Highlights
- Semaglutide, when combined with automated insulin delivery, increased the proportion of adults with type 1 diabetes and obesity achieving optimal glucose control and at least 5% weight loss.
- 36% of patients on semaglutide met the composite endpoint versus 0% on placebo.
- Improvements were observed in time-in-range, HbA1c, and body weight, without increased risk of severe hypoglycemia or diabetic ketoacidosis.
Study Background and Disease Burden
Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells resulting in absolute insulin deficiency. While the mainstay of T1D management is exogenous insulin, many patients, particularly those with obesity, struggle to achieve optimal glycemic control without weight gain or increased risk of hypoglycemia. Obesity is increasingly prevalent among adults with T1D, compounding cardiovascular risk and complicating insulin therapy. Currently, no adjunctive pharmacologic therapies are approved specifically for weight management in T1D, underscoring an urgent unmet need for interventions that improve both glycemia and weight outcomes safely in this population.
Semaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated robust efficacy in type 2 diabetes (T2D) and obesity for improving glycemic control and promoting weight loss. However, its efficacy and safety in adults with T1D have not been established due to concerns about hypoglycemia and diabetic ketoacidosis (DKA) in the context of absolute insulin deficiency. The ADJUST-T1D trial sought to rigorously evaluate whether semaglutide could provide meaningful metabolic benefit and weight reduction in adults with T1D and obesity, without compromising safety.
Study Design
This was a 26-week, randomized, double-blind, placebo-controlled trial (ADJUST-T1D) enrolling 72 adults with T1D, all of whom were using an automated insulin delivery (AID) system and had a body mass index (BMI) ≥30 kg/m². Participants were randomized 1:1 to once-weekly semaglutide (titrated up to 1 mg) or matching placebo.
The primary composite endpoint was achievement of all of the following by week 26:
- Continuous glucose monitoring (CGM)-derived time-in-range (70–180 mg/dl) >70%
- CGM time below 70 mg/dl <4%
- >5% reduction in body weight
Secondary endpoints included change in glycated hemoglobin (HbA1c), mean CGM time-in-range, and body weight. Safety outcomes focused on severe hypoglycemia, DKA, and adverse event profiles.
Key Findings
The semaglutide group demonstrated a strikingly greater proportion of patients achieving the primary composite endpoint compared to placebo (36% vs. 0%; absolute difference 36 percentage points; 95% CI, 20.6 to 52.2; P<0.001). This composite success reflects simultaneous achievement of glycemic and weight targets, a notable challenge in T1D clinical management.
Key secondary efficacy outcomes included:
- Glycemic Control: The least-squares mean difference in HbA1c change from baseline to week 26 was -0.3 percentage points (95% CI, -0.6 to -0.05) favoring semaglutide. Notably, mean CGM time-in-range improved by 8.8 percentage points (95% CI, 3.9 to 13.7) over placebo.
- Weight Loss: Participants in the semaglutide arm experienced a mean reduction in body weight of -8.8 kg (95% CI, -10.6 to -7.0), a clinically meaningful benefit in this high-risk cohort.
- Safety: Severe hypoglycemia was rare (two events in each group), and no DKA events were reported during the study. Overall, semaglutide did not increase the risk of clinically significant hypoglycemia or DKA compared to placebo.
These results indicate that semaglutide, when used adjunctively with AID, can safely and effectively improve both weight and glycemic metrics in adults with T1D and obesity, a population for whom therapeutic innovation is notably limited.
Expert Commentary
These findings represent a potential paradigm shift in the management of adults with T1D and obesity. GLP-1 receptor agonists like semaglutide, previously reserved for T2D and obesity, may offer dual benefits for glucose and weight management in T1D when paired with modern insulin delivery technology. Importantly, the absence of increased DKA or severe hypoglycemia risk addresses major historical concerns with adjunctive therapies in T1D.
However, several limitations must be emphasized. The trial was of modest size (N=72) and short duration (26 weeks), limiting insights into long-term safety, durability of benefit, and rare adverse events. The use of AID systems may have mitigated hypoglycemia risk, and generalizability to those not using AID merits further study. Additionally, the trial excluded those with lower BMI, so findings should be restricted to obese T1D populations.
Mechanistically, GLP-1 receptor agonists reduce appetite, slow gastric emptying, and may augment insulin sensitivity, offering plausible pathways for the observed benefits. However, their role in absolute insulin deficiency and the need for careful insulin dose titration in T1D remain critical considerations for broader clinical adoption.
Conclusion
The ADJUST-T1D trial provides compelling evidence that once-weekly semaglutide, added to automated insulin delivery, can facilitate clinically meaningful improvements in glycemic control and weight loss in adults with T1D and obesity without compromising safety. While these results are encouraging, larger and longer-term studies are essential to confirm these findings and establish guidelines for semaglutide use in this unique population. Until then, careful patient selection and monitoring will be paramount for any off-label use.
References
1. Shah VN, Akturk HK, Kruger D, Ahmann A, Bhargava A, Bakoyannis G, Pyle L, Snell-Bergeon JK. Semaglutide in Adults with Type 1 Diabetes and Obesity. NEJM Evid. 2025 Aug;4(8):EVIDoa2500173. doi: 10.1056/EVIDoa2500173. Epub 2025 Jun 23. PMID: 40550013.
2. American Diabetes Association. Standards of Medical Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S350.
