GLP-1 and GIP in Type 1 Diabetes, Evidence-Graded FAQ

Section 1, the basics

What are GLP-1 and GIP?

GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are incretin hormones released from the gut after meals. They stimulate insulin secretion where beta-cell function remains (not relevant in most T1D), suppress glucagon, slow gastric emptying, and reduce appetite. The medicines in this class include GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide, exenatide), dual GLP-1/GIP agonists (tirzepatide), and triple agonists (currently in trials).

Are these medicines licensed for type 1 diabetes?

No. None are licensed for T1D. All use is off-label. ISPAD 2024 stresses caution in paediatric and adolescent populations and calls explicitly for new RCTs before wider use in young people. The DTS Consensus 2025 is adults-only and flags the paediatric gap as urgent.

How do GLP-1 therapies work in the context of T1D physiology?

In T1D, insulin is delivered subcutaneously rather than directly into the portal circulation. Less insulin reaches the liver via the portal vein, which tends to produce higher glucagon levels and greater liver glucose release than in native insulin secretion. GLP-1 therapies help by suppressing postprandial glucagon at the alpha cell, slowing gastric emptying, reducing appetite, and lowering total insulin requirements. The result in trials is smoother postprandial glucose, lower insulin doses, and meaningful weight loss. Individual responses vary considerably. See Part 1 of the guide for the portal-vein-versus-peripheral-insulin physiology in more detail.

Section 2, the clinical trial evidence

The adult T1D evidence base is anchored on Professor Viral Shah’s clinical trial portfolio plus the foundational ADJUNCT trials. The brief version sits below; the full walk-through is in Part 2 of the guide.

The headline trials

• ADJUNCT ONE, Mathieu 2016. Liraglutide + insulin in 1,398 adults, 52 weeks. HbA1c ETDs versus placebo: -0.20 per cent at 1.8 mg; -0.15 per cent at 1.2 mg; -0.09 per cent (not significant) at 0.6 mg. Weight -4.9, -3.6 and -2.2 kg. Dose-related symptomatic hypoglycaemia and hyperglycaemia-with-ketosis at 1.8 mg. 22 per cent discontinuation. Grade A.
• ADJUNCT TWO, Ahrén 2016. Liraglutide + capped insulin in 835 adults, 26 weeks. Within-arm HbA1c change: -0.33/-0.22/-0.23 per cent versus +0.01 per cent placebo. Weight -5.1/-4.0/-2.5 kg versus -0.2 kg placebo. Hypoglycaemia and ketosis signals at the higher doses. Grade A.
• Pasqua 2025, Nature Medicine. Weekly semaglutide + AID versus placebo + AID in 24 adults, crossover. TIR +4.8 pp; HbA1c -0.5 per cent; weight -5.3 kg (5.1 per cent); TDD -22 per cent. No severe hypo, no DKA. 2 of 24 completers (8 per cent) had euglycaemic hyperketonaemia without acidosis. Grade A.
• ADJUST-T1D, Shah 2025, NEJM Evidence. Weekly semaglutide + AID in 72 adults with T1D and obesity, 26 weeks. Composite outcome (TIR above 70 per cent AND TBR under 4 per cent AND at least 5 per cent weight loss): 36 per cent versus 0 per cent placebo. HbA1c -0.3 pp; TIR +8.8 pp; weight -8.8 kg; TDD -22.3 units per day. No DKA. Grade A.
• Tirzepatide observational, Akturk and Shah 2025. 26 adults, 8 months. HbA1c -0.59 per cent at 8 months; weight -10.5 per cent at 6 months; TIR +12.6 pp at 3 months; TDD -18.9 units per day. One peroneal nerve palsy with rapid weight loss. No DKA. Grade C (single-centre observational, no control arm).
• ADJUNCT post-hoc, Shah 2024. Pre-specified completer-vs-non-completer analysis. Non-completers: lower BMI, longer T1D duration, higher proportion with undetectable C-peptide. Hypo and DKA not driving discontinuation; GI and metabolism adverse events are. Grade B.
• Park 2024 meta-analysis, JCEM. 24 RCTs, N=3,377. Pooled ETDs: liraglutide 1.8 mg HbA1c -0.28 per cent, weight -4.89 kg, TDD -7.51 U/day. Consistent dose-response across the class.
• Klein and Shah 2025 genetic-obesity substudy. 26 adults with severe early-onset obesity; mutation-positive patients met goal 36.4 per cent versus 80.0 per cent of controls. Continuous outcomes non-significant. Exploratory only. Grade C.

