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GLP-1s and Type 1 Diabetes: The Off-Label Evidence

No GLP-1 is approved for type 1 diabetes, and people with type 1 and obesity take them anyway. In ADJUNCT ONE the 1.8 mg dose produced the largest weight loss and the only significant rise in ketosis — an event rate ratio of 2.22.

Owen Castellanos10 min read
The dose that worked best carried the signalADJUNCT ONE: liraglutide added to insulin, 1,398 adults, 52 weeksLiraglutide 0.6 mg — weight −2.2 kgHyperglycemia with ketosis: no significant increaseLiraglutide 1.2 mg — weight −3.6 kgHyperglycemia with ketosis: no significant increaseLiraglutide 1.8 mg — weight −4.9 kgKetosis event rate ratio 2.22 (95% CI 1.13 to 4.34)Weight loss and HbA1c improved as the dose climbed.So did the ketosis rate, and only at the top rung.No GLP-1 receptor agonist is approved for type 1 diabetes.

People with type 1 diabetes develop obesity too, and the drug class that treats obesity was developed, tested and approved in people whose pancreas still makes insulin. That mismatch is the whole subject. The approvals in this class cover type 2 diabetes, obesity, cardiovascular risk and liver disease — the first split is described in the two-approvals article — and none of them covers type 1.

What the labels say, and what they do not say

The labels are not uniformly silent, and the difference matters. The Wegovy label states that use of the drug in patients with type 1 diabetes or in combination with insulin has not been evaluated.[1] The Ozempic, Mounjaro and Zepbound labels do not mention type 1 diabetes at all.[2][3] One is a declared gap and the others are an absence. Neither is an authorization, and none of the four carries a type 1 indication.

A 2026 consensus report from a group of diabetes technology and endocrinology bodies states the position directly: regulatory approval of weekly GLP-1 and dual GLP-1/GIP receptor agonists in type 1 diabetes has not been achieved. It names hypoglycemia and hyperglycemia-related ketosis as the potential safety risks, and makes a point that belongs on a telehealth page: because the obesity indication already provides access, people with type 1 diabetes obtain these drugs without the type 1 specific safety education that would accompany a licensed use.[4] That is a description of the actual purchasing route, not a hypothetical one.

The adjunct trials found a real effect and a real signal

ADJUNCT ONE randomized 1,398 adults with type 1 diabetes three to one to liraglutide 1.8, 1.2 or 0.6 mg daily or placebo, added to treat-to-target insulin, for 52 weeks. From a mean baseline HbA1c of 8.2%, the estimated treatment difference against placebo was −0.20% at 1.8 mg (95% CI, −0.32 to −0.07) and −0.15% at 1.2 mg (95% CI, −0.27 to −0.03). Body weight fell by 4.9 kg more than placebo at 1.8 mg (95% CI, −5.7 to −4.2). Insulin dose fell too, at an estimated treatment ratio of 0.92 (95% CI, 0.88 to 0.96).[5]

Then the column that gets left out. Symptomatic hypoglycemia rose in every liraglutide group, at rate ratios of 1.31, 1.27 and 1.17 descending with dose. Hyperglycemia with ketosis rose significantly at 1.8 mg only, at an event rate ratio of 2.22 (95% CI, 1.13 to 4.34).[5] The dose with the largest weight and glycemic benefit is the dose carrying the ketosis signal, and the trial’s own conclusion says those safety findings limit clinical use in this group.

ADJUNCT TWO ran 835 patients for 26 weeks on capped insulin and split the two harms across different rungs. Symptomatic hypoglycemia was higher than placebo at 1.2 mg (21.3 against 16.6 events per patient-year, P = 0.03), while hyperglycemia with ketosis above 1.5 mmol/L was higher at 1.8 mg (0.5 against 0.1 events per patient-year, P = 0.01).[6]No rung was clean, and the two risks did not sit on the same rung.

Why reduced insulin is the sharp end

In type 2 diabetes an insulin reduction is a convenience. In type 1 it is the mechanism by which ketoacidosis becomes possible, because there is no endogenous reserve to cover the gap. A post hoc analysis of a modern semaglutide trial measured how large that reduction gets and where it comes from: over 26 weeks the total daily dose fell 22.6% (95% CI, −28.3 to −17.0), driven more by bolus insulin (−30.5%) than basal (−15.6%), with the basal share of the total rising from 0.56 to 0.62 (P < 0.001).[7]

The same analysis separates cause from consequence over time. At week 4, 83% of the reduction was a direct drug effect and 17% attributable to weight loss. By week 26 it was 52% against 48%.[7] So the common reassurance that the insulin drop is simply a consequence of losing weight is false early in treatment and only half true later, which is the period when a dose is being escalated and the titration schedule is still moving.

