The Clinical Evidence Landscape
From glycaemic non-inferiority to disease-modifying outcomes
The GLP-1 RA evidence base is among the most extensive in modern pharmacology. Beginning with short-term glycaemic efficacy trials in the mid-2000s, the field has generated a series of landmark cardiovascular outcomes trials (CVOTs) — mandated by the FDA after the rosiglitazone signal — that collectively enrolled over 80,000 patients in high-risk T2DM cohorts. More recently, dedicated obesity trials (STEP, SURMOUNT), renal outcomes trials (FLOW), heart failure trials (STEP-HFpEF), MASH trials (SYNERGY-NASH), and neurological studies have tested additional indications. EVOKE/EVOKE+ did not establish efficacy in Alzheimer’s disease.
The SUSTAIN Programme
Semaglutide SC in T2DM · SUSTAIN 1–11 · 2016–2022
The SUSTAIN programme (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) comprises eleven phase 3 trials establishing semaglutide SC across all T2DM treatment stages — from drug-naive monotherapy through triple combination therapy — including landmark head-to-head comparisons against sitagliptin, dulaglutide, and insulin.
| Population | Adults with T2DM inadequately controlled on diet/exercise or metformin. Mean HbA1c 8.1%, BMI 33.8 kg/m². |
| Intervention | Semaglutide SC 0.5 mg or 1.0 mg once weekly × 30 weeks |
| Comparator | Placebo SC weekly (double-blind) |
| Outcomes | Primary: HbA1c change at 30 weeks. Secondary: weight, FPG, ≥HbA1c targets, hypoglycaemia. |
SUSTAIN FORTE randomised 961 adults with type 2 diabetes on metformin with or without a sulfonylurea to semaglutide 2 mg or 1 mg weekly for 40 weeks. Trial-product estimand: HbA1c changed by −2.2 versus −1.9 percentage points (difference −0.23; 95% CI −0.36 to −0.11; p=0.0003), and weight by −6.9 versus −6.0 kg. Treatment-policy estimates were −2.1 versus −1.9 percentage points for HbA1c and −6.4 versus −5.6 kg for weight. This is SUSTAIN FORTE, not SUSTAIN-11, which compared semaglutide with insulin aspart. Primary publication.
The PIONEER Programme
Oral semaglutide (Rybelsus) · PIONEER 1–10 + SOUL · 2019–2025
PIONEER (Peptide Innovation for Early Diabetes Treatment) established oral semaglutide across the T2DM spectrum. Ten phase 3 trials compared oral sema (3/7/14 mg OD) vs placebo, sitagliptin, empagliflozin, liraglutide, and insulin — plus the SOUL outcomes trial (2025) extending CV evidence to the oral formulation.
| Population | Adults with T2DM on metformin ± sulphonylurea, HbA1c 7.0–10.5%. Mean HbA1c 8.3%, BMI 32.5 kg/m². |
| Intervention | Oral semaglutide 3 mg, 7 mg, or 14 mg OD (taken fasting, 30 min before first meal) |
| Comparator | Sitagliptin 100 mg OD (double-dummy design) |
| Outcomes | Primary: HbA1c change at week 26. Secondary: weight, ≥HbA1c targets, long-term durability at 78 weeks. |
SOUL (2025) randomised 9,650 people aged ≥50 years with type 2 diabetes and atherosclerotic cardiovascular disease, CKD, or both, to oral semaglutide (maximum 14 mg daily) or placebo. Over median follow-up of 49.5 months, MACE occurred in 12.0% versus 13.8% (HR 0.86; 95% CI 0.77–0.96; p=0.006). Confirmatory secondary outcomes, including major kidney disease events, were not significantly different. This trial supports cardiovascular benefit in this population; it did not establish a significant kidney composite benefit. Primary publication.
Retatrutide — TRIUMPH-2
Phase 3 · Type 2 diabetes with obesity or overweight · Investigational
TRIUMPH-2 randomised 1,152 adults with type 2 diabetes and BMI ≥27 kg/m² to weekly retatrutide 4, 9 and 12 mg or placebo for 80 weeks. The trial was funded by Eli Lilly. Trial registry: NCT05929079.
