The trial spine

ADJUNCT ONE (Mathieu 2016, Diabetes Care)

1,398 adults with T1D, double-blind, treat-to-target, 52 weeks. Liraglutide 0.6, 1.2 or 1.8 mg once daily versus placebo, on top of insulin that could be up-titrated. The HbA1c estimated treatment differences versus placebo were -0.20 per cent (95 per cent CI -0.32 to -0.07) for the 1.8 mg arm, -0.15 per cent (-0.27 to -0.03) for 1.2 mg and -0.09 per cent (-0.21 to 0.03, not significant) for 0.6 mg. Weight changes were -4.9, -3.6 and -2.2 kg at the three doses, all significant. Symptomatic hypoglycaemia rate ratios ran 1.17 to 1.31; hyperglycaemia-with-ketosis was 2.22 times more frequent at 1.8 mg than placebo. Discontinuation for adverse events was 22 per cent. The HbA1c effect did not cross the 0.4 per cent regulatory threshold. PMID 27506222. Grade A.

ADJUNCT TWO (Ahrén 2016, Diabetes Care)

835 adults with T1D, double-blind, 26 weeks, insulin capped at the pre-randomisation dose (this matters: it isolates the drug effect from any insulin up-titration). Within-arm HbA1c change from baseline was -0.33, -0.22 and -0.23 per cent at 1.8, 1.2 and 0.6 mg respectively versus +0.01 per cent in the placebo arm. Within-arm weight change was -5.1, -4.0 and -2.5 kg versus -0.2 kg placebo. Symptomatic hypoglycaemia was elevated at 1.2 mg (21.3 vs 16.6 events per patient per year, P=0.03); hyperglycaemia with ketosis above 1.5 mmol/L at 1.8 mg was 0.5 vs 0.1 events per patient per year (P=0.01). 16.8 per cent discontinued. The HbA1c effect did not cross the 0.4 per cent regulatory threshold. PMID 27493132. Grade A.

Note on presentation: ADJUNCT ONE reports between-group estimated treatment differences (ETDs) versus placebo; ADJUNCT TWO reports within-arm change from baseline. The numbers are not directly comparable, and a larger absolute change-from-baseline figure does not mean a larger drug effect. The Park 2024 meta-analysis below pools both trials into per-mg-dose ETDs.

Pasqua 2025 semaglutide-plus-AID crossover (Nature Medicine)

24 adults with T1D, double-blind randomised crossover. Weekly semaglutide up to 1 mg plus investigational AID versus placebo plus the same AID, approximately 15 weeks per arm. Time in range (3.9 to 10 mmol/L, 70 to 180 mg/dL) rose by approximately 4.8 percentage points versus placebo, with no increase in time below range. HbA1c fell by approximately 0.5 per cent; weight by 5.3 kg (5.1 per cent); total daily insulin paired difference approximately 11.3 units per day (roughly 22.3 per cent). Safety: no severe hypoglycaemia, no DKA; 2 of 24 completers (8 per cent) developed euglycaemic hyperketonaemia without acidosis. The first RCT of weekly semaglutide combined with AID. PMID 39794615. Grade A.

ADJUST-T1D (Shah 2025, NEJM Evidence)

72 adults with T1D, BMI at least 30, already using AID for at least 3 months, HbA1c above 7 per cent. Weekly semaglutide titrated 0.25 to 0.5 to 1 mg versus placebo, 26 weeks, 4 US sites, FDA IND, DSMB oversight. Primary composite outcome (TIR above 70 per cent AND time below range under 4 per cent AND weight loss at least 5 per cent): 36 per cent semaglutide versus 0 per cent placebo (P below 0.001). HbA1c fell by 0.3 percentage points (95 per cent CI -0.6 to -0.05); TIR rose by 8.8 pp (3.9 to 13.7); TITR (3.9 to 7.8 mmol/L, 70 to 140 mg/dL) rose by 6.9 pp; time below range unchanged. Weight fell by 8.8 kg (95 per cent CI -10.6 to -7.0); BMI by 3.1 units; total daily insulin by 22.3 units per day (95 per cent CI -28.8 to -15.7). 75 per cent achieved at least 5 per cent weight loss; 47 per cent at least 10 per cent. Two severe hypoglycaemia episodes in each arm; no DKA; 1 high-ketone event attributed to an infusion-set failure. 5.5 per cent discontinued for persistent gastrointestinal events. Keystone adult RCT of semaglutide plus AID. PMID 40550013. Grade A.

