GLP-1RA and GLP-1/GIP in Type 1 Diabetes, the Evidence

1,398 adults with T1D, double-blind, treat-to-target, 52 weeks. Liraglutide 0.6, 1.2 or 1.8 mg daily versus placebo, on top of insulin that could be up-titrated. HbA1c estimated treatment differences versus placebo ran to -0.20 per cent at the 1.8 mg dose; weight changes -4.9, -3.6 and -2.2 kg at the three doses. Symptomatic hypoglycaemia rate ratios 1.17 to 1.31; hyperglycaemia-with-ketosis was 2.22 times more frequent at 1.8 mg than placebo. 22 per cent discontinued for adverse events. The HbA1c effect did not cross the 0.4 per cent regulatory threshold. PMID 27506222. Grade A.

835 adults with T1D, 26 weeks, insulin capped at the pre-randomisation dose to isolate the drug effect. Within-arm HbA1c change -0.33, -0.22 and -0.23 per cent at 1.8, 1.2 and 0.6 mg versus +0.01 per cent on placebo. Weight -5.1, -4.0 and -2.5 kg versus -0.2 kg placebo. Hyperglycaemia with ketosis above 1.5 mmol/L at 1.8 mg ran 0.5 versus 0.1 events per patient per year. 16.8 per cent discontinued. PMID 27493132. Grade A.

Note on presentation: ADJUNCT ONE reports between-group treatment differences; ADJUNCT TWO reports within-arm change from baseline. The numbers are not directly comparable. Park 2024 below pools both into per-mg-dose effects.

24 adults with T1D, double-blind randomised crossover. Weekly semaglutide up to 1 mg plus investigational AID versus placebo plus the same AID, around 15 weeks per arm. TIR (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; total daily insulin by approximately 11 units per day. 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.

72 adults with T1D, BMI at least 30, on 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. 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 -0.3 percentage points; TIR +8.8 pp; weight -8.8 kg; total daily insulin -22.3 units per day. Two severe hypoglycaemia episodes in each arm; no DKA; one high-ketone event attributed to an infusion-set failure. 5.5 per cent discontinued for persistent gastrointestinal events. The keystone adult RCT of semaglutide plus AID. PMID 40550013. Grade A.

26 adults with T1D, mean BMI 36.7, single-centre retrospective, weekly tirzepatide titrated 2.5 to 15 mg, 8 months. HbA1c fell by 0.59 per cent at 8 months; weight by 10.1 per cent; TIR rose by 12.6 pp at 3 months and held; 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 GLP-1RA RCTs. PMID 38317405. Grade C.

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 variants and others) reached the primary goal in 36.4 per cent versus 80.0 per cent of controls (P=0.04). The continuous outcomes 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.

Pre-specified completer-versus-non-completer analysis pooled across ADJUNCT ONE and TWO. Non-completers had lower BMI, longer T1D duration, and a higher proportion with undetectable C-peptide. Severe hypoglycaemia and DKA did not drive discontinuation; gastrointestinal and metabolism adverse events did. The clinical takeaway: the low-BMI, long-duration, C-peptide-negative adult is the one most likely to struggle with tolerance, a finding that shapes modern patient selection. PMID 39717993. Grade B.

19-member panel, 32 proposed recommendations, 31 passed. Adults only; the paediatric gap is flagged explicitly. Recommendation 11 anchors the start-low-go-slow titration; Recommendations 17 to 20 set the patient-selection criteria (overweight, obesity, insulin resistance, postprandial hyperglycaemia not controlled by optimised meal strategy, severe insulin resistance, high CVD or CKD risk). Recommendation 9 reminds us that gastrointestinal side effects can mimic DKA and that ketone monitoring stays standard of care. Recommendation 27 calls for AID systems to accommodate the TDD reduction GLP-1RA drives. PMID 39517127.

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 an overarching statement that “larger trials are needed”. Part 4 of this guide treats the paediatric question directly. PMID 39884261.

The ADA/EASD 2021 adult T1D consensus (Holt and colleagues, Diabetologia) is the definitive adult document as of 2026. It acknowledges GLP-1RA may be considered in adults with T1D and obesity, citing 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 cautious-reduction-at-initiation framework (10 to 20 per cent) is operationalised in the Saeed 2024 Clinical Diabetes companion paper. The ADA Standards of Care 2025 Section 9 aligns with the 2021 framework; adjunct indication remains not approved by the FDA. PMID 34590174 and PMID 39651989.