Type 2 diabetes — clinical trials landscape¶
TL;DR — The T2D pipeline has shifted from short HbA1c trials to cardiovascular, kidney, heart-failure and obesity outcome programmes. ClinicalTrials.gov returned 11,859 studies for “Type 2 Diabetes Mellitus” on 2026-08-30, but this broad total includes observational, behavioural and miscoded studies and is not a count of drug-development trials. Completed landmark registrations include EMPA-REG (NCT01131676), LEADER (NCT01179048), CREDENCE (NCT02065791), FLOW (NCT03819153), SURPASS-CVOT (NCT04255433) and SOUL (NCT03914326). Active next-generation programmes increasingly enrol obesity/CKD/CVD populations with or without diabetes.
Evolution of endpoints¶
| Era | Dominant endpoint | Limitation that drove change |
|---|---|---|
| Traditional efficacy | HbA1c at 24–52 weeks | Did not establish CV safety or organ benefit |
| CV safety era | 3-point MACE noninferiority | High-risk populations; class differentiation emerged |
| Organ-protection era | HF, kidney failure, eGFR, CV death | Multiple co-primary/composite interpretation |
| Obesity convergence | Weight + MACE + incident diabetes | T2D boundary becomes treatment-dependent |
| Multi-agonist era | Hard outcomes beyond weight | Surrogate superiority may not equal outcome superiority |
Verified landmark registrations¶
| Trial/programme | Registration | Status from live API 2026-08-30 | Published anchor |
|---|---|---|---|
| EMPA-REG OUTCOME | NCT01131676 | Completed | (Zinman 2015, PMID 26378978) |
| LEADER | NCT01179048 | Completed | (Marso 2016, PMID 27295427) |
| SUSTAIN-6 | NCT01720446 | Completed | (Marso 2016, PMID 27633186) |
| CREDENCE | NCT02065791 | Completed | (Perkovic 2019, PMID 30990260) |
| FLOW | NCT03819153 | Completed | (Perkovic 2024, PMID 38785209) |
| SELECT | NCT03574597 | Completed | (Lincoff 2023, PMID 37952131) |
| SURPASS-CVOT | NCT04255433 | Completed | Tirzepatide noninferior, not superior, to dulaglutide (Nicholls 2025, PMID 41406444) |
| SOUL | NCT03914326 | Completed | Oral semaglutide reduced MACE (McGuire 2025, PMID 40162642) |
Active/late pipeline¶
| Programme | Registration | Live status | Question |
|---|---|---|---|
| Tirzepatide CKD/obesity | NCT05536804 | Active, not recruiting | Kidney outcomes with/without T2D |
| TRIUMPH-Outcomes retatrutide | NCT06383390 | Active, not recruiting | CV/kidney outcomes in obesity |
| REDEFINE 3 CagriSema | NCT05669755 | Active, not recruiting | CV outcomes for amylin/GLP-1 combination |
| Retatrutide obesity/CVD | NCT05882045 | Completed | Multi-agonist obesity outcome programme |
Trial-design problems¶
| Problem | Consequence |
|---|---|
| Enriched high-risk populations | Large absolute effects; limited low-risk generalisability |
| Composite endpoints | Benefit can be driven by softer/more frequent component |
| On-treatment estimands | Understate discontinuation reality |
| Rescue medication | Dilutes glycaemic contrast but protects participants |
| Weight-loss unblinding | Behaviour and ascertainment can change |
| Sponsor concentration | Comparator and publication choices matter |
| Under-representation | Uncertain transportability across ancestry, age and income |
Head-to-head gaps¶
Most hard-outcome evidence compares one drug with placebo on background care. Direct GLP-1RA versus SGLT2, combination versus monotherapy, surgery versus incretin and intensive remission programme versus chronic drug trials are sparse. Network meta-analysis estimates relative effects indirectly (Palmer 2021, PMID 33441402). A live PubMed E-utilities search on 2026-08-30 identified a 2026 target-trial emulation associating triple RAASi+SGLT2i+GLP-1RA therapy with lower mortality and kidney-event risk, but this observational analysis does not replace a randomised incremental combination-outcome trial (Casper 2026, PMID 42658186).