Tirzepatide observational (Akturk and Shah 2025, JDST)

26 adults with T1D, mean BMI 36.7, single-centre retrospective, weekly tirzepatide titrated 2.5 to 15 mg, 8 months. HbA1c fell by 0.45 per cent at 3 months, 0.56 per cent at 6 months, 0.59 per cent at 8 months. Weight fell by 3.4 per cent at 3 months, 10.5 per cent at 6 months, 10.1 per cent at 8 months. TIR rose by 12.6 pp at 3 months and held. TITR rose by 10.7 pp at 3 months. TDD fell by 18.9 units per day. No DKA. One severe constipation episode led to discontinuation. One peroneal nerve palsy (foot drop) in association with rapid weight loss. The strongest signal we have for tirzepatide in T1D, but a single-centre N=26 observational cohort cannot be compared head-to-head with the RCT evidence for GLP-1RA. PMID 38317405. Grade C.

Klein and Shah 2025 genetic-obesity substudy (JDST)

26 adults with T1D plus severe early-onset obesity (BMI above 40), retrospective case-control, 6 months. Mutation-positive patients (leptin-melanocortin pathway, Bardet-Biedl or ciliopathy variants, NCOA1/SRC1, NRP2/BBS12) achieved the primary goal (at least 5 per cent weight loss OR at least 0.4 per cent HbA1c reduction) in 36.4 per cent versus 80.0 per cent of controls (P=0.04). The continuous outcomes (weight -5.75 kg vs -8.65 kg, P=0.44; HbA1c -0.28 per cent vs -0.43 per cent, P=0.64) did not reach significance. Exploratory only, but the first human-genetic signal that a meaningful minority of high-BMI T1D patients may have a blunted drug-class response. Grade C.

ADJUNCT post-hoc (Shah 2024, JDST)

Pooled ADJUNCT ONE + TWO (1,398 + 835) pre-specified completer-versus-non-completer analysis. Non-completers had lower BMI (27.8 vs 29.8 in ONE, P below 0.0001; 26.3 vs 29.2 in TWO), longer T1D duration (25.8 vs 21.0 years in ONE), and a higher proportion with undetectable C-peptide (91.5 vs 81.3 per cent in ONE). Severe hypoglycaemia and DKA rates did not drive discontinuation; gastrointestinal and metabolism adverse events did. Clinical takeaway: the low-BMI, long-duration, C-peptide-negative patient is the one most likely to struggle with tolerance, a finding that shapes modern patient selection. PMID 39717993. Grade B (pre-registered post-hoc of two Grade A trials).

The Park 2024 JCEM meta-analysis

The numerical anchor that sits behind everything above. Park and colleagues, Journal of Clinical Endocrinology and Metabolism 2024;109(1):279-292, DOI 10.1210/clinem/dgad471. 24 RCTs, N=3,377. Pooled ETDs (versus placebo) across the class, per-mg-dose:

• Liraglutide 1.8 mg daily. HbA1c -0.28 per cent (95 per cent CI -0.38 to -0.19). Weight -4.89 kg (-5.33 to -4.45). TDD -7.51 units per day (-9.52 to -5.49).
• Liraglutide 1.2 mg daily. HbA1c -0.21 per cent (-0.30 to -0.12). Weight -3.77 kg (-4.24 to -3.30). TDD -5.28 units per day (-8.53 to -2.04).
• Liraglutide 0.6 to 0.9 mg daily. HbA1c -0.17 per cent (-0.26 to -0.07). Weight -2.27 kg (-2.75 to -1.79). TDD -1.58 units per day (-3.40 to +0.24, not significant).
• Exenatide. HbA1c -0.17 per cent (-0.28 to 0.02). Weight -4.06 kg (-5.33 to -2.79). TDD -9.76 units per day (-15.59 to -3.92).

The Park meta-analysis is also cited in Table 2 of the 2025 Diabetes Technology Society (DTS) consensus, alongside the ADJUNCT trials and ADJUST-T1D. The underlying signal is consistent across analyses: modest HbA1c, meaningful weight, meaningful TDD reduction, a clear dose-response from 0.6 to 1.8 mg.