The DKA reputation belongs mostly to a different drug class

A 2026 systematic review of 90 studies of adjunct therapy in type 1 diabetes separated the two classes people conflate. For GLP-1 receptor agonists it found HbA1c −0.56%, weight −3.6 kg and BMI −1.05 kg/m², with severe hypoglycemia and DKA rare. For SGLT2 inhibitors it found a DKA relative risk of 2.19 (95% CI, 1.16 to 4.17), and no equivalent elevation for the GLP-1 class.[8]

A dedicated 2026 safety meta-analysis of 25 studies reached compatible numbers and graded them honestly. Overall hypoglycemia carried a relative risk of 1.01 and DKA a relative risk of 0.60 — but that DKA figure was rated very low certainty, the weakest grade in the paper.[9]What that review rated as moderate certainty was the tolerability penalty: nausea RR 2.89, vomiting RR 3.10, and early treatment withdrawal RR 2.02. Tolerability improved significantly after six months, so the same drug reads as intolerable at three months and manageable at twelve.[9]

A third pooled analysis, of 13 studies in adults with type 1 diabetes and a BMI of 25 or above, shows the two tails of the glucose distribution moving in opposite directions at once: hypoglycemic episodes rose (OR 1.34; 95% CI, 1.02 to 1.76) while hyperglycemic episodes fell (OR 0.69; 95% CI, 0.56 to 0.87), alongside weight −4.31 kg, HbA1c −0.25% and insulin −9.24 units per day.[10] Whether this class looks safe in type 1 depends on which tail is counted.

A ketosis endpoint is not a DKA endpoint

The distinction has been observed directly. A double-blind crossover trial added weekly semaglutide to automated insulin delivery in 28 adults with type 1 diabetes. Time in range improved by 4.8 percentage points (P = 0.006) with no increase in time below range, and there were no cases of diabetic ketoacidosis and no severe hypoglycemia. There were two episodes of recurrent euglycemic ketosis without acidosis during semaglutide.[11]

Recorded against a DKA endpoint, that trial reports zero events. Recorded against a ketone measurement, it reports two. Both statements are true, and only the second tells a reader with type 1 diabetes why a ketone meter is part of the conversation — as is what happens during an intercurrent illness, covered for the general case in the acute illness article.

What the newest randomized evidence shows

ADJUST-T1D randomized 72 adults with type 1 diabetes, a BMI of 30 or above and an automated insulin delivery system to semaglutide up to 1 mg weekly or placebo for 26 weeks. A composite of time in range above 70%, time below range under 4% and at least 5% weight loss was met by 36% against 0%, a difference of 36 percentage points (95% CI, 20.6 to 52.2). Weight fell 8.8 kg (95% CI, −10.6 to −7.0), time in range rose 8.8 points, and severe hypoglycemia occurred twice in each group with no DKA reported.[12]

That is 72 people for six months. Against it sits the largest observational dataset in this literature: 174,678 patients with type 1 diabetes in a national record, analyzed as a sequence of emulated trials. Five-year risk of major adverse cardiovascular events was 4.3% against 5.0% (hazard ratio 0.85; 95% CI, 0.77 to 0.95) and end-stage kidney disease 1.6% against 1.9% (hazard ratio 0.81; 95% CI, 0.69 to 0.95), with no increase in DKA hospitalization or severe hypoglycemia.[13] The kidney result in type 2 diabetes is in the FLOW article, and this is an observational echo of it in a population no trial has enrolled.

One more reversal worth keeping. A survey of 230 adults with type 1 diabetes using these drugs off-label found symptomatic hypoglycemia reported by 29% on tirzepatide against 13.4% on semaglutide (P < 0.001), with no difference in gastrointestinal events.[14] The agent that produces more weight loss produced roughly double the hypoglycemia reporting, which is the opposite of how the two are usually ranked on a tirzepatide price board.

What this does not settle

Nothing above makes a prescription appropriate or inappropriate for a particular person with type 1 diabetes. It establishes that the effect on weight and insulin requirement is real and reproducible, that the ketosis risk is dose-dependent and concentrated at the top of the ladder, and that the DKA alarm attached to adjunct therapy in general is mostly someone else’s finding.

The purchasing reading is narrower still. Compounded semaglutide and tirzepatide are not FDA-approved and are not reviewed by the FDA for safety, efficacy or quality before they are dispensed, so a compounded vial used in type 1 diabetes is an off-label use of an unapproved preparation — two separate distances from the evidence above, set out in the compounding article. An intake that never asks which type of diabetes an applicant has cannot route the question to anyone, which is one of the patterns in the telehealth article.

