VIENNA — Tirzepatide was associated with improvements in body weight and body composition, and with lower insulin doses, in the first-ever randomized controlled trial (RCT) of the drug in people with type 1 diabetes (T1D).

“Tirzepatide may play a role in weight management in adults with T1D and obesity, even at low doses,” Jennifer R. Snaith, MD, of the Garvan Institute of Medical Research and St. Vincent’s Hospital Sydney, both in Darlinghurst, Australia, said at European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.

Overweight and obesity affect about two thirds of adults with T1D, and blunt the beneficial effects of strict glycemic control. There is increasing off-label use of GLP-1 agonists and the dual GLP-1-glucose-dependent insulinotropic polypeptide agonist tirzepatide in people with T1D, “creating an urgent need for formal trial evidence,” Snaith explained. “Tirzepatide has not been previously assessed in type 1 diabetes in a controlled setting,” she noted.

A retrospective study of 57 adults with T1D who received tirzepatide off-label was also presented at the meeting.

TIRTLE1: A Phase 2 RCT

The TIRTLE1 study — a phase 2, 12-week, randomized, double-blind, placebo-controlled clinical trial — enrolled adults with T1D duration longer than 2 years and BMI > 30. At baseline, the 24 study participants had an average age of 41 years, 42% were women, and they had mean diabetes duration of 23 years, BMI 33.7, A1c 7.3%, time in range 65%, and daily insulin dose of 69 units.

Participants were randomized 1:1 to tirzepatide or volume-matched placebo. Tirzepatide dose was titrated from 2.5 mg to 5.0 mg. Participants were provided with weekly phone support for insulin titration by glucose response. Eleven in each group completed the trial. By the conclusion of the trial, the tirzepatide group were all at the 5-mg dose except for one patient, who remained at 2.5 mg.

The trial met its primary outcome, change in body weight over 12 weeks, with a loss of 10.3 kg in the tirzepatide group vs just 0.7 kg in the placebo group. The between-group difference was -8.7 kg (P < .001), equating to 3.0 BMI points and 8.8% body weight reduction over 12 weeks. All in the tirzepatide group lost at least 5% of their body weight vs just 9% in the placebo group, and 45% lost 10% of their body weight compared with none in the placebo group.

The tirzepatide group also had significantly greater losses of fat mass, with an insignificant change in fat-free mass, Snaith reported.

A1c was reduced by 0.5 percentage points with tirzepatide vs 0.2 percentage points with placebo, a significant 0.4 point between-group difference (P = .05). Time in range and time below range didn’t differ, but the mean amplitude of glucose excursion was significantly reduced with tirzepatide (-12.8 vs -1.4; P = .03).

Insulin dose requirements were also significantly reduced with tirzepatide, 35% vs 0% with placebo (P = .0002), with both basal and bolus doses reduced. The reduction in insulin dose was seen at 2 weeks, became significant at 6 weeks, and was sustained at 12 weeks.

“The early reduction suggests that the effect occurred before weight loss,” Snaith noted, adding that this “raises a new hypothesis regarding the effect of tirzepatide on insulin sensitivity in T1D.” 

Energy intake was significantly reduced with tirzepatide (-491 vs +17 kcal; P = .05), and there were no differences in energy expenditure or self-reported physical activity.

No serious adverse events occurred in either group. A total of 14 nonserious adverse events were reported in nine patients in the tirzepatide group vs just one patient in the placebo group. The events in the tirzepatide group included transient nausea (n = 4), persistent nausea (n = 2), vomiting (n = 2), and reflux (n = 2). Adverse events leading to discontinuation occurred in one with tirzepatide and none with placebo. There were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA).

Asked whether the study medication helped address their diabetes treatment needs, 100% of the tirzepatide group said yes compared with 37% of the placebo group.

‘Fantastic’ Findings, but Larger Studies to Come

Asked to comment, session moderator Alice Y. Y. Cheng, MD, an endocrinologist and associate professor at the University of Toronto, Toronto, Ontario, Canada, told Medscape Medical News that she thought the findings were “fantastic.” 

“It’s lovely to see a prospective, randomized controlled, dedicated trial in T1D to look for adjunctive therapies beyond insulin,” she said.

Cheng called the amount of weight loss in the trial “impressive,” despite the small sample size, noting that “all of this is in keeping with what we’ve been seeing in the clinic with off-label use.” 

However, she added, “I think the concerns or fears that people will have and may have are around hypoglycemia and what to do with their insulin. If we drop the doses of insulin dramatically, could we end up dropping it too much and then run into issues of inadequate insulin replacement, which could then, in theory, result in DKA. We need to remind patients that they still need insulin, although the amount may be lower.”

Also asked to comment, independent industry consultant Charles Alexander, MD, noted that, while the data look good, it’s a small study and that Lilly’s two much larger ongoing phase 3 trials of tirzepatide in T1D, SURPASS-T1D-1 (NCT06914895), and SURPASS-T1D-2 (NCT06962280), aimed at obtaining FDA approval, will produce more definitive results.

Alexander also pointed out that Novo Nordisk is not conducting a similar RCT of semaglutide in T1D. “At the end of the day,” if it’s approved, “all you’re going to have [in terms of incretin drugs] is tirzepatide licensed for T1D.” 

Snaith’s team is also conducting a further study, TIRTLE2, with insulin resistance as the primary outcome.

Snaith and Alexander reported no disclosures. Cheng reported receiving fees for advisory board and/or consulting and/or speaking from Abbott, Amgen, Aspen, AstraZeneca, Bausch, Bayer, Biomea Fusion, Boehringer Ingelheim, Dexcom, Eisai, Eli Lilly, GlaxoSmithKline, HLS Therapeutics, Insulet, Medtronic, Novo Nordisk, Pfizer, Sandoz, Sanofi, and Vertex; and consulting fees on clinical trials from Applied Therapeutics, Novo Nordisk, and Sanofi.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.