 mL/min/1.73m² AND UACR ≥100 mg/g) to reduce the risk of kidney failure, cardiovascular events, and death, in addition to background standard-of-care therapy including RAAS blockade. (Grade 1A)
KDIGO Grade 1A is the strongest recommendation level — equivalent to "we recommend" based on high-quality evidence. This is the first KDIGO recommendation for a GLP-1 RA at Grade 1A:
- Evidence: FLOW trial (NEJM 2024, n=3,533) — primary composite HR 0.76 (95% CI 0.66–0.88, p=0.0003); all-cause mortality HR 0.80; trial stopped early for overwhelming efficacy
- Applicable population: T2DM + eGFR 25–75 mL/min/1.73m² + UACR ≥100 mg/g — approximately 20–30% of people with T2DM in secondary care have CKD meeting these criteria
- KDIGO explicitly states: "Do not withhold semaglutide due to CKD — the CKD itself is part of the indication"
- No dose adjustment needed for eGFR 25–75; use with caution eGFR <25; avoid if eGFR <15 or dialysis (no data)
- GI-induced dehydration is a risk in CKD — counsel on adequate hydration; hold semaglutide if severe GI illness (>48 hours significant vomiting/diarrhoea)
1B
KDIGO Rec 2 — Additive renoprotection with SGLT2i
We suggest adding semaglutide to background SGLT2 inhibitor therapy (or vice versa) in patients with T2DM and CKD who are at high risk of kidney failure or cardiovascular events, as the combination provides additive cardiorenal benefit compared with either agent alone. (Grade 1B)
The additive benefit recommendation is based on the FLOW pre-specified SGLT2i subgroup analysis:
- FLOW: renal composite benefit was consistent in participants on baseline SGLT2i (HR 0.78, CI 0.62–0.99) and those not on SGLT2i (HR 0.75, CI 0.63–0.91); no significant interaction (p=0.76)
- This is the most direct evidence available that GLP-1 RA and SGLT2i provide additive (not redundant) renoprotection
- No dedicated combination RCT exists — the Grade 1B (rather than 1A) reflects this limitation
- Mechanistic complementarity: SGLT2i reduces intraglomerular pressure through tubuloglomerular feedback; GLP-1 RA reduces albuminuria through anti-inflammatory and haemodynamic mechanisms — different pathways
- Priority: if only one agent can be prescribed, choose based on eGFR (SGLT2i needs ≥20; GLP-1 RA usable to eGFR 15) and tolerability
2B
KDIGO Rec 3 — GLP-1 RA in CKD stages G4–G5 (eGFR <25)
We suggest considering semaglutide in people with T2DM and CKD stage G4 (eGFR 15–25 mL/min/1.73m²) where the clinical benefits are judged to outweigh risks, with careful monitoring for GI-induced volume depletion and acute kidney injury. Insufficient data exist to make a recommendation for eGFR <15 or dialysis. (Grade 2B)
The weaker Grade 2B for advanced CKD reflects genuine data gaps — FLOW enrolled eGFR 25–75 and did not include eGFR <25:
- Semaglutide is primarily eliminated by proteolysis (not renal excretion) — pharmacokinetic accumulation risk in severe CKD is theoretically lower than renally-eliminated drugs
- However, GI side effects + severe CKD = high AKI risk from volume depletion — requires very careful monitoring
- Clinical practice: if T2DM+CKD G4 patient has compelling CV or weight indication, semaglutide may be appropriate with specialist oversight and meticulous hydration counselling
- Exenatide and lixisenatide: contraindicated eGFR <45 — do not use in G3b or worse
- Tirzepatide in advanced CKD: limited data; approach with same caution as semaglutide; KDIGO does not yet make a specific recommendation
Synthesis
Unified Clinical Algorithm
Synthesising NICE NG28 · ADA 2025 · ESC · KDIGO into a single clinical decision framework
No single patient is managed by one guideline alone. The following unified algorithm integrates the core decision logic from NICE NG28 (UK primary), ADA 2025 (international reference), ESC/EASD (CV indication), and KDIGO 2024 (renal indication) into a practical single framework applicable to UK clinical practice.
Unified GLP-1 RA Clinical Decision Algorithm — UK Practice 2026
Analysis
Key Divergences Between Guidelines
Where NICE, ADA, ESC, AACE, KDIGO, and EASO disagree — and why it matters
Despite broad convergence on the value of GLP-1 RAs in cardiometabolic medicine, meaningful divergences exist between guidelines that have direct clinical and commissioning implications. The following table summarises the most clinically significant differences and provides a UK practice recommendation for each.
