Open questions — type 2 diabetes¶
Last curated: 2026-08-30
Stable IDs persist across future updates. A question moves to “answered” only when the relevant outcome—not merely a surrogate—has adequate evidence.
Tier 1 — practice-changing and designable now¶
OQ-1 — How should remission durability be increased?¶
DiRECT remission fell from 46% at one year to 36% at two years and 13% in the five-year extension group; maintained weight loss is strongly associated with persistence, but β-cell reserve and environment may explain additional relapse (Lean 2018, PMID 29221645; Lean 2019, PMID 30852132; Lean 2024, PMID 38423026). A factorial maintenance trial could compare behavioural intensity, intermittent formula diet and pharmacologic maintenance, stratified by duration/C-peptide.
OQ-2 — What should drug-dependent normoglycaemia be called and measured as?¶
Consensus remission requires HbA1c <6.5% without glucose-lowering medication, excluding clinically valuable normoglycaemia during GLP-1/tirzepatide therapy (Riddle 2021, PMID 34462270; Frías 2021, PMID 34170647). A 2026 review now proposes “pharmacological remission,” and a 14,141-person observational study produced frequencies from 5.8% to 18.3% under four definitions (Bianchi 2026, PMID 41852334; Fadini 2025, PMID 41142657). The unresolved task is consensus validation against off-treatment durability, complications and treatment burden.
OQ-3 — Is routine GLP-1RA plus SGLT2 therapy superior to either alone on hard outcomes?¶
Indirect evidence suggests complementary strengths—SGLT2 for HF, GLP-1RA for stroke and both for kidney/mortality. GLP-1RA effects appear consistent with baseline SGLT2 use, but only 1,743/17,072 participants in the relevant meta-analysis used SGLT2 at baseline; this tests interaction, not randomised incremental combination benefit (Palmer 2021, PMID 33441402; Neuen 2024, PMID 39210781). A 2026 target-trial emulation associated triple RAASi+SGLT2i+GLP-1RA therapy with lower mortality and kidney-event risk, but residual confounding remains (Casper 2026, PMID 42658186). A pragmatic factorial outcome trial in dual cardiorenal risk is feasible.
OQ-4 — Does early organ-protective therapy create a legacy effect?¶
UKPDS demonstrates benefits persisting 24 years after early glycaemic assignment, but whether finite early SGLT2/GLP-1 exposure changes long-term trajectories is unknown (Adler 2024, PMID 38772405). Withdrawal or delayed-start extensions with ethical rescue rules could test persistence.
OQ-5 — Which modern strategy is best over ten years: surgery, incretin therapy or structured diet?¶
Each approach achieves substantial glycaemic/weight benefit in unlike trials; surgery has longer follow-up, incretins have large CVOTs, and DiRECT has primary-care remission evidence (Courcoulas 2024, PMID 38411644; Aronne 2025, PMID 40353578; Lean 2024, PMID 38423026). A live 2026 search found a systematic review of six retrospective surgery-versus-GLP-1RA cohorts but no decade-long randomised hard-outcome comparison (Campbell 2026, PMID 42660781). A preference-aware pragmatic comparative-effectiveness trial should measure hard outcomes, treatment burden and total cost.
OQ-6 — Can youth-onset T2D complication trajectories be altered?¶
By mean age 26.4 years, 60.1% of TODAY follow-up participants had at least one microvascular complication. RISE showed neither glargine→metformin nor metformin alone halted β-cell decline, while DINAMO established 26-week empagliflozin HbA1c efficacy but not organ protection (TODAY 2021, PMID 34320286; RISE 2018, PMID 29941500; Laffel 2023, PMID 36738751). A live search through 2026-08-30 found efficacy and cohort evidence but no paediatric organ-outcome strategy trial; long trials need β-cell, kidney, retina and cardiovascular endpoints rather than adult extrapolation.