Section 3, insulin reduction: individualised, not 30 per cent for everyone

How much does insulin typically need reducing when starting a GLP-1?

Insulin reduction must be individualised. The following are starting bands used in specialist practice. They are conversation starters for your diabetes care team, not prescriptions. The four-row mapping is a GNL operational framework that adds stratification based on John Pemberton’s clinical synthesis; the underlying published consensus (Holt 2021 ADA/EASD; Saeed 2024 Clinical Diabetes companion; DTS Consensus 2025) recommends 10 to 20 per cent cautious reduction at initiation without stratification.

• HbA1c above 9.0 per cent (above 75 mmol/mol) or TIR below 40 per cent: reduction of approximately 10 per cent.
• HbA1c 7.5 to 9.0 per cent (58 to 75 mmol/mol) or TIR 40 to 60 per cent: reduction of approximately 20 per cent.
• HbA1c below 7.5 per cent (below 58 mmol/mol) or TIR above 60 per cent: reduction of up to approximately 30 per cent.
• Time below range above 4 per cent (high hypoglycaemia risk): approximately 30 per cent with close CGM monitoring.

The algorithm: smallest reduction compatible with baseline risk, CGM review every 1 to 2 weeks, iterate with your care team.

How should the reduction be applied across different regimens?

Short version below; full three-track onboarding model (MDI, standard pump, AID) lives in Part 3 of the guide.

• MDI or standard pump (approximately 50:50 basal:bolus): reduce basal, carb ratios and correction factors proportionally.
• Basal-heavy regimen (approximately 75 per cent basal): basal -20 per cent; bolus, carb ratios and corrections relaxed by approximately 40 per cent.
• Bolus-heavy regimen (approximately 70 to 75 per cent bolus): bolus -20 per cent; basal -40 per cent.
• Tandem t:slim X2: program multiple personal profiles (-10 per cent, -20 per cent, -30 per cent, -40 per cent) and step through them as effect establishes.
• Omnipod 5, CamAPS FX: relax carb ratios, start with higher glucose targets.
• Medtronic 780G: extend Active Insulin Time and start with a higher target.
• iLet Bionic Pancreas: raise glucose target initially, or enter 20 to 40 per cent fewer carbs as a workaround.
• Fallback for any system: reduce carb entries by 20 to 40 per cent.

Settings changes must be agreed with your diabetes care team before they go live. See the AID Systems Guide for system-specific detail beyond the GLP-1 context.

Section 4, the four safety pillars

1. Ketosis and DKA

Euglycaemic hyperketonaemia is the signal to watch, not classic hyperglycaemic DKA. Pasqua 2025 showed this pattern in 2 of 24 completers (approximately 8 per cent). Modern AID-era trials (ADJUST-T1D, tirzepatide cohort) had no DKA. ADJUNCT ONE and TWO did show hyperglycaemia-with-ketosis at 1.8 mg liraglutide in the pre-AID era. Mitigation: never stop basal insulin; maintain home ketone monitoring; check ketones during illness, unexplained hyperglycaemia, nausea, or reduced food intake; avoid rapid over-reduction. DTS Consensus Recommendation 9 is explicit that ketone monitoring remains standard of care.

2. Hypoglycaemia

Driven by aggressive insulin reduction running behind the physiology, not by GLP-1RA itself. Use CGM with alerts enabled throughout titration. On AID systems, start with higher glucose targets and lower them gradually as tolerance confirms.

3. Lean mass and bone

Appetite suppression and reduced food intake can drive loss of muscle mass and may have long-term effects on bone. T1D carries a baseline fracture risk 2 to 5 times the general population. Adolescents are a particular concern because the skeleton is still developing; long-term data are lacking. Protect with protein around 1.5 g per kg body weight per day split across 3 to 4 meals, resistance training 2 to 4 times per week, and vitamin D, iron and B12 monitoring. The strongest interventional protection signal comes from the Jensen 2024 JAMA Network Open RCT (exercise + GLP-1RA preserves BMD better than GLP-1RA alone; obesity population, directional support for T1D).