International consensus

Consensus reports carry Grade C under GNL methodology: consensus guidelines are Grade C regardless of journal; only RCTs and systematic reviews or meta-analyses are Grade A. Consensus is where expert opinion meets the evidence, not where the evidence lives. It matters because it translates the evidence into practice recommendations, not because it is itself Grade A data.

Diabetes Technology Society (DTS) Consensus (Shah, Klonoff and colleagues 2025, JDST)

19-member panel, 3 meetings in 2024, 32 proposed recommendations, 31 passed. Adults only; paediatric gap flagged explicitly. Recommendation 11: individualised titration, low start, slow up-titration, to minimise side effects and discontinuation. Recommendations 17 to 20: patient selection (adults with T1D plus overweight, obesity, insulin resistance, high insulin requirements, postprandial hyperglycaemia not controlled by optimised meal strategy, severe insulin resistance barring AID use, high CVD or CKD risk). Recommendation 9: gastrointestinal side effects can mimic DKA; ketone monitoring remains standard of care. Recommendation 27: AID systems should accommodate the TDD reduction that GLP-1RA drives. Recommendation 25: Phase 3 regulatory trials in T1D are urgently needed. PMID 39517127. Grade C.

ISPAD 2024, Adjunctive Therapies chapter (Cengiz, Danne, Ng and colleagues)

Paediatric and adolescent scope. Explicit: no Phase 3 RCTs exist for GLP-1RA, tirzepatide or SGLT2i in paediatric T1D. Paediatric GLP-1RA approvals are for obesity or T2D only (liraglutide, exenatide, dulaglutide from age 10 and above), not for T1D. The chapter language is “could be considered adjunctive therapy in specific populations of children and adolescents with T1D and obesity”, inside a gap-first overarching statement that “larger trials are needed”. Part 4 of this guide treats the paediatric question directly. PMID 39884261. Grade C.

ADA/EASD adult T1D consensus (Holt and colleagues 2021, Diabetologia)

The definitive adult T1D consensus as of 2026. Acknowledges that GLP-1RA may be considered in adults with T1D and obesity; cites observed effects around 0.2 to 0.4 per cent HbA1c reduction, approximately 5 kg weight loss, and reductions in insulin doses. Adults only. The specific cautious-reduction-at-initiation framework (10 to 20 per cent) is operationalised in the Saeed 2024 Clinical Diabetes companion paper rather than in Holt 2021 directly. PMID 34590174. Grade C.

ADA Standards of Care 2025, Section 9 (Pharmacologic Approaches)

Annual Standards of Care document, distinct from the 2021 adult T1D consensus. Aligned with the ADA/EASD 2021 framework; adults only; adjunct indication remains not approved by the FDA. PMID 39651989. Grade C.

What the totality of evidence suggests

In adults with T1D, particularly those with overweight or obesity or with clinical insulin resistance:

• GLP-1RA reduces TDD by roughly 10 to 25 per cent, improves TIR by up to 9 percentage points, and produces clinically meaningful weight loss (4 to 10 kg at 6 months, depending on agent and baseline BMI). Multiple Grade A RCTs; Park 2024 meta-analysis pools the signal.
• HbA1c change is modest, typically 0.2 to 0.6 per cent at the group level. ADJUNCT ONE and TWO did not cross the 0.4 per cent regulatory threshold, which (combined with safety signals) contributed to the FDA not approving liraglutide for T1D.
• CGM-based metrics tell a richer story. TIR and TAR shifts are larger than HbA1c changes suggest; post-meal excursion patterns improve; many individuals experience a clinically meaningful change that an HbA1c number can understate.
• Tirzepatide in T1D remains a Phase 3 gap. The observational evidence is encouraging but the comparison to GLP-1RA monotherapy is not head-to-head. SURPASS-T1D-1 (NCT06914895) and SURPASS-T1D-2 (NCT06962280) are in flight.
• Paediatric T1D is absent from the Phase 3 evidence base. ISPAD 2024 flags this as the most important paediatric adjunct-therapy gap. Part 4 treats it directly.
• Tolerance predictors are known. Low BMI, long T1D duration and absent C-peptide predict intolerance and discontinuation (ADJUNCT post-hoc, Shah 2024).