OQ-7 — How can SGLT2 sick-day rules reduce DKA without avoidable permanent discontinuation?¶
Euglycaemic DKA is rare but diagnostically hazardous, particularly with surgery, fasting and acute illness (Dutta 2022, PMID 35495849). A live search through 2026-08-30 found perioperative guidance and outcome syntheses but no randomised sick-day implementation pathway; cluster-randomised studies could compare written rules, EHR prompts, ketone access and restart pathways.
OQ-8 — Does anti-stigma care improve clinical outcomes?¶
Consensus evidence links stigma to distress and care barriers (Speight 2024, PMID 38128969). A 21-clinician randomised pilot improved attitudes toward stigma-free language but did not measure sustained clinician behaviour or any patient outcome (Joiner 2026, PMID 42579884). A larger clinic-level language/training intervention with validated stigma, attendance, medication-persistence and clinical outcomes is now the relevant next test.
OQ-9 — Which biomarker adds enough value to guide treatment?¶
Clusters and multi-omics predict heterogeneity, but simple clinical variables often match cluster-based treatment-response prediction (Dennis 2019, PMID 31047901; Carrasco-Zanini 2024, PMID 37889320). A live search through 2026-08-30 retrieved biomarker validation/prediction studies but no randomised test-use strategy with patient outcomes; future trials must randomise use of the test, not merely validate association.
OQ-10 — How should rapid HbA1c improvement be managed in advanced retinopathy?¶
SUSTAIN-6 detected retinopathy complications during rapid improvement, while ACCORD Eye and its follow-on show lower long-term retinopathy progression after intensive glycaemia (Marso 2016, PMID 27633186; Chew 2010, PMID 20587587; ACCORDION Eye 2016, PMID 27289122). A live search through 2026-08-30 found reviews and observational/legacy evidence but no randomised monitoring-or-titration strategy for early worsening; such trials could test whether monitoring or slower reduction preserves long-term benefit.
Tier 2 — important but requiring method or infrastructure development¶
OQ-11 — Is there a stable mechanistic taxonomy of T2D?¶
Data-driven clusters reproduce phenotypic variation but depend on continuous variables, timing and treatment; genetic pathways demonstrate heterogeneity without a validated clinical taxonomy (Ahlqvist 2018, PMID 29503172; Suzuki 2024, PMID 38374256). A live search through 2026-08-30 found cluster validation and response-prediction studies, but no randomised cluster-guided outcome strategy.
OQ-12 — What is the operational biomarker of the personal fat threshold?¶
The twin-cycle model explains remission through ectopic-fat reduction, yet no scalable liver/pancreas-fat or adipose-capacity threshold guides care across ancestries (Taylor 2024, PMID 39038473).
OQ-13 — How should global incidence be measured consistently?¶
IDF and GBD reconcile unlike tests, age ranges and source quality; low-resource settings have the largest diagnostic gaps (Sun 2022, PMID 34879977; GBD 2021 Diabetes Collaborators 2023, PMID 37356446). A standard repeated biochemical-surveillance platform is needed.
OQ-14 — Which prevention policies work without widening inequity?¶
High BMI and diet account for large modelled burden fractions, but comparative-risk models do not identify locally effective, equitable policies (GBD 2021 Diabetes Collaborators 2023, PMID 37356446; O'Hearn 2023, PMID 37069363).
OQ-15 — How much benefit is lost through discontinuation, shortage and cost?¶
Efficacy trials provide free drug and structured follow-up; global disease scale and expenditure make persistence/access central (Sun 2022, PMID 34879977; González-González 2021, PMID 34244276). Linked pharmacy, clinical and patient-reported datasets are needed.
OQ-16 — What is the correct complication-surveillance schedule after remission?¶
Consensus recommends continued observation because prior glycaemic exposure persists (Riddle 2021, PMID 34462270; Adler 2024, PMID 38772405). A live search through 2026-08-30 found consensus recommendations and observational risk studies, but no trial comparing surveillance intervals or deintensification after remission.
OQ-17 — Can diabetes-related MASLD fibrosis be screened without overdiagnosis?¶
T2D is a high-risk context, but liver enzymes are insensitive and simple fibrosis scores have age-related false positives. Sequential test strategies require prospective clinical-outcome validation (Driessen 2025, PMID 38147315).
