Sodium–glucose cotransporter 2 inhibitor‐associated diabetic ketoacidosis in patients with type 1 diabetes: Metabolic imbalance as an underlying mechanism

Ogawa, Wataru; Hirota, Yushi

doi:10.1111/jdi.13026

Cited by 8 publications

(6 citation statements)

References 14 publications

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“…However, these RCTs also showed substantial increases in the risk of SGLT2 inhibitor-associated diabetic ketoacidosis (DKA) [4][5][6][7][8] . The underlying mechanism for this type of DKA is reportedly associated with a metabolic imbalance between glucose-lowering and anticatabolic effects of SGLT2 inhibitors, which are intensified by an inadequate reduction in insulin dose 10 . A recent meta-analysis showed a combined risk ratio of 2.66 for DKA (95% confidence interval [CI] 1.32-5.35) in RCTs comparing canagliflozin, dapagliflozin or empagliflozin with a placebo 11 .…”

Section: Introductionmentioning

confidence: 99%

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

Horii

Oikawa

Atsuda

et al. 2021

J of Diabetes Invest

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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

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Section: Introductionmentioning

confidence: 99%

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

Horii

Oikawa

Atsuda

et al. 2021

J of Diabetes Invest

View full text Add to dashboard Cite

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“…Since SGLT-2 inhibitors can cause metabolic imbalance, the administration of SGLT-2 inhibitors significantly increases the incidence of diabetic ketoacidosis in patients with type 1 diabetes (6). SGLT-2 inhibitors also reportedly increased endogenous glucose production, serum glucagon levels (7), and serum ketones (8). Although, the patient's carbohydrate and fluid intake in their diet prevented the development of ketosis.…”

Section: Discussionmentioning

confidence: 99%

A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes

et al. 2022

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IntroductionWe report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor.Case ReportWe present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination.ConclusionThe vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.

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“…While this is noteworthy, care is warranted as some patients with reduced β-cell function may be at a higher risk of euglycemic diabetic ketoacidosis [21] caused by insulin deficiency and dehydration [22]. Although this study examined the insulin-sparing effects of ipragliflozin in T2DM, it is advised that extra caution be used in patients with type 1 diabetes mellitus [23, 24].…”

Section: Discussionmentioning

confidence: 99%

Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing Insulin Dose in Patients with Type 2 Diabetes Mellitus Receiving Insulin Therapy

et al. 2019

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Background and ObjectiveTo avoid insulin-induced hypoglycemia and weight gain, the minimum dose of insulin should be used. In this study, therefore, we examined insulin dose reduction by ipragliflozin add-on therapy in Japanese patients with type 2 diabetes mellitus treated with long-acting basal insulin.MethodsIn this multicenter, open-label study, patients received one ipragliflozin 50-mg tablet once daily in combination with basal insulin for 24 weeks. The primary efficacy endpoint was the change and percent change in insulin dose from baseline to Week 24. Secondary efficacy endpoints included changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), glycoalbumin, cholesterol, leptin, adiponectin, C-peptide, glucagon, body weight, and blood pressure, and number of patients achieving withdrawal of insulin at the end of treatment (EOT). Treatment-emergent adverse events (TEAEs) were evaluated for safety.ResultsIn total, 114 patients were screened, 103 were registered, and 97 completed the study. The mean age was 59 years and 72.8% of patients were male. The mean change in insulin dose from baseline at Week 24 was − 6.6 ± 4.4 units/day (p < 0.001); the mean percent change was − 29.87%. HbA1c, FPG, glycoalbumin, glucagon levels, body weight, and blood pressure significantly decreased from baseline to EOT (p < 0.05). Cholesterol, leptin, and adiponectin were unaffected. One patient was able to stop insulin treatment at Week 16. The incidence of TEAEs was 60.2%. Hypoglycemia (10.7%) and pollakiuria (13.6%) were the most common drug-related TEAEs. Conclusions Once-daily 50-mg ipragliflozin enabled a 30% dose reduction of insulin by Week 24 compared with baseline. No major safety concerns were raised.Clinical Trial RegistrationClinicalTrials.gov (NCT02847091)Electronic supplementary materialThe online version of this article (10.1007/s40261-019-00851-z) contains supplementary material, which is available to authorized users.

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Sodium–glucose cotransporter 2 inhibitor‐associated diabetic ketoacidosis in patients with type 1 diabetes: Metabolic imbalance as an underlying mechanism

Cited by 8 publications

References 14 publications

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

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

A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes

Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing Insulin Dose in Patients with Type 2 Diabetes Mellitus Receiving Insulin Therapy

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