GLP-1 Drugs and Type 1 Diabetes Insulin Needs
Autoimmune Diabetes and GLP-1
35% insulin dose reduction
In a phase 2 trial, tirzepatide reduced total daily insulin requirements by 35.1% versus placebo in adults with type 1 diabetes and obesity.
Snaith et al., Diabetes Care, 2026
Snaith et al., Diabetes Care, 2026
View as imagePeople with type 1 diabetes produce little or no insulin. They depend on exogenous insulin for survival, and the total daily dose is the single most important variable in their management. A growing body of clinical trial data now shows that GLP-1 receptor agonists, originally developed for type 2 diabetes, can reduce insulin requirements in type 1 diabetes by measurable amounts. The largest meta-analysis to date, pooling 24 studies and 3,377 patients, found that liraglutide reduced total daily insulin by 4.32 IU per milligram of drug administered.[1] For broader context on how GLP-1 drugs interact with autoimmune diabetes biology, see our pillar article on autoimmune diabetes and GLP-1.
No GLP-1 receptor agonist is approved for type 1 diabetes by any regulatory agency. Every use in this population is off-label, and the evidence base, while growing rapidly, contains important safety signals that complicate the picture.
Key Takeaways
- A meta-analysis of 24 studies (3,377 patients) found liraglutide reduced total daily insulin dose by 4.32 IU per mg of drug, primarily through bolus insulin reductions (Park et al., 2023)
- The ADJUNCT ONE trial (1,398 adults, 52 weeks) showed liraglutide 1.8 mg reduced insulin requirements by 8% but doubled the rate of hyperglycemia with ketosis (Mathieu et al., 2016)
- Semaglutide 1 mg weekly increased time in glucose target range by 8.8 percentage points and reduced weight by 8.8 kg in 72 adults with T1D and obesity (Shah et al., 2025)
- Tirzepatide reduced total daily insulin dose by 35.1% versus placebo in a 12-week phase 2 trial of adults with T1D and BMI above 30 (Snaith et al., 2026)
- In newly diagnosed T1D, liraglutide halved insulin requirements (0.23 vs 0.43 U/kg/day) and enabled 13 of 34 patients to temporarily stop insulin entirely (Dejgaard et al., 2024)
- No GLP-1 drug is approved for type 1 diabetes; safety concerns include euglycemic ketosis and increased hypoglycemia
What the ADJUNCT Trials Established
The two largest randomized controlled trials of GLP-1 drugs in type 1 diabetes remain the ADJUNCT ONE and ADJUNCT TWO trials, both published in 2016 in Diabetes Care. Together they enrolled 2,233 adults with established type 1 diabetes.
ADJUNCT ONE randomized 1,398 adults 3:1 to liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to treat-to-target insulin over 52 weeks.[2] The results showed a dose-dependent pattern: liraglutide 1.8 mg reduced HbA1c by an additional 0.20 percentage points versus placebo, reduced total daily insulin dose (treatment ratio 0.92, meaning an 8% reduction), and reduced body weight by 4.9 kg. The 1.2 mg dose produced a 5% insulin reduction with 3.6 kg weight loss. The 0.6 mg dose did not significantly reduce insulin requirements.
ADJUNCT TWO used a different design: 835 subjects received liraglutide added to a capped (fixed) insulin dose for 26 weeks.[3] Without the ability to uptitrate insulin, the glycemic effects were clearer. Liraglutide 1.8 mg reduced HbA1c by 0.33 percentage points from a baseline of 8.1%, reduced body weight by 5.1 kg, and produced significant reductions in daily insulin dose.
Both trials revealed the same safety trade-off. Symptomatic hypoglycemia increased across liraglutide groups. In ADJUNCT ONE, the rate ratio for liraglutide 1.8 mg versus placebo was 1.31 (95% CI 1.07-1.59). The more concerning signal was hyperglycemia with ketosis: at the 1.8 mg dose, the event rate ratio was 2.22 (95% CI 1.13-4.34), a statistically significant doubling of risk.[2]
These safety findings effectively ended Novo Nordisk's pursuit of a type 1 diabetes indication for liraglutide. The drug company itself concluded that the benefit-risk balance limited clinical use in this population.
Pooled Evidence: What Meta-Analyses Show
Two meta-analyses have synthesized the broader evidence on GLP-1 analogues in type 1 diabetes.