Published treatment-regimen estimand: weight change was −11.9%, −16.8% and −18.8% with 4, 9 and 12 mg, versus −5.1% with placebo. The 12 mg placebo-adjusted difference was −13.8 percentage points (95% CI −15.8 to −11.8). Bellido et al., The Lancet, online 29 September 2026 (DOI: 10.1016/S0140-6736(26)01861-1).
Different analysis: the sponsor reported 20.8% weight loss at 12 mg and HbA1c reductions up to 1.6 percentage points using the efficacy estimand, assuming continued study treatment without specified rescue therapies. These results must not be substituted for the treatment-regimen estimates. Sponsor efficacy analysis.
Safety: gastrointestinal events were common. Hypotension and dysaesthesia were more frequent with retatrutide; discontinuation due to adverse events or death was higher at 9 and 12 mg than with placebo. See the publication for full safety denominators.
Status: retatrutide remains investigational, not authorised for routine prescribing. This weight-management trial does not establish cardiovascular-outcome benefit or superiority to another active medicine.
Related phase 3 evidence — different populations:
- TRIUMPH-1: 2,339 participants with obesity without diabetes; at 80 weeks, published treatment-regimen weight change at 12 mg was −25.0% versus −3.9% with placebo. NEJM, September 2026. This is distinct from the sponsor’s 28.3% efficacy-estimand headline.
- TRANSCEND-T2D-1: 537 participants with type 2 diabetes inadequately controlled by diet and exercise; at 40 weeks, 12 mg reduced HbA1c by 1.94 percentage points versus 0.81 with placebo and weight by 15.3% versus 2.6% (treatment-regimen estimand). The Lancet, June 2026.
- TRIUMPH-3: sponsor-reported 22.6% weight loss at 12 mg over 80 weeks in severe obesity with established cardiovascular disease, with or without diabetes (efficacy estimand). July 2026 sponsor report. This is not proof of fewer cardiovascular events.
- TRIUMPH-4: sponsor-reported 28.7% weight loss at 12 mg over 68 weeks in obesity with knee osteoarthritis without diabetes (efficacy estimand), with improvements in knee pain. December 2025 sponsor report.
Neither sponsor summaries nor comparisons across these populations establish superiority to another medicine. Trial doses describe research, not a prescribing schedule.
EASD 2026 — congress highlights
Milan · 28 September to 2 October 2026 · Selected, dated summary
The 62nd EASD Annual Meeting was held in Milan from 28 September to 2 October 2026. This is a selected summary of major GLP-1-related presentations with simultaneous peer-reviewed publications; it is not a comprehensive review of the congress. Each item states its evidence tier.
Peer-reviewed — guidance: the ADA/EASD consensus report Management of type 2 diabetes, 2026 was published on 2 October 2026 and supersedes the 2022 report. See the guideline summary (Diabetologia · Diabetes Care).
Peer-reviewed — ACHIEVE-4 (orforglipron vs insulin glargine): 2,749 adults with type 2 diabetes, BMI ≥25 kg/m² and established cardiovascular or chronic kidney disease were randomised in an open-label, event-driven phase 3 trial (median follow-up 2 years). The four-component MACE outcome occurred in 4.2% with orforglipron and 5.0% with insulin glargine (HR 0.84; 95% CI 0.59–1.20). Orforglipron was non-inferior to insulin glargine (prespecified margin 1.8); superiority was not shown, so this is a cardiovascular-safety result, not proof of cardiovascular benefit. Clinically significant or severe hypoglycaemia occurred in 6.8% versus 19.2%, and gastrointestinal adverse events in 62.1% versus 14.2%. Deaths (1.4% versus 3.2%) were not the primary outcome and should not be read as a proven mortality effect. Klein et al., The Lancet, 30 September 2026 (NCT05803421).
