The paediatric gap

ISPAD 2024 is unambiguous: 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). None are approved for paediatric T1D. The chapter language “could be considered adjunctive therapy in specific populations of children and adolescents with T1D and obesity” sits inside a gap-first overarching recommendation that “there is limited evidence for the use of adjunctive medication in children and adolescents with T1D; larger trials are needed”. The DTS Consensus 2025 also flags this as a major research gap.

Known concerns in this age group:

• Gastrointestinal side effects in up to 30 per cent of paediatric patients using GLP-1RA for obesity or T2D indications.
• Unknown effect on peak bone mass accrual. Adolescence is the window during which most bone is laid down; any sustained effect on bone turnover has potentially lifelong consequences.
• Unknown effect on growth and puberty.
• Adherence patterns differ from adult populations.

There is no short-form paediatric answer that is safer than “speak to your paediatric diabetes team”. Any paediatric off-label use should be led by a specialist paediatric diabetes team, with explicit discussion of the evidence gap, ketone education, CGM with alerts, and growth and puberty monitoring. Evidence grade for paediatric T1D adjunct therapy is D by absence of Phase 3 data.

Tirzepatide in T1D, the Phase 3 gap

Tirzepatide (dual GLP-1/GIP agonist) in T1D is currently anchored on a single-centre retrospective observational cohort of 26 adults (Akturk and Shah 2025; see Part 2) and the Klein and Shah 2025 genetic-obesity substudy. Neither is an RCT. The signal is encouraging: larger weight loss than monotherapy GLP-1RA, meaningful TIR gains, no DKA, one peroneal nerve palsy linked to rapid weight loss. But the evidence grade is C.

Two Phase 3 trials are in flight:

• SURPASS-T1D-1 (ClinicalTrials.gov NCT06914895). Tirzepatide in adults with T1D, weekly, multi-centre, placebo-controlled.
• SURPASS-T1D-2 (NCT06962280). Tirzepatide in adults with T1D, parallel design.

Until these read out, head-to-head claims that tirzepatide is incrementally better than semaglutide in T1D rest on within-subject observational data. The 2025 DTS Consensus is explicit on this point.

Long-term bone and lean mass

Mechanistically, Sherk, Schauer and Shah 2020 showed that GLP-1, GIP and GLP-2 each acutely suppress bone resorption (as measured by CTX) in healthy adults and in people with T1D. This is mechanistic evidence, not fracture-outcome evidence. In T2D meta-analyses, GLP-1RA and DPP-4i are not associated with increased fracture risk. T1D itself carries a fracture risk that is 2 to 5 times the general population. Long-term fracture end-points with GLP-1RA or tirzepatide in T1D have not been measured.

The strongest interventional protection signal comes from the Jensen 2024 JAMA Network Open RCT, which showed that exercise added to GLP-1RA-induced weight loss preserves BMD better than GLP-1RA alone. The population was obesity (not T1D), so the signal is directional support rather than direct evidence. The practical protection framework (1.5 g per kg per day protein, resistance training 2 to 4 times per week, vitamin D, iron and B12 monitoring) is drawn from general sports-nutrition guidance applied to this context and remains Grade D for T1D-specific outcomes until proper T1D trials run.

Key open questions:

• Fracture end-points in adult T1D over 2 to 5 years on GLP-1RA or tirzepatide.
• Bone-density trajectories in adolescents during the peak-bone-mass window.
• Body-composition preservation across semaglutide, tirzepatide and liraglutide, head-to-head, with structured resistance training protocols.

AID algorithm adaptation

Current AID algorithms were designed for a non-adjunct context. When TDD falls by 20 per cent or more over 12 weeks because of GLP-1RA, the algorithm’s insulin-history buffer, its learning behaviour, and its ceiling of maximum basal suppression are all being asked to absorb a shift they were not explicitly designed for. In practice, manual settings adjustment (Part 3, Track 3) sits alongside the algorithm response. The DTS Consensus 2025 (Recommendations 12 and 13) calls directly for algorithm-level work.

Open questions:

• Automated detection of GLP-1RA-driven TDD shifts, so the algorithm can re-tune without manual profile-switching.
• Per-system comparison of adaptation timing across Tandem Control-IQ, Omnipod 5, CamAPS FX, Medtronic 780G and iLet in GLP-1RA users.
• Faster insulin analogue compatibility: DTS Consensus Recommendation 16 flags the kinetic alignment between ultra-rapid insulin and delayed gastric emptying in GLP-1RA users as a design opportunity.

Equity of access

ADJUST-T1D was 88 per cent non-Hispanic White and 88 per cent privately insured. The real-world uptake of GLP-1RA in T1D, off-label, is shaped heavily by supply, price, insurance and geography. Registry-based monitoring of uptake, outcomes and discontinuation across race, ethnicity and insurance status is an urgent adjacent question. The DTS Consensus raises this; most national diabetes societies have not yet addressed it in formal policy.

Other open questions

• Weekly GLP-1RA plus AID Phase 3 programme. ADJUST-T1D was N=72. A multi-site Phase 3 programme is needed before regulatory approval is realistic. Industry has not yet committed.
• C-peptide stratification. The ADJUNCT post-hoc signal (absent C-peptide predicts intolerance) is clinically actionable if replicated in a prospective trial.
• Genetic obesity response. Klein and Shah 2025 exploratory signal needs validation in a larger multicentre cohort. Monogenic obesity testing could change expectations for a meaningful minority of high-BMI T1D patients.
• Combination with SGLT2i. Liraglutide plus dapagliflozin showed additive glycaemic benefit but two DKA events in a small trial. The next frontier if DKA risk can be managed.
• Behavioural-health effects. Mood, anxiety, disordered-eating patterns, and relationship to weight stigma are live questions; not covered directly by the current RCT evidence base.

Live trials list

Public ClinicalTrials.gov registrations as of April 2026. This list is not exhaustive; it is the small set most relevant to a person with T1D tracking the field.

• SURPASS-T1D-1, tirzepatide in adults with T1D, Phase 3 placebo-controlled. NCT06914895.
• SURPASS-T1D-2, tirzepatide in adults with T1D, parallel Phase 3 design. NCT06962280.
• ADJUST-T1D extension, extension of the 26-week parent trial (Shah 2025). Check ClinicalTrials.gov for current status.
• Paediatric GLP-1RA in T1D, no registered Phase 3 programmes as of April 2026. This is the most visible absence in the evidence base.

A live trial-tracking page is in planning at GNL. In the meantime, ClinicalTrials.gov search terms “type 1 diabetes” + “GLP-1” or “tirzepatide” will surface current entries.