GLP-1 receptor agonists in type 1 diabetes: expanding the therapeutic landscape beyond insulin

Metabolic control in type 1 diabetes (T1D) remains challenging. Despite advances in insulin therapies and technology,¹ most individuals fail to achieve glycaemic targets and remain at risk of hypoglycaemia, high glucose variability, ketoacidosis, weight gain, oxidative stress, and cardiovascular/renal complications. Disrupted intra-islet insulin regulation of glucagon secretion also leads to hyperglucagonaemia.²

Insulin resistance, a major barrier to optimal metabolic control, develops early in T1D. Alongside hyperglycaemia, hyperglucagonaemia, and weight gain, iatrogenic hyperinsulinaemia contributes to insulin resistance, creating a self-perpetuating cycle that further worsens both hyperinsulinemia and insulin resistance.² Therefore, insulin doses for treatment should be kept as low as possible, which in turn requires reducing hyperglucagonaemia and preventing weight gain to improve insulin sensitivity. Treating T1D is particularly complex, and effective management should address targets beyond glycaemic control alone.²

GLP-1RAs lower glucagon and enhance insulin secretion through glucose-dependent mechanisms; slow β-cell apoptosis; promote weight loss; delay gastric emptying, thereby facilitating postprandial glycaemic control; improve insulin sensitivity through direct and indirect mechanisms; increase vasodilation; exert anti-inflammatory effects; and reduce oxidative stress, thereby conferring cardio-renal, and mortality benefits.³ These agents may therefore be ideal as adjuncts to insulin in T1D and are often prescribed off-label in clinical practice. Most T1D studies have focused on weekly injectable semaglutide. SGLT-2 inhibitors have also been used with insulin in T1D but appear less effective and carry a higher risk of ketoacidosis than GLP-1RAs.⁴

In the July issue of The Lancet Regional Health-Europe, Yazdanfard and colleagues⁵ conducted the first long-term, two-year nationwide real-world study using Danish registries to investigate, under everyday-life conditions, the effects of off-label semaglutide (0.25 mg/week gradually increased to 2.40 mg/week) combined with insulin in 879 individuals with T1D treated with multiple daily injections/MDI, or insulin pumps (baseline HbA1c 7.9%, BMI 31.9 kg/m²), compared with 3516 age/HbA1c/BMI-matched non-users. During the first six months of semaglutide, HbA1c decreased by 0.52%, with only a small further reduction at two years, while remaining unchanged in controls. Greater reductions were observed among individuals with higher baseline HbA1c, with similar effects in MDI and insulin pump users. Total insulin prescriptions declined by 8.2%, suggesting an insulin-sparing effect, whereas they increased by 4.2% in controls. BMI changes were not assessed due to 59% missing data. However, it is well-established that semaglutide 2.4 mg/week produces an average 16% weight loss in overweight/obese individuals, exceeding 25% in some cases.⁶ Complementing the findings of Yazdanfard and colleagues, a recent study⁷ demonstrated that 26 weeks of semaglutide (0.25 mg/week, titrated up to 1 mg/week) in individuals with T1D (baseline HbA1c 7.8%, BMI 35 kg/m², time-in-range 70–180 mg/dl/TIR 56.2%, insulin 73 units/day) decreased HbA1c and weight by 0.3% and 9.5%, respectively, increased TIR by 20%, and reduced both basal and prandial insulin units/day by 20%, with greater reductions in prandial insulin. Glycaemic control improved in the first four weeks despite lower semaglutide and insulin doses and minimal weight loss, suggesting a direct insulin-sparing effect via improved insulin sensitivity. Insulin doses may therefore need to be reduced by 20–30% shortly after starting semaglutide to mitigate the risk of hypoglycaemia.

Yazdanfard and colleagues also demonstrated that semaglutide was not associated with increased hospitalizations for hypoglycaemia or ketoacidosis, supporting its real-world safety profile. Adherence declined from 71% at six months to 25% at two years, mainly due to gastrointestinal side effects and lack of reimbursement. Discontinuation rates appear higher in real-world settings than in clinical trials.⁸ Further studies are needed to comprehensively assess adverse events associated with GLP-1RAs, clarify reasons, and improve adherence in T1D.

Several issues remain unresolved. The effects of GLP-1RAs on cardiovascular and renal complications in T1D remain to be fully investigated. After discontinuing semaglutide and other GLP-1RAs, individuals may regain 50–70% of the weight lost within 1–2 years. GLP-1RAs may also reduce muscle mass. These effects warrant investigation into whether structured lifestyle interventions can preserve muscle mass, and limit weight regain. Oral semaglutide offers a promising alternative to injections, and may reduce treatment burden in T1D. Tirzepatide reduces HbA1c and weight more than semaglutide, warranting randomized and real-world studies in T1D to confirm safety and efficacy, assess cardiometabolic benefits, and define its long-term role. Vision-related complications with GLP-1RAs and their association with rapid glycaemic improvement also require investigation in T1D. Residual insulin secretion and glucagon suppression in T1D facilitate glycaemic control; GLP-1RAs may preserve remaining β-cell mass. Novel incretin-based co-agonists with promising metabolic and clinical potential await evaluation in T1D, including GLP-1/glucagon, GLP-1/GIP/glucagon, Semaglutide/Amylin, and the oral small-molecule GLP-1RA orforglipron.8, 9, 10

Contributors

GD searched the literature and wrote the manuscript. VL reviewed and edited the manuscript. Both authors directly accessed and verified the underlying data reported in the manuscript.

Declaration of interests

GD has no conflicts of interest to declare within the past 36 months. VL has received honoraria in the context of Advisory Boards, research grants, clinical trials, speakers bureau, and consultancy by Novartis, Sanofi, NovoNordisk, MSD, EliLilly, Boehringer, Vianex, Haemoglobe, AstraZeneca, Mylan, Amgen, Elpen, Amryt, Medtronic, Menarini, Bios, Abbott.