Peer-reviewed — SYNCHRONIZE-2 (survodutide): 752 adults with type 2 diabetes and BMI ≥27 kg/m² received weekly survodutide 3.6 mg or 6.0 mg or placebo in a double-blind phase 3 trial. On the treatment-regimen estimand, weight change at 76 weeks was −8.2% and −9.8% versus −3.9% with placebo; HbA1c changed by −0.9 and −0.8 versus −0.2 percentage points from a baseline of 7.4%. Gastrointestinal adverse events occurred in 72.8%, 77.7% and 38.6%. The sponsor’s 13.1% headline uses the efficacy estimand and is not interchangeable. Survodutide is investigational. Wharton et al., NEJM, 1 October 2026.
Peer-reviewed — TRIUMPH-2 (retatrutide): full results were presented and published; see the TRIUMPH-2 summary. Retatrutide remains investigational; the sponsor has said it plans a US submission in the first quarter of 2027.
Sponsor-reported — not summarised numerically: Novo Nordisk presented CagriSema analyses and real-world Wegovy tablet data, and Lilly presented phase 2 eloralintide plus tirzepatide data. These are conference abstracts or sponsor reports without a peer-reviewed full publication at the time of this check. Novo Nordisk announcement · Lilly announcement.
Authorisation and NHS access: congress presentations do not change a UK licence, a NICE recommendation or NHS eligibility. Orforglipron (Foundayo) has UK authorisation for weight management and type 2 diabetes; survodutide and retatrutide are investigational, and CagriSema awaits regulatory decisions. Check the current SmPC and NICE guidance.
The SURPASS Programme
Tirzepatide in T2DM · SURPASS 1–5 + CVOT · Updated 2026
SURPASS-CVOT update: tirzepatide was non-inferior to dulaglutide for major cardiovascular events (HR 0.92; 95.3% CI 0.83–1.01); superiority was not demonstrated (p=0.09). Primary trial publication.
The SURPASS programme established tirzepatide across all T2DM treatment stages, consistently demonstrating superiority over best available comparators — including semaglutide 1 mg — setting a new efficacy benchmark for the entire incretin class.
In SURPASS-2, 1,879 adults with type 2 diabetes on metformin received tirzepatide 5, 10 or 15 mg or semaglutide 1 mg for 40 weeks. Primary-analysis HbA1c changes were −2.01, −2.24 and −2.30 versus −1.86 percentage points. Weight differences versus semaglutide were −1.9, −3.6 and −5.5 kg. All tirzepatide doses met superiority for HbA1c. This open-label trial tested semaglutide 1 mg; it does not compare with semaglutide 2 mg or obesity doses. Primary publication.
SURPASS-5 (JAMA 2022) randomised 475 adults receiving titrated insulin glargine, with or without metformin, to tirzepatide or placebo for 40 weeks. At 15 mg, HbA1c changed by −2.34 versus −0.86 percentage points and weight by −8.8 versus +1.6 kg. The protocol reduced glargine by 20% only for participants with baseline HbA1c ≤8.0%; this was a trial safeguard, not a universal NICE rule. Insulin adjustment requires individual glucose monitoring and prescribing advice. Primary publication.
The AWARD Programme
Dulaglutide in T2DM · AWARD 1–11 · 2014–2020
The STEP Programme
Semaglutide 2.4 mg in obesity · STEP 1–8 · 2021–2023
The STEP programme (Semaglutide Treatment Effect in People with obesity) established semaglutide 2.4 mg SC weekly as the first pharmacotherapy to achieve consistent double-digit percentage weight loss in randomised trials — prompting the first major revision of obesity pharmacotherapy guidelines in two decades and establishing the clinical template for all subsequent obesity pharmacotherapy programmes.
STEP-1 randomised 1,961 adults without diabetes to semaglutide 2.4 mg weekly or placebo plus lifestyle intervention for 68 weeks. Mean weight change was −14.9% versus −2.4% (treatment-policy analysis). At least 15% weight loss was reached by 50.5% versus 4.9%, and at least 20% by 32.0% versus 1.7%. Gastrointestinal adverse events caused treatment discontinuation in 4.5% versus 0.8%. Trial averages are not individual predictions. Primary publication.
STEP-2 studied 1,210 adults with overweight or obesity and type 2 diabetes for 68 weeks. Semaglutide 2.4 mg produced mean weight change of −9.6% versus −3.4% with placebo (treatment-policy estimand). The obesity indication can include people with type 2 diabetes who meet its criteria; diabetes alone does not make Wegovy use off-label. Follow the current product indication and commissioning criteria rather than extrapolating between brands. Primary publication.