OQ-18 — How should patient-defined benefit enter treatment algorithms?¶
Preferences vary across route, adverse effects, weight, hypoglycaemia and cost, yet algorithms usually optimise disease outcomes first (González-González 2021, PMID 34244276; Davies 2022, PMID 36148880).
OQ-19 — Which intervention repairs the global diagnosis-to-control cascade?¶
In 2023, an estimated 55.8% of people with diabetes were diagnosed, 91.4% of those diagnosed were treated, but only 41.6% of treated people had optimal glycaemia; in 55 LMIC surveys, only 4.6% received all recommended treatments (Stafford 2025, PMID 40934935; Flood 2021, PMID 35211689). Cluster-randomised health-system trials should compare screening linkage, medicine supply, team care and risk-factor bundles using population-level control—not clinic attendees alone—as denominator.
OQ-20 — Is youth β-cell decline modifiable or only suppressible while treatment continues?¶
RISE found progressive β-cell deterioration on glargine→metformin or metformin, followed by worsening after withdrawal; liraglutide and empagliflozin improve HbA1c over 26–52 weeks (RISE 2018, PMID 29941500; Hannon 2020, PMID 32985775; Tamborlane 2019, PMID 31034184). A live search through 2026-08-30 found no youth T2D treatment-withdrawal study demonstrating durable secretion preservation; a withdrawal-aware trial should pair clamp/C-peptide measures with clinical durability.
OQ-21 — Is remission causal, or a marker of favourable biology and weight response?¶
Look AHEAD remission was associated with CKD HR 0.67 and CVD HR 0.60, and SOS remission with mortality HR 0.71, but remission is a post-randomisation state correlated with weight loss, fitness and β-cell reserve (Gregg 2024, PMID 38233592; Carlsson 2024, PMID 38896851). Mediation analyses and randomised maintenance interventions are needed before surveillance or risk treatment is de-escalated.
OQ-22 — What is the net benefit of different default HbA1c targets in the low-hypoglycaemia era?¶
ACP proposed 7%–8% for most adults while ADA/AACE often support lower individual targets; older intensive-control trials used therapies with different weight and hypoglycaemia profiles from current incretin/SGLT2 strategies (Qaseem 2018, PMID 29507945; Blonde 2022, PMID 35963508). A live search through 2026-08-30 found modern drug-comparison studies but no randomised default-target strategy built around incretin/SGLT2 therapy; such a trial should stratify by age, frailty and drug class.
OQ-23 — Can MASLD screening in T2D improve outcomes rather than referrals?¶
Meta-analysis estimates MASLD in 65.33% of people with T2D and advanced fibrosis in 15.49% of biopsy cohorts, but verification bias inflates histologic estimates (Younossi 2024, PMID 38521116). A live search through 2026-08-30 found biomarker and guideline studies but no randomised screening-to-clinical-outcome strategy; sequential FIB-4→elastography should be tested against usual care for cirrhosis, liver events, treatment burden and cost.
OQ-24 — Does CGM improve complications or mainly short-term glycaemia in non-prandial-insulin T2D?¶
MOBILE improved HbA1c by 0.4 points and time-in-range by 15 points over eight months in basal-insulin users; smaller non-insulin studies confound sensor feedback with education (Martens 2021, PMID 34077499; Martens 2025, PMID 39757879). A live search through 2026-08-30 found CGM measurement, association and short-term randomised studies but no complication-endpoint strategy trial in this population; longer pragmatic trials should measure severe hypoglycaemia, complications, distress, equity and total cost.
OQ-25 — How should active-comparator outcome trials alter sequencing?¶
SURPASS-CVOT established tirzepatide noninferiority but not superiority to dulaglutide (MACE HR 0.92, 95.3% CI 0.83–1.01), answering a different question from placebo-controlled SOUL (HR 0.86, 95% CI 0.77–0.96) (Nicholls 2025, PMID 41406444; McGuire 2025, PMID 40162642). Decision models need absolute outcomes, weight, adverse effects, discontinuation and cost under contemporary background therapy.