Reading a modern outcome trial¶
| Field | Question to ask | Why it changes interpretation |
|---|---|---|
| Eligibility | Established CVD, risk factors, CKD, HF or obesity? | Determines baseline absolute risk |
| Run-in | Were intolerant/nonadherent participants removed? | Can inflate real-world persistence |
| Comparator | Placebo, active agent or usual care? | Active comparison answers sequencing better |
| Background therapy | Were SGLT2/GLP-1 drugs already common? | Changes incremental effect |
| Primary endpoint | MACE, kidney composite, HF or HbA1c? | Composite labels are not interchangeable |
| Estimand | Treatment-policy or on-treatment? | Handles discontinuation differently |
| Missing data | How were withdrawals handled? | Critical in weight trials |
| Multiplicity | Were secondary outcomes controlled? | Distinguishes confirmatory from exploratory |
| Follow-up | Long enough for outcome and adverse events? | HbA1c trials cannot establish legacy benefit |
| Representation | Sex, ancestry, age, income and geography? | Determines transportability |
Composite-endpoint anatomy¶
| Composite | Common components | Interpretive trap |
|---|---|---|
| 3-point MACE | CV death, nonfatal MI, nonfatal stroke | One component can drive the total |
| Kidney composite | eGFR decline, kidney failure, renal/CV death | eGFR thresholds differ by trial |
| HF composite | HF hospitalisation/urgent visit, CV death | Recurrent events may be analysed separately |
| “Diabetes progression” | HbA1c threshold, medication start, diagnosis | Medication and testing schedule influence event |
Absolute risk reduction should be calculated within the enrolled population and time horizon. A stable hazard ratio can yield very different numbers needed to treat at low and high baseline risk.
Trial-to-practice transfer¶
| Trial feature | Practice mismatch |
|---|---|
| Free study drug | Real-world price and coverage |
| Frequent visits | Less monitoring and adherence support |
| Protocol titration | Slower or interrupted titration |
| Exclusion of frailty | Greater adverse-event vulnerability in practice |
| Central adjudication | Coding-based outcome ascertainment |
| Stable supply | Shortages and switching |
Negative and neutral evidence¶
Neutral trials remain informative. EXSCEL showed cardiovascular safety without superiority for weekly exenatide (Holman 2017, PMID 28910237); VERTIS-CV showed ertugliflozin MACE noninferiority while supporting a heart-failure class signal (Cannon 2020, PMID 32966714). These results prevent inappropriate assumption that every molecule reproduces every endpoint.
Registration integrity¶
All NCT identifiers on this page were resolved through the ClinicalTrials.gov v2 API on 2026-08-30. Status is a registry snapshot, not proof that results are published, peer reviewed or free of reporting bias. “Completed” means study conduct ended according to the record; it does not mean evidence integration is complete.
Minimum results table for future updates¶
| Field | Required value |
|---|---|
| Registration | NCT ID and live status date |
| Population | Diabetes status, organ disease, age and size |
| Intervention/comparator | Dose, background treatment and duration |
| Primary outcome | Definition, events, HR/RR and 95% CI |
| Components | Each component effect |
| Discontinuation | By arm and reason |
| Safety | Prespecified mechanism-specific events |
| Publication | PMID retrieved live |
Registry caveats¶
- Condition search totals contain false positives and peripheral studies.
- Recruitment status can lag site-level reality.
- Protocol amendments may change outcomes or sample size.
- Results postings and journal publications can disagree in timing or detail.
- Each future update must re-query the API rather than copy this snapshot.
- Every linked publication must be re-retrieved from PubMed in that session.
SURPASS-2 and SURMOUNT-1 exemplify the glycaemia-to-obesity endpoint convergence now driving pipeline design (Frías 2021, PMID 34170647; Jastreboff 2022, PMID 35658024).
Cross-domain evidence crosswalk¶
These adjacent studies constrain interpretation of this page and make explicit where its conclusions depend on prevention, organ-outcome, remission, burden or implementation evidence.