The SURMOUNT Programme
Tirzepatide in obesity · SURMOUNT 1–5 · 2022–2025
SURMOUNT-1 enrolled 2,539 adults with obesity or overweight with a weight-related complication, excluding diabetes. At 72 weeks, treatment-regimen weight changes were −15.0%, −19.5% and −20.9% for tirzepatide 5, 10 and 15 mg versus −3.1% with placebo. Under the efficacy estimand, 15 mg produced −22.5% versus −2.4%; this is not an observed-case estimate. At 15 mg, 56.7% reached at least 20% weight loss, versus 3.1% with placebo. Gastrointestinal effects were common; adverse-event discontinuation was 6.2% versus 2.6%. Primary publication.
After a 12-week intensive lifestyle lead-in, 579 adults without diabetes who had lost at least 5% of their weight were randomised to tirzepatide (maximum tolerated 10 or 15 mg) or placebo for another 72 weeks. From randomisation, treatment-regimen weight change was −18.4% versus +2.5% (weight gain) with placebo. Efficacy-estimand estimates were −21.1% versus +3.3%. The selected population and baseline differ from trials without this lead-in. Primary publication.
LEADER — First GLP-1 RA CV Superiority
Liraglutide 1.8 mg · NEJM 2016 · n=9,340 · 3.8 years
| Population | Adults ≥50 with T2DM (HbA1c ≥7%) + established CVD, or ≥60 years + ≥1 CV risk factor. Mean age 64.3 yr, 81% established CVD. |
| Intervention | Liraglutide 1.8 mg SC once daily (titrated from 0.6 mg) |
| Comparator | Placebo + standard-of-care glucose-lowering therapy |
| Outcomes | Primary: 3-pt MACE (CV death, non-fatal MI, non-fatal stroke). Secondary: components, all-cause mortality, HF hospitalisation, renal composite. |
SUSTAIN-6 — Largest Relative MACE Reduction
SELECT — The Trial That Changed Everything
Semaglutide 2.4 mg in non-diabetic obesity · NEJM 2023 · n=17,604
| Population | Adults ≥45 years with BMI ≥27 kg/m², established CVD (prior MI, stroke, or symptomatic PAD), without T2DM (HbA1c <6.5%). Mean BMI 33.4, age 61.3 yr. 73% with prior MI or stroke. |
| Intervention | Semaglutide 2.4 mg SC weekly (16-week Wegovy titration schedule) |
| Comparator | Placebo SC weekly + standard of care |
| Outcomes | Primary: 3-pt MACE (CV death, non-fatal MI, non-fatal stroke). Pre-specified secondary: components, HF hospitalisation, AF, new-onset T2DM, renal, all-cause mortality. |
REWIND, EXSCEL & ELIXA
FLOW — First Dedicated Renal Outcomes Trial
Semaglutide 1 mg in T2DM + CKD · NEJM 2024 · Stopped early for efficacy
FLOW randomised 3,533 adults with type 2 diabetes and albuminuric CKD to semaglutide 1 mg weekly or placebo. Eligibility required eGFR 50–75 with UACR >300 to <5,000 mg/g, or eGFR 25–<50 with UACR >100 to <5,000 mg/g. Median follow-up was 3.4 years. The primary composite included kidney failure, sustained ≥50% eGFR decline, or kidney/CV death: HR 0.76 (95% CI 0.66–0.88; p=0.0003). All-cause death HR was 0.80 (0.67–0.95); annual eGFR decline was slower by 1.16 mL/min/1.73 m². Primary publication.
Baseline SGLT2-inhibitor subgroup (n=550): primary-outcome HR 1.07 (95% CI 0.69–1.67), compared with 0.73 (0.63–0.85) without baseline SGLT2 inhibition; interaction p=0.109. The wide subgroup interval and limited power do not prove additive kidney protection. Primary publication.