Divergence point
NICE NG28 (UK)
ADA / AACE (US)
UK practice recommendation
Metformin as prerequisite
Metformin required unless CI; GLP-1 RA at step 2–3
ADA: GLP-1 RA may be first-line if CVD/CKD. AACE: Tirz first in obese T2DM regardless of prior metformin
Follow current NICE NG28 — initial therapy is now comorbidity-led and person-centred rather than a universal metformin-first rule. Local formulary and licensed indications still apply.
HbA1c threshold for prescribing
≥58 (7.5%) standard; ≥53 (7.0%) with CVD; no threshold for established CVD stream
ADA: no HbA1c threshold when CVD/CKD/obesity is the indication. AACE: complication-centric — threshold is secondary
NICE NG28 applies in NHS. The CV stream B (no HbA1c threshold for established ASCVD) aligns NICE with the ADA principle for the most important subset. The remaining HbA1c thresholds reflect NHS cost-effectiveness modelling.
Tirzepatide positioning
Separate NICE recommendations and stopping rules; not co-equal in every pathway
AACE 2024: tirzepatide preferred first-line in BMI ≥30 T2DM. ADA: co-equal with sema
Either sema or tirz acceptable per NICE NG28. Practical choice based on patient preference, weight loss target, cost, and supply. Tirz preferred when maximum weight loss is the goal; sema preferred when strongest CV evidence is required.
Obesity treatment duration
NICE TA875: initial 2-year period; continuation requires annual review
ADA: long-term treatment required (no time limit). EASO: lifelong treatment model. AACE: no time limit
Clinical case for lifelong treatment supported by STEP-4 and SURMOUNT-4 withdrawal data. Advocate for individual patients requiring >2 years through NHS England annual review process. EASO and SfE positions provide clinical authority for continuation.
Specialist referral for obesity
NICE TA875: Tier 2/3 specialist service required for Wegovy
ADA/FDA: no specialist referral required in US; prescribable in primary care. EASO: calls for primary care access
Follow NICE TA875 for NHS. Tier 3 referral required for Wegovy on NHS. Note: T2DM patients with BMI ≥35 may access GLP-1 RA (Ozempic/Mounjaro) via NG28 T2DM pathway without Tier 3 referral — practically important.
GLP-1 RA in CKD G3b–4
Sema: use with caution eGFR 15–29; no dose adjustment eGFR ≥30
KDIGO 2024: Grade 1A for sema 1 mg in eGFR 25–75; Grade 2B consideration for eGFR 15–25. ADA: recommends in CKD
Follow KDIGO 2024 for the renal indication — FLOW data supersedes older NICE guidance on renal caution. Sema 1 mg can be used to eGFR 15 with monitoring. Do not withhold due to CKD — CKD is the indication.
HbA1c target
NICE: <48 mmol/mol (6.5%) if on agent with no hypo risk; <53 (7.0%) otherwise
ADA: individualised; ≤6.5% achievable with GLP-1 RA/tirz without hypo risk. AACE: ≤6.5% recommended for most
AACE target appropriate when using sema or tirz in non-frail patients — GLP-1 RAs carry no intrinsic hypo risk, so targeting ≤48 mmol/mol (6.5%) is clinically safe and appropriate. Adjust upward to ≤58 (7.5%) in frailty or high hypo risk from co-medications.
Mental health screening
Not explicitly mentioned in NG28 for GLP-1 RA prescribing
EASO 2024: PHQ-9/GAD-7 screening; eating disorder exclusion. ADA: notes depression as comorbidity to assess
Adopt EASO approach — screen for eating disorders (anorexia, bulimia) before prescribing for obesity. NICE TA875 does not mandate this, but EASO's guidance reflects emerging clinical evidence and pharmacovigilance signals. Document mental health status at baseline.
Clinical Pearl — The Single Most Important Divergence for UK Practice
The most clinically impactful divergence between NICE NG28 and international guidelines is the treatment duration for obesity. NICE TA875 imposes a 2-year initial commissioning period; EASO, ADA, AACE, SfE, and all other guidelines support indefinite treatment. STEP-4 and SURMOUNT-4 demonstrate complete weight regain within 12 months of stopping — making the 2-year limit incompatible with the chronic disease model. UK clinicians should be aware of this tension and use the annual review process to document continued clinical benefit, advocate for continuation, and refer to specialist services where primary care prescribing authority is insufficient for ongoing treatment.
