TouchENDOCRINOLOGY coverage from EASD 2025:

At the EASD 2025 congress (Vienna, Austria; 15–19 September), Dr Jennifer Snaith presented results from TIRTLE1 (ACTRN12624000111572), the first randomized, controlled trial of tirzepatide in adults with type 1 diabetes (T1D) and obesity. The 12-week study demonstrated significant reductions in body weight, primarily from fat mass, alongside meaningful decreases in insulin dose and improvements in glycaemic control, with a reassuring safety profile. We spoke with Dr Snaith about the rationale, design and potential clinical implications of this important early study. 

Q. Tirzepatide has shown strong efficacy in type 2 diabetes and obesity, but type 1 diabetes is a very different condition. What motivated your team to investigate its potential in this patient group, and what clinical need were you aiming to address?

We designed the study after noticing that people with T1D were already using tirzepatide off label, despite there being no clinical trial evidence to support its use. That created an urgent need to generate formal trial data.

In type 2 diabetes (T2D) and obesity, tirzepatide is highly effective at improving metabolic health, and many of the same challenges, particularly overweight and obesity, are also common in T1D. These issues contribute to cardiovascular risk and make glucose management more difficult. We wanted to see whether tirzepatide could offer a safe and effective option for weight management in this population.

Q. What was the design of the TIRTLE1 trial, including eligibility criteria, dosing and the primary and secondary endpoints?

TIRTLE1 was a phase 2, placebo-controlled trial in 24 adults with T1D. Participants were aged 18 years or older, had been living with diabetes for more than 2 years, and all had obesity, defined as a BMI above 30 kg/m². There was no HbA1c requirement. For safety reasons, we excluded individuals with a recent history of diabetic ketoacidosis or severe hypoglycaemia.

Participants were randomized to weekly tirzepatide 5 mg or placebo for 12 weeks. This is a relatively low dose compared with the 15 mg used in other populations, and our aim was to take a cautious approach to safety while getting a short-term snapshot of efficacy. The primary endpoint was change in body weight, with secondary endpoints including insulin dose, HbA1c, dietary intake and body composition.

Q. What were the main findings in terms of weight, body composition, insulin dose and glycaemic control, and were there any notable safety observations?

The trial met its primary endpoint. Participants receiving tirzepatide lost an average of 8.7 kg more than placebo over 12 weeks. In absolute terms, weight loss in the tirzepatide group exceeded 10 kg, but there was also some weight loss in the placebo group, hence the adjusted figure of 8.7 kg.

Importantly, most of this loss was fat mass, around 80%, with only about 20% coming from lean mass. HbA1c also improved modestly, by around 0.4% compared with placebo.

What really stood out was the reduction in insulin requirements. By 12 weeks, total daily insulin dose was reduced by around 35%. We expected this would mainly reflect lower bolus insulin needs due to appetite suppression, but we also saw reductions in basal insulin, which hints at additional underlying mechanisms worth exploring.

From a safety perspective, we saw no cases of diabetic ketoacidosis or severe hypoglycaemia. Side effects were generally mild and consistent with what we know about tirzepatide in other settings.

Q. What do these results mean for the potential clinical impact of tirzepatide in type 1 diabetes, particularly for patients with obesity and high insulin requirements?

These findings are very encouraging, and we’re excited that a phase 3 programme is now underway. While TIRTLE1 was only a small phase 2 study, it provides the first early signals that tirzepatide could be an effective adjunct in T1D. Phase 3 trials will be critical for confirming safety and efficacy and moving closer to potential regulatory approval.

In the meantime, these results can help guide clinicians managing off-label use. They highlight the need to adjust insulin dosing early, given the rapid and substantial dose reductions we observed (as early as 2 weeks after starting medication).

For people with obesity and high insulin needs, options like tirzepatide are particularly important. Insulin therapy alone can drive weight gain, in part because insulin delivered subcutaneously doesn’t mimic the physiology of insulin released directly from the pancreas into the liver. Tirzepatide seems to work synergistically in the T1D setting, supporting weight loss and reducing insulin resistance. Interestingly, the weight loss we observed appeared to exceed that seen in T2D and obesity trials, which makes these results especially exciting.

The next steps are to look at the mechanisms and why T1D is so different and why the effects are so good.

Q. What are the next steps for research, and what questions remain unanswered about tirzepatide in type 1 diabetes?

There are still many important questions. First, we need longer-term studies to evaluate durability, safety and optimal dosing. Our study only lasted 12 weeks and used a relatively low 5 mg dose, whereas tirzepatide can be titrated up to 15 mg. It remains to be seen whether higher doses are needed in T1D or whether lower doses may be sufficient.

We also need to better understand safety, particularly the risks of hypoglycaemia and ketosis. Although our trial was reassuring, the sample size was too small to make definitive conclusions.

Our group is already planning another trial called TIRTLE2, which will look more deeply at mechanisms of action in T1D. This will include exploring effects on insulin resistance, glucagon and other metabolic pathways. Ultimately, our goal is to build the rationale for tirzepatide as a treatment option in T1D, while recognizing that the physiology differs from T2D and requires dedicated investigation.