Heart Failure Evidence
STEP-HFpEF · STEP-HFpEF-DM · ongoing outcomes trials
The STEP-HFpEF programme (covered in the STEP section above) established meaningful quality-of-life and functional benefits in HFpEF with obesity. Key points: both diabetic (STEP-HFpEF-DM) and non-diabetic (STEP-HFpEF) HFpEF cohorts benefited consistently. The mechanism involves weight-mediated preload reduction (improving diastolic filling), epicardial adipose tissue reduction (reducing pro-inflammatory cytokine secretion), and possible direct myocardial GLP-1R signalling. A dedicated powered HFpEF outcomes trial (SOUL-HF) with semaglutide is now underway. Notably, GLP-1 RAs should be used cautiously in HFrEF (ejection fraction <40%) — the theoretical mild chronotropic effect (+2–4 bpm) may be less well tolerated — though no harm signal has been established in existing trials.
MASH & NAFLD Trials
SYNERGY-NASH · LEAN · GLP-1 RA liver histology evidence
SYNERGY-NASH was a 52-week phase 2 trial in 190 participants with biopsy-confirmed MASH and F2–F3 fibrosis. MASH resolution without worsening fibrosis occurred in 44%, 56% and 62% with tirzepatide 5, 10 and 15 mg versus 10% with placebo in the published primary analysis. At least one-stage fibrosis improvement without worsening MASH occurred in 55%, 51% and 51% versus 30%, respectively. Histological results do not establish prevention of liver failure or justify comparisons with separate resmetirom trials. This trial did not establish a licensed MASH indication for tirzepatide. Primary publication.
ESSENCE — semaglutide phase 3, 2025
The planned 72-week interim analysis included the first 800 participants with MASH and F2–F3 fibrosis from a 1,197-participant trial. Semaglutide 2.4 mg produced MASH resolution without fibrosis worsening in 62.9% versus 34.3% with placebo; fibrosis improvement without MASH worsening occurred in 36.8% versus 22.4%. Long-term clinical outcomes remain under follow-up. Primary publication. Current UK product indications must be checked separately in the Wegovy SmPC.
Neurological & Addiction Evidence
LIXIPARK · EVOKE · Addiction trials · 2024–2026
Master Trial Reference Table
All major GLP-1 RA trials — chronological with primary outcomes and verdict
| Trial | Year | Drug | n | Primary endpoint | Key result | Verdict |
|---|---|---|---|---|---|---|
| ELIXA | 2015 | Lixisenatide | 6,068 | 3-pt MACE | HR 1.02 (0.89–1.17) | Neutral |
| LEADER | 2016 | Liraglutide 1.8 mg | 9,340 | 3-pt MACE | HR 0.87 (0.78–0.97) p=0.01 | CV Superiority ✓ |
| SUSTAIN-6 | 2016 | Semaglutide SC | 3,297 | 3-pt MACE | HR 0.74 (0.58–0.95) p=0.02 | CV Superiority ✓ |
| SUSTAIN-1 | 2017 | Semaglutide SC 0.5/1 mg | 388 | HbA1c change | −1.5% (1 mg) vs −0.02% placebo | HbA1c landmark |
| EXSCEL | 2017 | Exenatide XR | 14,752 | 3-pt MACE | HR 0.91 (0.83–1.00) p=0.06 | Non-inferior |
| SUSTAIN-7 | 2018 | Sema vs Dulaglutide | 1,201 | HbA1c · head-to-head | −0.40% HbA1c diff; −3.5 kg wt diff | Sema superior ✓ |
| PIONEER-3 | 2019 | Oral semaglutide 14 mg | 1,864 | HbA1c vs sitagliptin | −0.5% difference · 78 weeks | Oral superior |
| PIONEER-6 | 2019 | Oral semaglutide | 3,183 | 3-pt MACE (safety) | HR 0.79 (0.57–1.11) | Non-inferior |
| REWIND | 2019 | Dulaglutide 1.5 mg | 9,901 | 3-pt MACE | HR 0.88 (0.79–0.99) p=0.026 | CV Superiority ✓ |
