Can premixed insulin be combined with a Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitor in type 1 diabetes?

Premixed Insulin and SGLT2 Inhibitors in Type 1 Diabetes

SGLT2 inhibitors are not recommended for routine use in type 1 diabetes due to the significantly increased risk of diabetic ketoacidosis (DKA), and this risk may be further heightened when combined with premixed insulin formulations. 1

Safety Concerns with SGLT2 Inhibitors in Type 1 Diabetes

• SGLT2 inhibitors were temporarily approved by the European Medicines Agency (EMA) for type 1 diabetes but this approval was later withdrawn due to safety concerns, primarily the risk of diabetic ketoacidosis (DKA) 1
• The US Food and Drug Administration (FDA) has not approved SGLT2 inhibitors for use in type 1 diabetes due to concerns about DKA risk 1
• SGLT2 inhibitors should be used with caution and appropriate patient education in patients with insulin deficiency, which includes all type 1 diabetes patients 2
• Case reports of diabetic ketoacidosis with SGLT2 inhibitors continue to raise concerns, especially in insulin-dependent patients 2

Specific Risks with Premixed Insulin Formulations

• Premixed insulin regimens are not routinely recommended even for inpatient use due to increased hypoglycemia risk compared to basal-bolus therapy 2
• For patients with type 1 diabetes, dosing insulin based solely on premeal glucose levels (as often done with premixed insulin) does not account for basal insulin requirements or caloric intake, increasing the risk of both hypoglycemia and hyperglycemia 2
• An insulin regimen with separate basal and correction components is necessary for all patients with type 1 diabetes, with the addition of prandial insulin if the patient is eating 2

Potential Interactions Between SGLT2 Inhibitors and Premixed Insulin

• When SGLT2 inhibitors are combined with insulin therapy, there is a risk of hypoglycemia that requires careful insulin dose adjustment 3
• Substantial initial reductions in insulin dose (>20%) should be avoided after initiation of SGLT2 inhibitors due to increased DKA risk 2
• Patients on complex insulin regimens or with history of labile blood glucose should have an SGLT2 inhibitor initiated only in collaboration with the diabetes care provider 2
• In studies examining SGLT2 inhibitor use in type 1 diabetes, specific insulin dose reduction protocols were needed to minimize hypoglycemia risk 4

Alternative Approaches for Type 1 Diabetes Management

• For patients with type 1 diabetes, the preferred insulin regimen typically involves multiple daily injections with short-acting or rapid-acting insulin before meals together with one or more daily separate injections of intermediate or long-acting insulin 5
• If combination therapy is being considered for type 1 diabetes, automated insulin delivery systems combined with low-dose SGLT2 inhibitors have been studied but still carry DKA risk 6
• The target HbA1c for all children and adults with type 1 diabetes is recommended to be <7.5%, aiming to minimize both hyperglycemia and severe hypoglycemia 5

Monitoring Requirements If Combination Is Used

• If SGLT2 inhibitors are used in type 1 diabetes despite the risks, patients should be informed about the risk of euglycemic diabetic ketoacidosis and advised to seek immediate care if they develop symptoms potentially associated with DKA (nausea, vomiting, abdominal pain, generalized weakness) 2
• Blood ketone monitoring would be essential for patients with type 1 diabetes on SGLT2 inhibitors 1
• Patients should be selected carefully - those with a body mass index ≥27 kg/m² were included in the temporary EMA approval 1
• Renal function should be monitored as SGLT2 inhibitors should not be initiated if eGFR is <30 mL/min/1.73m² 2, 7

Conclusion

• The combination of premixed insulin with SGLT2 inhibitors in type 1 diabetes presents significant safety concerns, particularly regarding the risk of diabetic ketoacidosis 2, 1
• If SGLT2 inhibitors are considered in type 1 diabetes despite the risks, they should be used with separate basal and bolus insulin components rather than premixed formulations 2
• Patient selection, education, and close monitoring are critical if SGLT2 inhibitors are used in type 1 diabetes 2, 1