OQ-26 — Which patient-reported outcomes are actionable in routine care?¶
Diabetes distress and self-management are the most consistently endorsed diabetes-specific outcomes, but screening without a response pathway can add burden (Hamilton 2023, PMID 37672919). Trials should randomise measurement-plus-response, not questionnaire administration alone, and include distress, safety, HbA1c, attendance and clinician workload.
Dots not yet connected¶
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D-1 | DiRECT weight-loss/remission dose response | GLP-1/tirzepatide withdrawal and chronic dosing | Randomised pharmacologic maintenance after diet-induced remission | OQ-1, OQ-2 |
| D-2 | UKPDS 24-year legacy | Rapid SGLT2/GLP-1 organ benefit | Delayed-start/withdrawal evidence for an organ-protection legacy | OQ-4 |
| D-3 | FLOW GLP-1 kidney benefit | SGLT2 CKD foundation | Direct incremental combination kidney-outcome trial | OQ-3 |
| D-4 | TODAY rapid β-cell failure | Adult incretin/SGLT2 outcome benefits | Long youth trial with β-cell and organ endpoints | OQ-6 |
| D-5 | Retinopathy early-worsening signal | Large modern HbA1c reductions | Eye-risk-guided titration strategy | OQ-10 |
| D-6 | Genetic pathway heterogeneity | GRADE comparative treatment response | Genotype-guided randomised drug selection | OQ-9, OQ-11 |
| D-7 | Ectopic-fat/twin-cycle biology | Multi-ancestry body-composition differences | Scalable personal-fat-threshold measurement | OQ-12 |
| D-8 | Stigma consensus | Clinical outcomes and adherence | Cluster intervention testing language as a care technology | OQ-8 |
| D-9 | Trial efficacy | Patient preference/treatment burden | Preference-concordant prescribing effect on persistence and outcomes | OQ-15, OQ-18 |
| D-10 | Surgery decade-long glycaemic evidence | Incretin CVOT and obesity efficacy | Direct long-horizon comparative effectiveness | OQ-5 |
| D-11 | GBD attributable dietary risk | Local food insecurity and programme reach | Equity-sensitive policy trial with incidence endpoint | OQ-14 |
| D-12 | Remission definition | UKPDS legacy complications | Evidence-based surveillance interval after remission | OQ-16 |
| D-13 | T2D–MASLD cardiovascular overlap | Noninvasive fibrosis triage | Screening strategy linked to liver and CV outcomes | OQ-17 |
| D-14 | SGLT2 euglycaemic DKA cases | EHR medication/surgery workflows | Automated hold–ketone–restart pathway trial | OQ-7 |
| D-15 | Global care-cascade modelling | LMIC comprehensive-treatment coverage | Population-denominator trial of diagnosis-to-control packages | OQ-19 |
| D-16 | RISE β-cell decline | Paediatric liraglutide/empagliflozin efficacy | Durable disease-modification trial with withdrawal phase | OQ-6, OQ-20 |
| D-17 | Remission-associated lower CKD/CVD | Post-randomisation responder biology | Causal mediation plus maintenance randomisation | OQ-1, OQ-21 |
| D-18 | ACP versus ADA/AACE targets | Modern low-hypoglycaemia drugs | Target-strategy trial disentangling target from treatment | OQ-22 |
| D-19 | High T2D–MASLD prevalence | Sequential noninvasive fibrosis tests | Screening-to-outcome strategy trial | OQ-17, OQ-23 |
| D-20 | CGM short-term time-in-range benefit | Legacy microvascular evidence | Long-term CGM strategy trial with hard and patient-reported outcomes | OQ-24 |
| D-21 | Active-comparator SURPASS-CVOT | Placebo-controlled SOUL/FLOW | Contemporary sequencing model and pragmatic trial | OQ-3, OQ-25 |
| D-22 | Patient-reported outcome consensus | Distress-intervention heterogeneity | Measurement-plus-response trial | OQ-8, OQ-18, OQ-26 |