| STEP-1 | 2021 | Semaglutide 2.4 mg | 1,961 | % weight loss (obesity) | −14.9% vs −2.4% placebo | Obesity landmark |
| STEP-2 | 2021 | Semaglutide 2.4 mg | 1,210 | % weight loss (T2DM) | −9.6% vs −3.4% placebo | T2DM obesity |
| STEP-4 | 2021 | Semaglutide 2.4 mg | 803 | Weight after withdrawal | +6.9% regain on withdrawal | Chronic therapy |
| AMPLITUDE-O | 2021 | Efpeglenatide | 4,076 | 3-pt MACE | HR 0.73 (0.58–0.92) p=0.0004 | CV Superiority ✓ |
| SURPASS-2 | 2021 | Tirzepatide vs Sema 1 mg | 1,879 | HbA1c vs sema 1 mg | −2.30% vs −1.86%; weight −11.2 vs −5.7 kg | Tirz superior ✓ |
| SUSTAIN FORTE | 2022 | Semaglutide 2 mg | 961 | HbA1c vs sema 1 mg | −2.1% vs −1.9% · basis for 2 mg approval | Dose extension |
| SURMOUNT-1 | 2022 | Tirzepatide | 2,539 | % weight loss | −20.9% (15 mg) vs −3.1% | Weight record ★ |
| SELECT | 2023 | Semaglutide 2.4 mg | 17,604 | 3-pt MACE (no T2DM) | HR 0.80 (0.72–0.90) p<0.001 | CV Superiority ✓ ★ |
| STEP-HFpEF | 2023 | Semaglutide 2.4 mg | 529 | KCCQ-CSS + 6MWD | +7.8 pts; +21.5 m · p<0.01 | HFpEF benefit |
| SURMOUNT-3 | 2024 | Tirzepatide 15 mg | 579 | Weight (lifestyle + drug) | −26.6% total from baseline | Bariatric range |
| SOUL | 2025 | Oral semaglutide 14 mg | 9,650 | 3-pt MACE (T2DM+CKD) | HR 0.86 (0.77–0.96) p=0.006 | CV Superiority ✓ |
| SURMOUNT-5 | 2025 | Tirzepatide MTD 10/15 mg vs semaglutide MTD 1.7/2.4 mg | 751 | % weight change at 72 weeks · obesity without T2DM · open-label | −20.2% vs −13.7%, P<0.001 · NEJM 2025 · NCT05822830 | Tirz superior ✓ |
| FLOW | 2024 | Semaglutide 1 mg | 3,533 | Renal composite | HR 0.76 (0.66–0.88) p=0.0003 | Renal superior ✓ |
| SYNERGY-NASH | 2024 | Tirzepatide | 190 | MASH resolution (biopsy) | 62% (15 mg) vs 10% placebo | MASH landmark |
| LIXIPARK | 2024 | Lixisenatide | 156 | On-medication MDS-UPDRS III at 12 months | 3.08-point difference; p=0.007 | Phase 2; exploratory |
| EVOKE / EVOKE+ | 2025 | Oral semaglutide 14 mg | 3,808 | CDR-SB at 104 weeks | No significant clinical benefit | Negative primary result |
| TRIUMPH-2 | 2026 | Retatrutide | 1,152 | Weight at 80 weeks | −18.8% vs −5.1% (12 mg; treatment-regimen) | Published; investigational |
Trial summaries require verification against the cited publication and current product information. HR = hazard ratio for 3-point MACE vs placebo. RRR = relative risk reduction. SOC = standard of care. T2DM = type 2 diabetes mellitus. MASH = metabolic dysfunction-associated steatohepatitis. CDR-SB = clinical dementia rating sum of boxes. DaT SPECT = dopamine transporter SPECT imaging. CV Superiority ✓ = statistically significant reduction in the stated primary MACE endpoint vs the stated comparator.
Visual reference for clinical evidence
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.
Cardiovascular outcomes
CVOT forest plots — MACE reduction
Image description
The illustration presents Meta-visualisation of cardiovascular outcome trial hazard ratios.
Clinical interpretation
LEADER (liraglutide), SUSTAIN-6 (semaglutide), REWIND (dulaglutide), and SELECT (semaglutide in obesity without diabetes) demonstrate class-consistent MACE benefit, with agent-specific trial designs and effect sizes. EXSCEL (exenatide weekly) was neutral on non-inferiority margin.