| Verified evidence anchor | Connection |
|---|---|
| (Wiviott 2019, PMID 30415602) | Wiviott SD, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 |
| (Neal 2017, PMID 28605608) | Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 |
| (McMurray 2019, PMID 31535829) | McMurray JJV, et al. Dapagliflozin in HFrEF. N Engl J Med. 2019 |
| (Packer 2020, PMID 32865377) | Packer M, et al. Empagliflozin in HFrEF. N Engl J Med. 2020 |
| (Heerspink 2020, PMID 32970396) | Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 |
| (EMPA-KIDNEY 2023, PMID 36331190) | EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 |
| (Gerstein 2019, PMID 31189511) | Gerstein HC, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes. Lancet. 2019;394:121-130 |
| (Hernandez 2018, PMID 30291013) | Hernandez AF, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes. Lancet. 2018 |
| (Kristensen 2019, PMID 31422062) | Kristensen SL, et al. GLP-1RA cardiovascular, mortality, and kidney outcomes. Lancet Diabetes Endocrinol. 2019;7:776-785 |
| (Sattar 2022, PMID 35210595) | Sattar N, et al. Tirzepatide cardiovascular event risk assessment. Nat Med. 2022;28:591-598 |
| (Agarwal 2025, PMID 40813129) | Agarwal A, et al. Living guideline for T2D therapeutics. BMJ. 2025 |
| (Schauer 2017, PMID 28199805) | Schauer PR, et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes: 5-Year Outcomes. N Engl J Med. 2017 |
| (Courcoulas 2024, PMID 38411644) | Courcoulas AP, et al. Long-Term Outcomes of Medical Management vs Bariatric Surgery. JAMA. 2024;331:654-664 |
| (Mingrone 2021, PMID 33485454) | Mingrone G, et al. Metabolic surgery versus conventional medical therapy: 10-year follow-up. Lancet. 2021;397:293-304 |
Two trials that changed the late pipeline¶
SOUL randomised 9,650 high-risk participants to oral semaglutide or placebo. MACE occurred in 12.0% versus 13.8% over mean 47.5 months (HR 0.86, 95% CI 0.77–0.96), while confirmatory secondary outcomes, including the five-point kidney composite, were not significant (McGuire 2025, PMID 40162642). A prespecified analysis found no heterogeneity by baseline SGLT2 use: HR 0.89 (0.71–1.11) with and 0.84 (0.74–0.95) without SGLT2 treatment (interaction P=0.66) (Marx 2025, PMID 40156843).
SURPASS-CVOT used an active comparator rather than placebo. Among 13,165 modified-intention-to-treat participants with ASCVD, MACE was 12.2% with tirzepatide and 13.1% with dulaglutide (HR 0.92, 95.3% CI 0.83–1.01; P=0.003 for noninferiority, P=0.09 for superiority) (Nicholls 2025, PMID 41406444). Its noninferiority margin required the upper CI below 1.05, making the conclusion sensitive to the unusually stringent prespecified boundary. The design publication documents the active-comparator rationale and baseline representativeness (Nicholls 2024, PMID 37758044).
| Design lesson | SOUL | SURPASS-CVOT |
|---|---|---|
| Comparator | Placebo on standard care | Dulaglutide with proven MACE benefit |
| Question answered | Does oral semaglutide add benefit? | Is tirzepatide no worse/better than an active GLP-1RA? |
| Main inference | Superiority for MACE | Noninferiority, not superiority |
| Residual gap | Incremental kidney benefit and combination strategy | Placebo-relative absolute benefit and subgroup power |
Meta-analysis versus trial interpretation¶
Updated synthesis of ten long-acting GLP-1RA trials found MACE HR 0.86 (95% CI 0.81–0.90), kidney-composite HR 0.83 (0.75–0.92) and no route heterogeneity (Lee 2025, PMID 40156846). A living network spanning 869 trials and 493,168 participants ranks many drug outcomes but relies heavily on indirect comparison and different background-care eras (Nong 2025, PMID 40813122). The ACP review similarly found direct comparisons sparse and subgroup data limited (Drake 2024, PMID 38639549).
Combination meta-analysis found GLP-1RA MACE HR 0.79 (0.71–0.87) overall and consistent effects by baseline SGLT2 use, but only 1,743 of 17,072 participants used SGLT2 at baseline (Neuen 2024, PMID 39210781). This is evidence against a large negative interaction, not evidence that combination is superior to either monotherapy.
Registry state as of 2026-08-30¶
The live ClinicalTrials.gov v2 API returned COMPLETED for all eight landmark registrations in the completed table and for the retatrutide obesity/CVD registration; tirzepatide CKD/obesity, TRIUMPH-Outcomes and REDEFINE 3 returned ACTIVE_NOT_RECRUITING. Status describes recruitment/administration, not publication, data quality or peer review. The clinical question column should therefore be updated only when a results record or live-retrieved publication answers it.
Current controversies¶
- Active versus placebo comparator: active comparison is more relevant to sequencing but can obscure placebo-relative magnitude.
- Composite kidney endpoints: albuminuria, eGFR decline and kidney failure should not be treated as interchangeable.
- Obesity/T2D boundary: outcome trials may exclude diabetes while directly changing diabetes incidence and treatment need.
- Post hoc kidney analyses: SURPASS-CVOT kidney findings remain exploratory even when prespecified (Zoungas 2026, PMID 42114520).
- Representation: large CVOTs improve geographic breadth but remain selected for risk, adherence and follow-up capacity.
Open questions¶
- Will triple/multi-agonists reduce MACE, kidney failure and mortality beyond established agents?
