On‐label use of sodium–glucose cotransporter 2 inhibitors might increase the risk of diabetic ketoacidosis in patients with type 1 diabetes

Abstract

Aims/Introduction: This study aimed to investigate the risk of diabetic ketoacidosis (DKA) in insulin-treated type 1 diabetes patients administered sodium-glucose cotransporter 2 (SGLT2) inhibitors in real-world clinical practice. Materials and Methods: We carried out a real-world, retrospective, observational cohort study using Japanese Medical Data Vision, a diagnosis procedure combination database. We identified insulin-treated adult type 1 diabetes patients enrolled from December 2018 to October 2019. We assessed the incidence and risk of DKA in type 1 diabetes patients using SGLT2 inhibitors in an 'on-label' manner. Cox multivariate regression analyses were carried out to determine clinical factors linked to SGLT2 inhibitor-associated DKA. Results: Of 11,475 type 1 diabetes patients, 1,898 (16.5%) were prescribed SGLT2 inhibitors. DKA occurred in 139 (7.3%) of these patients, with 20.2 incidences per 100 personyears. These patients also showed significantly higher DKA rates than did those not receiving SGLT2 inhibitors (hazard ratio 1.66, 95% confidence interval 1.33-2.06; P < 0.001). The mean time until DKA onset in SGLT2 inhibitor-treated type 1 diabetes patients was 30.6 -30.1 days. The risk of SGLT2 inhibitor-associated DKA increased in type 1 diabetes patients irrespective of sex, age or body mass index. However, the risk did not increase in type 1 diabetes patients receiving continuous subcutaneous insulin infusion, which warrants further investigation because of the small number of type 1 diabetes patients receiving continuous subcutaneous insulin infusion. Conclusions: 'On-label' SGLT2 inhibitor use might increase DKA risk among insulin-treated type 1 diabetes patients irrespective of sex, age or body mass index. Both type 1 diabetes patients and healthcare providers should be wary of DKA, especially during the first month of initiating SGLT2 inhibitors.patients achieve target glycated hemoglobin A1c of <7% (53 mmol/mol) 2 . Thus, non-insulin adjunctive therapies are required to improve long-term glycemic control in type 1 diabetes patients.Presently, sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used for the treatment of type 2 diabetes. SGLT2 inhibitors reduce hyperglycemia by inhibiting proximal tubular reabsorption of glucose in the kidney, making the glucose-lowering effect independent of insulin secretion 3 . Thus, SGLT2 inhibitors are considered effective glucose-lowering agents, and are prescribed as insulin therapy adjuncts for type 1 diabetes

Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?

“…In the present study of patients with T1D and a mean BMI of 25.5 kg/m 2 , DKA occurred in only three (1.4%) over 52 weeks, which represents a lower incidence than that previously reported for patients with T1D who were not taking an SGLT2i (7.1%) [28]. The three patients did not respond appropriately during sick days and had BMIs above the mean (Supplementary Table 5).…”

“…The three patients did not respond appropriately during sick days and had BMIs above the mean (Supplementary Table 5). DKA was more likely to occur during the initiation (insulin adjustment) period and was not associated with baseline BMI in a previous study of Japanese patients with T1D [28]. Therefore, we believe that there is no need to limit the use of SGLT2i to patients with T1D and obesity or overweight, as is the case in Europe, because they demonstrate efficacy in normal-weight patients.…”

“…The European Medicines Agency has approved the drug for use only in patients with a BMI ≥27 kg/m 2 under specialist care [26]; this is because a phase 3 trial of Western patients with T1D showed that the incidence of DKA is higher in those with a BMI <27 kg/m 2 than in those with a BMI ≥27 kg/m 2 (4.0% vs. 1.7%) [27]. In contrast, Horii et al [28] reported that SGLT2is increased the risk of DKA by 1.66-fold (hazard ratio 1.66; 95% CI, 1.33-2.06; p < 0001) based on an analysis of a database of 11,475 Japanese patients with T1D, considerably lower than in Western patients with T1D. Similarly, the incidences of DKA were low in the two phase 3 trials of the use of SGLT2is conducted in Japanese patients with T1D [10,12,13].…”

Off‐label use of sodium glucose co‐transporter inhibitors among adults in type 1 diabetes exchange registry

“…However, recent real-world data from Japan assessing a cohort of 11 475 patients with T1D, including 1898 (16.5%) SGLTi users indicated that DKA risk was higher in SGLTi users compared with non-users (hazard ratio 1.66, 95% CI 1.33-2.06; p < .001). 9 The higher incidence of SH among SGLTi users in T1DX, even after adjusting for demographic differences, was unexpected. It is possible that selection bias exists; for example, those electing for SGLTi may strive for tighter control and thereby have an increased risk of hypoglycaemia.…”

A new era of diabetic kidney disease treatment with sodium–glucose cotransporter‐2 inhibitors

“…This increased glucose excretion is expected to lead to various metabolic improvements such as weight loss and reduction in blood glucose. Initially, there were several concerns about its potential adverse effects such as ketoacidosis, particularly in type 1 diabetes 1 , but their use has now become widespread as a relatively safe drug 2 . This is especially true among patients with type 2 diabetes, because of the strong cardio‐ and renoprotection of these inhibitors 3,4 .…”