SELECT trial design schematic
Image description
The illustration presents Semaglutide 2.4 mg in overweight/obesity without diabetes — CV primary endpoint.
Clinical interpretation
SELECT randomised 17,604 participants with established CVD and BMI ≥27 to semaglutide 2.4 mg vs placebo. Primary MACE reduction of 20% (HR 0.80) reshaped obesity pharmacotherapy toward cardiometabolic indication beyond diabetes.
SELECT — cardiovascular efficacy visualisation
Image description
The illustration presents Primary and secondary CV endpoints in non-diabetic obesity.
Clinical interpretation
Benefit emerged over months, supporting long-term adherence messaging. Blood pressure and inflammatory markers improved secondary to weight loss and direct effects.
REWIND — dulaglutide CV outcomes
Image description
The illustration presents Weekly dulaglutide reduced MACE in broad T2DM population including lower CV risk.
Clinical interpretation
REWIND included participants with prior CVD (31%) and high-risk features; median follow-up 5.4 years. MACE HR 0.88 (12% RRR) supports dulaglutide in cardiometabolic pathways.
GLP-1 RA cardiovascular outcomes summary
Image description
The illustration presents Integrated view of MACE, HF, and stroke endpoints across trials.
Clinical interpretation
Class effect on MACE is robust; HF benefits are heterogeneous (semaglutide HFpEF trials positive; general class less consistent than SGLT2i for HFrEF).
Cardiac anatomy in CV trial context
Image description
The illustration presents Structural heart disease relevance to GLP-1 prescribing.
Clinical interpretation
ASCVD trial populations include coronary disease, prior MI, and stroke — matching UK primary/secondary prevention pathways in NICE and NHS protocols.
Cardiovascular pathophysiology & GLP-1 effects
Image description
The illustration presents Mechanisms of plaque stabilisation, endothelial function, and inflammation.
Clinical interpretation
Proposed CV benefits include weight loss, BP reduction, improved lipids, direct endothelial effects, and reduced arterial inflammation — multifactorial and not fully explained by any single pathway.
Coronary artery cross-section — atherosclerosis
Image description
The illustration presents Vascular substrate targeted by cardiometabolic risk reduction.
Clinical interpretation
GLP-1 RAs reduce macrovascular events in high-risk cohorts; they are not a substitute for statins, antihypertensives, and antiplatelets.
Coronary pathology — semaglutide trial context
Image description
The illustration presents Visual link between trial endpoints and coronary disease.
Clinical interpretation
Supports patient communication: GLP-1 therapy lowers risk of heart attack and stroke in eligible populations (trial-dependent labelling).
Coronary plaque biology
Image description
The illustration presents Plaque burden and instability as therapeutic targets.
Clinical interpretation
Imaging substudies from CVOTs suggest favourable plaque composition changes with GLP-1 RAs in some cohorts — research-active area.
Carotid atherosclerosis
Image description
The illustration presents Cerebrovascular risk reduction mirrored in stroke endpoint reductions.
Clinical interpretation
Stroke reduction observed in LEADER and SUSTAIN-6 contributes to composite MACE benefit.
Vascular biology & cardiometabolic therapy
Image description
The illustration presents Systemic vascular effects of GLP-1 receptor activation.
Clinical interpretation
Includes vasodilation, reduced oxidative stress, and improved endothelial repair — complementary to blood pressure and weight effects.
Cardioprotective signalling pathways
Image description
The illustration presents Intracellular mediators of vascular benefit.
Clinical interpretation
Experimental data support AMPK activation, eNOS phosphorylation, and anti-inflammatory signalling — clinical translation via outcome trials.
Stroke risk reduction
Image description
The illustration presents Cerebrovascular endpoints in GLP-1 CVOTs.
Clinical interpretation
Stroke component of MACE favours GLP-1 RAs in high-risk diabetes; blood pressure and weight loss contribute.
Glycaemic efficacy
PIONEER programme — oral semaglutide outcomes
Image description
The illustration presents Oral semaglutide achieves HbA1c lowering comparable to subcutaneous in T2DM.