Frequently asked

Is any GLP-1 approved for type 1 diabetes?
No. The approvals in this class cover type 2 diabetes, obesity, cardiovascular risk and liver disease. The Wegovy label states that use in patients with type 1 diabetes or in combination with insulin has not been evaluated, and a 2026 consensus report confirms that regulatory approval in type 1 diabetes has not been achieved. Any use in type 1 is off-label.
Do these drugs cause diabetic ketoacidosis in type 1 diabetes?
The signal is real but narrower than its reputation. In ADJUNCT ONE, hyperglycemia with ketosis rose significantly only at the 1.8 mg liraglutide dose, at an event rate ratio of 2.22. A 2026 review of 90 adjunct-therapy studies found an elevated DKA risk for SGLT2 inhibitors, at a relative risk of 2.19, and no equivalent elevation for GLP-1 receptor agonists.
How much does insulin dose fall on a GLP-1 in type 1 diabetes?
In a post hoc analysis of ADJUST-T1D, total daily insulin fell 22.6% over 26 weeks, with bolus insulin down 30.5% against 15.6% for basal. At week 4 about 83% of that reduction was a direct drug effect rather than a consequence of weight loss; by week 26 the split was roughly even.
What did the newest randomized trial in type 1 diabetes find?
ADJUST-T1D randomized 72 adults with type 1 diabetes and obesity using automated insulin delivery to semaglutide or placebo for 26 weeks. A composite endpoint of time in range, time below range and at least 5% weight loss was met by 36% on semaglutide and 0% on placebo, with weight down 8.8 kg and no DKA reported.
Is tirzepatide or semaglutide the safer off-label choice in type 1?
No randomized head-to-head exists in this population. A survey of 230 adults with type 1 diabetes using both off-label found symptomatic hypoglycemia reported by 29% on tirzepatide against 13.4% on semaglutide, with no difference in gastrointestinal events. That is self-reported data from one clinic, not a trial result.

Sources

  1. [1] Novo Nordisk Pharmaceutical Industries, LP (2026). WEGOVY (semaglutide) injection, solution; WEGOVY (semaglutide) tablet — prescribing information, section 5.4 DailyMed, U.S. National Library of Medicine. Source
  2. [2] Novo Nordisk Pharmaceutical Industries, LP (2026). OZEMPIC (semaglutide) injection, solution — prescribing information, section 1 DailyMed, U.S. National Library of Medicine. Source
  3. [3] Eli Lilly and Company (2026). ZEPBOUND (tirzepatide) injection and MOUNJARO (tirzepatide) injection — prescribing information, section 1 DailyMed, U.S. National Library of Medicine. Source
  4. [4] Garg SK, Akturk HK, Garg S, et al. (2026). Adjunctive Treatment with GLP-1 and Dual GLP-1/GIP Receptor Agonists for People with Type 1 Diabetes: Consensus Report and Practical Guidelines for Safe Use. Diabetes Technol Ther. PMID 42246488
  5. [5] Mathieu C, Zinman B, Hemmingsson JU, et al. (2016). Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care. PMID 27506222
  6. [6] Ahrén B, Hirsch IB, Pieber TR, et al. (2016). Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial. Diabetes Care. PMID 27493132
  7. [7] Karakus KE, Akturk HK, Kruger D, et al. (2026). Effect of Semaglutide on Insulin Dose Reduction in Adults With Type 1 Diabetes and Obesity Using Automated Insulin Delivery Systems: ADJUST-T1D Post Hoc Analysis. Diabetes Care. PMID 41429002
  8. [8] Abdel-Rahman SM, Al-Shiab R, Shah E, et al. (2026). Efficacy and safety of GLP-1 receptor agonists and SGLT2 inhibitors as adjuncts to insulin in type 1 diabetes: Systematic review and meta-analysis. Diabetes Obes Metab. PMID 41605813
  9. [9] Kateel R, Parida A, Chogtu B, et al. (2026). Safety of GLP-1 receptor agonists in type 1 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract. PMID 42105869
  10. [10] Purcell AR, Zhen XM, Wong J, et al. (2026). Glucagon-like peptide-1 receptor agonist treatment reduces body weight and improves glycaemic outcomes in patients with concurrent overweight/obesity and type 1 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. PMID 41334580
  11. [11] Pasqua MR, Tsoukas MA, Kobayati A, et al. (2025). Subcutaneous weekly semaglutide with automated insulin delivery in type 1 diabetes: a double-blind, randomized, crossover trial. Nat Med. PMID 39794615
  12. [12] Shah VN, Akturk HK, Kruger D, et al. (2025). Semaglutide in Adults with Type 1 Diabetes and Obesity. NEJM Evid. PMID 40550013
  13. [13] Xu Y, Malek ND, Chang AR, et al. (2026). Glucagon-like peptide-1 receptor agonists for major cardiovascular and kidney outcomes in type 1 diabetes. Nat Med. PMID 41857198
  14. [14] Akturk HK, Mason E, Cengiz D, et al. (2026). Patient-Reported Adverse Events with Adjunctive Tirzepatide or Semaglutide Treatment in Adults with Type 1 Diabetes. Diabetes Technol Ther. PMID 41804758

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