Patoulias et al. (2020) pooled five randomized controlled trials with 2,445 participants, all using liraglutide.[4] The results showed a modest HbA1c reduction of 0.24% with liraglutide 1.8 mg (95% CI -0.32 to -0.16), weight loss of 4.87 kg (95% CI -5.31 to -4.43), and decreased total daily insulin dose driven primarily by reductions in bolus insulin. Severe hypoglycemia was not significantly increased (OR 0.80, 95% CI 0.57-1.14), but gastrointestinal adverse events rose sharply: nausea had an odds ratio of 4.70 (95% CI 3.68-6.00). No association with diabetic ketoacidosis or malignancies was identified.
Park et al. (2023) conducted the most comprehensive analysis to date, incorporating 24 studies and 3,377 patients across four different GLP-1 analogues.[1] This meta-analysis quantified effects on a per-milligram basis: each milligram of liraglutide reduced HbA1c by 0.09%, body weight by 2.2 kg, and total daily insulin by 4.32 IU. Liraglutide dose was the strongest predictor of weight loss and insulin reduction. The odds of nausea were 6.5 (95% CI 5.0-8.4) and ketosis 1.8 (95% CI 1.1-2.8). Neither severe nor symptomatic hypoglycemia was significantly elevated across all analyses. Patients with residual C-peptide positivity showed greater HbA1c improvement (-0.51% vs -0.28%) but similar weight loss and insulin dose effects.
The C-peptide finding carries clinical implications. People with type 1 diabetes who retain some beta-cell function may derive greater glycemic benefit from GLP-1 drugs, which aligns with the C-peptide biomarker role in diabetes classification.
Semaglutide: The Newer Data
Two randomized trials published in 2025 tested semaglutide specifically in type 1 diabetes, producing larger effect sizes than the earlier liraglutide data.
The ADJUST-T1D trial (Shah et al., 2025), published in NEJM Evidence, randomized 72 adults with type 1 diabetes, obesity (BMI 30 or higher), and automated insulin delivery (AID) systems to semaglutide up to 1 mg weekly or placebo for 26 weeks.[5] The primary composite endpoint, achieving all three targets of time in range above 70%, time below range under 4%, and at least 5% body weight reduction, was met by 36% of semaglutide participants versus 0% on placebo (difference 36 percentage points, 95% CI 20.6-52.2, P less than 0.001). HbA1c improved by an additional 0.3 percentage points. Time in target glucose range increased by 8.8 percentage points. Body weight decreased by 8.8 kg more than placebo. Two severe hypoglycemia events occurred in each group, and no diabetic ketoacidosis was reported.
Pasqua et al. (2025), published in Nature Medicine, conducted a smaller crossover trial of 28 adults with type 1 diabetes using AID systems.[6] After titrating semaglutide up to 1 mg over 11 weeks, participants used AID for 4 weeks. Semaglutide increased time in the 3.9-10.0 mmol/L target range by 4.8 percentage points (P = 0.006) without increasing time below 3.9 mmol/L (P = 0.19). No DKA or severe hypoglycemia occurred, but two episodes of recurrent euglycemic ketosis without acidosis were observed during semaglutide use.
Both semaglutide trials restricted enrollment to people using AID systems, which limits generalizability to those on multiple daily injections. The sample sizes, while adequate for proof-of-concept, remain small. For a broader look at how these drugs compare, see short-acting vs long-acting GLP-1 agonists.
Tirzepatide: The Largest Insulin Reductions Yet
The most dramatic insulin dose reductions have come from tirzepatide, a dual GLP-1/GIP receptor agonist. Snaith et al. (2026) published a phase 2, double-blind, placebo-controlled trial in Diabetes Care that enrolled adults with type 1 diabetes and BMI above 30.[7]
Over 12 weeks, tirzepatide (2.5 mg for 4 weeks, then 5.0 mg for 8 weeks) produced a mean weight change of -10.3 kg versus -0.7 kg with placebo (treatment difference -8.7 kg, 95% CI -12.0 to -5.5, P less than 0.0001). This represented 8.8% total body weight loss. HbA1c improved by 0.4 percentage points versus placebo (P = 0.05). Total daily insulin dose fell by 24.2 units/day with tirzepatide versus 0.3 units/day with placebo, a relative reduction of 35.1% (95% CI -46.5 to -21.3%, P = 0.0002).
The 35% insulin reduction is substantially larger than any figure from the liraglutide trials, where reductions ranged from 5-8%. Whether this reflects tirzepatide's dual agonism (activating both GLP-1 and GIP receptors), the population studied (all obese), or the short duration (12 weeks, before potential adaptation), the signal is robust enough to justify the larger trials now being planned.