4. Rare neuromuscular events

Peroneal palsy was reported with rapid weight loss in the tirzepatide observational cohort. The takeaway: avoid the temptation to push doses rapidly.

Section 5, lifestyle, nutrition and exercise

Why is resistance training relevant?

Resistance training helps preserve lean mass during GLP-1-induced weight loss. Two to four sessions per week, combining compound movements and bodyweight work. The Exercise and T1D Practical Guide covers the full detail.

How should diet adapt during titration?

Smaller, more frequent meals tend to reduce nausea in the early titration period. Heavy, fatty meals are generally better avoided initially. Spreading protein intake evenly across the day supports lean mass.

How much protein is generally recommended?

Approximately 1.5 g per kg of body weight per day, split across 3 to 4 meals. Lean meats, fish, eggs, beans, lentils, dairy and soy are commonly prioritised sources. See Overcoming Insulin Resistance in T1D for the role of protein and resistance training together.

How are nutritional deficiencies avoided when appetite is reduced?

Prioritise nutrient-dense foods (lean protein, colourful vegetables, whole grains, nuts, seeds); use lower-fibre vegetables if fullness is an issue; consider a multivitamin and mineral supplement; check laboratory markers (renal function, liver function, vitamin D, iron, B12) regularly with your care team.

Section 6, common questions

Is there benefit for people who are not overweight?

Possible benefits include glucagon suppression, smoother postprandial glucose, and reduced insulin requirements, even without a weight-loss goal. However, GI side effects become proportionally more important without weight-loss benefit, and lean-mass protection becomes a more prominent priority. Use the minimum effective dose and discuss the context carefully with your care team.

Will a GLP-1 replace insulin in T1D?

No. Insulin remains essential. GLP-1 therapies reduce the amount of insulin needed; they do not remove the requirement for it. Basal insulin must not be stopped. Social-media claims that GLP-1RA can replace insulin in T1D contradict every consensus on record and are not supported by any RCT.

How does this relate to insulin resistance in T1D?

GLP-1 therapies can reduce insulin resistance through their effects on weight, glucagon and satiety. See Overcoming Insulin Resistance in T1D, Eight Causes of Insulin Resistance, and Seven Ways to Improve Insulin Sensitivity.

What are the common side effects?

Gastrointestinal symptoms (nausea, vomiting, diarrhoea) dominate, particularly in early titration. Appetite suppression can lead to undernutrition if diet is not well managed. Loss of lean mass can occur if resistance training and protein intake are not maintained. Rare: peroneal palsy with very rapid weight loss.

How is nausea typically managed?

Starting at the lowest dose and titrating slowly (monthly) is the most consistent approach across guidelines. Small, frequent meals; avoiding heavy, fatty food at initiation; moderate fibre intake early on.

Section 7, paediatric T1D

No Phase 3 RCTs exist for GLP-1RA, tirzepatide or SGLT2i in paediatric T1D. ISPAD 2024 is explicit: paediatric GLP-1RA approvals are for obesity or T2D only (liraglutide, exenatide, dulaglutide from age 10 and above). None are approved for paediatric T1D. Any paediatric off-label use should be led by a specialist paediatric diabetes team, with explicit discussion of the evidence gap, ketone education, CGM alerts, and growth and puberty monitoring. Part 4 of the guide treats this gap directly.

The four-part Adjunctive Therapies guide

• Part 1, overview. Why insulin alone leaves a gap; portal-vein vs peripheral insulin physiology.
• Part 2, evidence. Full trial walk-through; Park 2024 meta-analysis; international consensus.
• Part 3, starting safely. The MDI, standard pump and AID onboarding model; reduction bands; first 12 weeks.
• Part 4, open questions. Paediatric gap; tirzepatide RCTs; bone and lean mass; trials list.

Related GNL resources

• Episode 17, GLP-1 in T1D with Professor Viral Shah
• Downloadable PDF FAQ (10 September 2025)
• Overcoming Insulin Resistance in T1D
• Eight Causes of Insulin Resistance in T1D
• Episode 14, T1D and Insulin Resistance
• Seven Ways to Improve Insulin Sensitivity
• Exercise and T1D Practical Guide
• Automated Insulin Delivery Systems Guide
• Continuous Glucose Monitoring Guide