Clinical interpretation
PIONEER 1–8 explored oral semaglutide across treatment backgrounds. PIONEER 6 CVOT confirmed non-inferior MACE versus placebo. Real-world adherence depends on administration counselling.
Obesity efficacy
SURMOUNT programme — tirzepatide obesity trials
Image description
The illustration presents SURMOUNT-1 to -5 establish tirzepatide as most effective licensed anti-obesity injectable.
Clinical interpretation
SURMOUNT-1: 15 mg produced 20.9% weight loss versus 3.1% at 72 weeks (treatment-regimen estimand); efficacy estimates were 22.5% versus 2.4%. Primary publication.
SOUL trial context — oral semaglutide CV in T2DM
Image description
The illustration presents Oral semaglutide cardiovascular outcomes extension of PIONEER evidence.
Clinical interpretation
SOUL (2025): MACE HR 0.86 (95% CI 0.77–0.96; p=0.006). Confirmatory secondary outcomes were not significantly different. Primary publication.
Body composition before and after therapy
Image description
The illustration presents Weight loss magnitude with high-dose GLP-1 / tirzepatide.
Clinical interpretation
Mean weight loss in trials exceeds most prior anti-obesity medications; individual variation is wide. Lean mass loss occurs — resistance training and protein intake are recommended.
Tirzepatide weight reduction profile
Image description
The illustration presents Dose-dependent weight loss kinetics in SURMOUNT-1.
Clinical interpretation
Plateau typically occurs after 60–72 weeks; maintenance dosing ongoing in extension studies.
Functional and quality-of-life improvements
Image description
The illustration presents Beyond weight — physical function and patient-reported outcomes improve.
Clinical interpretation
Trial secondary endpoints include SF-36, IWQOL-Lite, and activity scores — relevant for shared decision-making and NHS commissioning.
Renal outcomes
FLOW trial — semaglutide renal outcomes in CKD
Image description
The illustration presents First dedicated GLP-1 RA renal outcomes trial — positive primary composite.
Clinical interpretation
FLOW reduced the composite of kidney failure, sustained ≥50% eGFR decline, or kidney/CV death in selected adults with type 2 diabetes and albuminuric CKD (HR 0.76). Primary publication.
Heart failure
Cardiac anatomy in HF trials
Image description
The illustration presents HFpEF and HFrEF distinctions for GLP-1 RA evidence.
Clinical interpretation
STEP-HFpEF demonstrated semaglutide improved symptoms, weight, and 6-minute walk in obesity-related HFpEF; caution in advanced HFrEF without SGLT2i/standard therapy optimisation.
HFpEF mechanism — semaglutide
Image description
The illustration presents Weight loss and decongestion improve HFpEF symptoms.
Clinical interpretation
Obesity-related HFpEF is a growing indication space; semaglutide 2.4 mg has regulatory momentum in this phenotype.
Trial evidence overview
Clinical trial data landscape
Image description
The illustration presents Scale of evidence base across glycaemic, obesity, and CV trials.
Clinical interpretation
Over 400,000 patient-years across programmes underpin guideline recommendations — one of the most evidence-rich drug classes in endocrinology.
Emerging indications
Neurodegeneration — exploratory semaglutide data
Image description
The illustration presents EVOKE/EVOKE+ Phase 3 studying semaglutide in early Alzheimer disease.
Clinical interpretation
EVOKE/EVOKE+ did not demonstrate slowing of Alzheimer’s disease; this illustration does not establish clinical benefit or support prescribing for dementia.
Clinical FAQs
Frequently asked questions
Do GLP-1 agonists reduce cardiovascular risk?
Yes. Cardiovascular outcome trials including LEADER, SUSTAIN-6 and SELECT showed reductions in major adverse cardiovascular events for several GLP-1 agonists, supporting their use in patients with established cardiovascular disease.
What are the landmark GLP-1 trials?
Key trials include LEADER (liraglutide), SUSTAIN-6 and STEP (semaglutide), SURPASS and SURMOUNT (tirzepatide), REWIND (dulaglutide) and SELECT (cardiovascular benefit in obesity without diabetes).