No significant adverse events were reported, though the 12-week duration is too short to capture rare events like DKA. Any comparison between tirzepatide and semaglutide in this population must account for differences in study design, duration, and baseline characteristics.
Newly Diagnosed Type 1 Diabetes: A Different Question
The NewLira trial (Dejgaard et al., 2024) asked a fundamentally different question: can liraglutide preserve residual beta-cell function in newly diagnosed type 1 diabetes?[8]
Sixty-eight adults with newly diagnosed type 1 diabetes and measurable C-peptide (above 0.2 nmol/L) were randomized 1:1 to liraglutide 1.8 mg or placebo for 52 weeks, followed by a 6-week washout. The results diverged sharply from the ADJUNCT trials in established disease.
After 52 weeks, C-peptide response (4-hour AUC following a mixed-meal test) was maintained with liraglutide but declined with placebo (P = 0.002). Average total daily insulin dose decreased from 0.30 to 0.23 U/kg/day with liraglutide but increased from 0.29 to 0.43 U/kg/day with placebo (P less than 0.001). Thirteen of 34 liraglutide-treated patients achieved periods without any insulin, lasting an average of 22 weeks (range 3-52 weeks), versus just 2 of 34 on placebo (average 6 weeks). Hypoglycemia was lower with liraglutide than with placebo.
The catch: six weeks after stopping liraglutide, C-peptide levels were similar between groups. The beta-cell preservation effect did not persist once the drug was withdrawn. This suggests liraglutide augmented existing beta-cell function rather than modifying the underlying autoimmune destruction. For the related question of off-label use patterns, the evidence base continues to evolve.
The Safety Trade-Offs
Three safety concerns emerge consistently across the type 1 diabetes GLP-1 literature.
Euglycemic ketosis. GLP-1 drugs suppress glucagon secretion, which in type 1 diabetes may blunt the counterregulatory response to insulin dose reduction. If patients reduce insulin too aggressively, ketone production can rise even with normal or low blood glucose, a condition called euglycemic diabetic ketoacidosis (euDKA). In ADJUNCT ONE, liraglutide 1.8 mg doubled the rate of hyperglycemia with ketosis.[2] The semaglutide AID trial reported two euglycemic ketosis episodes.[6] This risk is the primary reason no GLP-1 has received regulatory approval for type 1 diabetes.
Hypoglycemia. Adding a glucose-lowering drug to insulin therapy predictably increases hypoglycemia risk. The ADJUNCT trials showed 17-31% increases in symptomatic hypoglycemia rates with liraglutide.[2] The semaglutide trials, which used AID systems that automatically adjust insulin delivery, did not show significant hypoglycemia increases, suggesting that technology-mediated insulin adjustment may mitigate this risk.
Gastrointestinal effects. Nausea is the most common adverse event, with odds ratios of 4.7-6.5 across meta-analyses.[1][4] In a population already managing complex daily regimens, drug-induced nausea and vomiting contribute to treatment discontinuation and may paradoxically worsen glycemic control.
Why This Matters for Insulin Management
The rising prevalence of obesity in type 1 diabetes has changed the clinical calculus. An estimated 50% of people with type 1 diabetes in the United States are now overweight or obese. Excess weight increases insulin resistance, raises total daily insulin doses, and compounds cardiovascular risk that is already elevated by type 1 diabetes itself.
GLP-1 receptor agonists address this intersection directly. The weight loss (consistently 3-10 kg across trials) improves insulin sensitivity and reduces the total insulin burden. Lower insulin doses may reduce weight gain from insulin itself, creating a potentially positive feedback loop. The cardiovascular benefits demonstrated in type 2 diabetes trials add another dimension to the risk-benefit analysis, though no cardiovascular outcome trial has been completed in type 1 diabetes.
The evidence has a clear gradient. Semaglutide and tirzepatide produce larger insulin dose reductions and better glycemic improvements than liraglutide. Whether this reflects pharmacological superiority, better patient selection (obese populations, AID users), or more modern trial design remains unclear.
The Bottom Line
GLP-1 receptor agonists reduce insulin requirements in type 1 diabetes by 5-35%, depending on the drug, dose, and population studied. The strongest evidence comes from semaglutide and tirzepatide in adults with type 1 diabetes and obesity using automated insulin delivery systems. Safety concerns, particularly euglycemic ketosis and increased hypoglycemia, have prevented regulatory approval. The data are most compelling for the subset of type 1 diabetes patients with concurrent obesity and insulin resistance, where the weight loss and insulin-sensitizing effects of GLP-1 drugs directly address clinical needs unmet by insulin alone.