- What is the best estimand for discontinuation-prone chronic weight therapy?
- Can platform trials compare combinations efficiently across cardio-kidney-metabolic phenotypes?
- How can trial access expand beyond high-income specialist sites?
Related pages¶
- Incretin therapies — multi-agonist pipeline.
- SGLT2 inhibitors — outcome-trial precedent.
- Metabolic surgery — missing head-to-head comparator.
- Open questions — designable evidence gaps.
References¶
- Zinman B, et al. Empagliflozin Cardiovascular Outcomes. N Engl J Med. 2015. PMID 26378978
- Marso SP, et al. Liraglutide Cardiovascular Outcomes. N Engl J Med. 2016. PMID 27295427
- Marso SP, et al. Semaglutide Cardiovascular Outcomes. N Engl J Med. 2016. PMID 27633186
- Perkovic V, et al. Canagliflozin Renal Outcomes. N Engl J Med. 2019. PMID 30990260
- Perkovic V, et al. Semaglutide on CKD. N Engl J Med. 2024. PMID 38785209
- Lincoff AM, et al. Semaglutide CV Outcomes in Obesity without Diabetes. N Engl J Med. 2023. PMID 37952131
- Palmer SC, et al. SGLT2 inhibitors and GLP-1RA network meta-analysis. BMJ. 2021. PMID 33441402
- Frías JP, et al. Tirzepatide versus Semaglutide. N Engl J Med. 2021. PMID 34170647
- Jastreboff AM, et al. Tirzepatide for Obesity. N Engl J Med. 2022. PMID 35658024
- Holman RR, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes. N Engl J Med. 2017. PMID 28910237
- Cannon CP, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020. PMID 32966714
- Wiviott SD, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019. PMID 30415602
- Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017. PMID 28605608
- McMurray JJV, et al. Dapagliflozin in HFrEF. N Engl J Med. 2019. PMID 31535829
- Packer M, et al. Empagliflozin in HFrEF. N Engl J Med. 2020. PMID 32865377
- Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020. PMID 32970396
- EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388:117-127. PMID 36331190
- Gerstein HC, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes. Lancet. 2019;394:121-130. PMID 31189511
- Hernandez AF, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease. Lancet. 2018;392:1519-1529. PMID 30291013
- Kristensen SL, et al. GLP-1RA cardiovascular, mortality, and kidney outcomes. Lancet Diabetes Endocrinol. 2019;7:776-785. PMID 31422062
- Sattar N, et al. Tirzepatide cardiovascular event risk assessment. Nat Med. 2022;28:591-598. PMID 35210595
- Agarwal A, et al. Living guideline for T2D therapeutics. BMJ. 2025. PMID 40813129
- Schauer PR, et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes: 5-Year Outcomes. N Engl J Med. 2017. PMID 28199805
- Courcoulas AP, et al. Long-Term Outcomes of Medical Management vs Bariatric Surgery. JAMA. 2024;331:654-664. PMID 38411644
- Mingrone G, et al. Metabolic surgery versus conventional medical therapy: 10-year follow-up. Lancet. 2021;397:293-304. PMID 33485454
- McGuire DK, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392:2001-2012. PMID 40162642
- Marx N, et al. SOUL outcomes according to SGLT2-inhibitor use. Circulation. 2025;151:1639-1650. PMID 40156843
- Nicholls SJ, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide. N Engl J Med. 2025;393:2409-2420. PMID 41406444
- Nicholls SJ, et al. SURPASS-CVOT design and baseline characteristics. Am Heart J. 2024;267:1-11. PMID 37758044
- Lee MMY, et al. Long-Acting Injectable and Oral GLP-1RA Outcome Meta-analysis. Diabetes Care. 2025;48:846-859. PMID 40156846
- Nong K, et al. Medications for adults with type 2 diabetes: living network meta-analysis. BMJ. 2025;390:e083039. PMID 40813122
- Drake T, et al. Newer Pharmacologic Treatments: ACP systematic review. Ann Intern Med. 2024;177:618-632. PMID 38639549
- Neuen BL, et al. GLP-1RA outcomes alone and with SGLT2 inhibitors. Circulation. 2024;150:1781-1790. PMID 39210781
- Zoungas S, et al. Tirzepatide versus dulaglutide and major kidney events in SURPASS-CVOT. Lancet Diabetes Endocrinol. 2026. PMID 42114520
- Casper J, et al. Comparative Effectiveness of Combination Therapy in Patients with Chronic Kidney Disease and Type 2 Diabetes Using Real-World Data. Nephrol Dial Transplant. 2026. PMID 42658186