Guidelines summarised on this page: NICE NG28 (February 2026) · NICE TA875 (March 2023) · SfE Pharmacological Management of Obesity 2024 · ADA Standards of Medical Care in Diabetes 2025 · AACE Comprehensive T2DM Management Algorithm 2024 · AHA/ACC Guideline for Obesity and CVD 2023 (with SELECT update) · ADA/EASD Consensus Report on Hyperglycaemia Management in T2DM (Davies et al. 2022, updated 2023) · ESC Guidelines on CVD in Patients with Diabetes 2023 · EASO Clinical Practice Recommendations for Obesity Management 2024 · KDIGO Clinical Practice Guideline for Diabetes Management in CKD 2024. All recommendation grades, class levels, and evidence gradings are reproduced from original source documents. This page is for educational purposes and does not constitute prescribing advice — apply guidelines in the context of individual patient clinical circumstances, local formulary, and current regulatory status. Check guideline body websites for most recent updates as guidelines are revised periodically.
Annotated figure library
Visual reference for prescribing guidelines
Each illustration below is paired with a clinical summary and detailed explanation. Click any image to expand. Figures are numbered in teaching order and grouped by theme.
UK guidelines
Figure 1
NICE NG28 (February 2026) — T2DM management
Image description
The illustration presents UK primary reference for GLP-1 RA prescribing in type 2 diabetes.
Clinical interpretation
NG28 positions GLP-1 RAs at second/third line with specific HbA1c thresholds; February 2026 update added tirzepatide and clarified CV-risk-based prescribing independent of HbA1c when ASCVD is present.
Clinical pearl
Check full NG28 and TA875 (obesity) for commissioning criteria — ICS formularies may add restrictions.
Figure 2
NICE health technology assessment
Image description
The illustration presents Cost-effectiveness framework for GLP-1 agents in NHS.
Clinical interpretation
Technology appraisals define which populations receive NHS-funded therapy; obesity pathways often require specialist weight management service referral.
Figure 3
NICE NG203 — CKD assessment and management
Image description
The illustration presents Intersection with FLOW evidence for renal protection.
Clinical interpretation
NG203 alongside NG28 guides SGLT2i and GLP-1 RA use in diabetic kidney disease — combination therapy increasingly standard.
Figure 4
NICE technology appraisal context
Image description
The illustration presents Appraisal documentation for newer agents.
Clinical interpretation
TA documents define eligible populations, comparators, and managed access — essential for formulary committees.
International guidelines
Figure 5
ADA Standards of Care 2025/2026 — unified algorithm
Image description
The illustration presents US algorithm prioritising agents with cardiorenal benefit.
Clinical interpretation
ADA places GLP-1 RAs with proven CV benefit high in algorithm for T2DM with ASCVD/high risk, alongside SGLT2i, often independent of HbA1c or metformin use.
Figure 6
Therapeutic stewardship principles
Image description
The illustration presents Appropriate agent selection, titration, and deprescribing considerations.
Clinical interpretation
Stewardship emphasises matching agent to indication (glycaemia vs obesity vs CV/renal), avoiding duplication, and planning therapy around procedures (aspiration risk).
Treatment algorithms
Figure 7
Clinical positioning of GLP-1 RAs
Image description
The illustration presents Where GLP-1 fits among metformin, SGLT2i, insulin, and lifestyle.
Clinical interpretation
Decision tree: ASCVD → GLP-1 or SGLT2i; obesity predominant → higher-dose semaglutide/tirzepatide; renal disease → SGLT2i + GLP-1 RA with FLOW-class evidence.
Figure 8
Shared decision-making framework
Image description
The illustration presents Patient-centred choice among agents with different devices and schedules.
Clinical interpretation
Weekly vs daily injection, oral option, weight loss magnitude, supply issues, and cost/access shape real-world selection as much as trial hazard ratios.
Clinical FAQs
Frequently asked questions
What do NICE guidelines say about GLP-1 prescribing?
NICE recommends GLP-1 receptor agonists for type 2 diabetes when specific criteria are met, and semaglutide (Wegovy) for weight management within a specialist service subject to BMI thresholds. Always check current NICE guidance and local formularies before prescribing.