Intensive insulin therapy (multiple daily injections -MDI- or continuous subcutaneous insulin infusion) is the mainstay of treatment for people living with type 1 diabetes mellitus (PLWT1DM) [1]. The main goal of this therapeutic approach is to achieve optimal glycemic control in order to reduce the risk of disease-associated complications [2]. However, despite remarkable innovations in the management of type 1 diabetes mellitus (T1DM) developed in recent years, most PLWT1DM do not achieve this glycemic target, and also experience significant adverse events, such as hypoglycemia or weight gain, and a significant self-care burden [3,4]. Therefore, additional strategies are needed in the management of T1DM.

In this context, use of different sodium-glucose cotransporter 2 inhibitors (SGLT2i), such as dapagliflozin, as an adjunct to insulin therapy is associated with improvements in glycemic control, weight loss, and reduced insulin requirements in PLWT1DM, as demonstrated in long-term, large-scale randomized clinical trials [5], [6], [7], [8]. Indeed, these positive effects may also be relevant in patients using hybrid closed-loop systems [9,10]. In addition, it should be noted that SGLT2is have pleiotropic effects beyond glycemic control, and have demonstrated significant benefits in patients with chronic kidney disease or heart failure regardless of the presence of diabetes [11,12]. Therefore, the use of dapagliflozin or other SLGT2is may also be associated with cardiovascular and renal benefits in PLWT1DM [13], [14], [15], [16], [17]. Therefore, the prescription of these agents should be considered in PLWT1DM with these conditions, although further research is needed.

On the other hand, similar to other SGLT2is, important safety concerns have been raised regarding the reported increased risk of diabetic ketoacidosis (DKA) associated with the use of dapagliflozin in PLWT1DM [5], [6], [7], [8]. This fact has prompted debate about the use of this agent in this specific population, although it should be noted that careful selection of appropriate patients for the prescription of dapagliflozin or other SGLT2is, as well as the implementation of strategies to mitigate DKA, may minimize the risk of this complication [18], [19], [20], [21]. Accordingly, in general, this treatment should be considered in PLWT1DM with overweight/obesity, with stable optimized insulin therapy (not having low insulin requirements), committed to control ketone levels, and educated about potential risk factors for DKA and how to recognize this complication [18], [19], [20], [21]. In fact, some of these measures should also be considered in people living with type 2 diabetes mellitus (PLWT2DM), as a higher risk of DKA may also be observed among this group associated with the use of dapagliflozin and other SGLT2is [22]. Of note, although dapagliflozin became the first SGLT2i authorized by the European Medicines Agency (EMA) for T1DM in 2019 [23], this indication was withdrawn in 2021 based on AstraZeneca's decision [24].

Notably, previous real-world studies have evaluated the clinical effects and safety profile of different SGLT2is [25], [26], [27], [28], although evidence is still limited. In fact, a few studies have included the incidence of DKA as a primary outcome measure, with mixed results [29,30]. However, it should be noted that most of these studies had a reduced sample size, and enrolled PLWT1DM on different SGLT2is (i.e., empagliflozin, dapagliflozin and canagliflozin) in the same cohort. Moreover, a high rate of off-label use of SGLT2is (often even prior to the publication of data from clinical trials conducted in PLWT1DM, or the generalization of specific DKA risk reduction strategies/appropriate patient selection) has been observed in previous studies. Given that dapagliflozin was the first SGLT2i approved by the EMA for use in PLWT1DM [23] and has become the most widely used SGLT2i in Europe, real-world evidence on the use of this drug may provide useful data.

Therefore, in this multicenter study, we evaluate the 12-month safety (primary outcome) and effectiveness (secondary outcome) of dapagliflozin as add-on therapy to insulin in PLWT1DM in a real-world setting.