A Possible Novel Effect for Dapagliflozin in the Management of Subcutaneous Insulin Resistance Syndrome: A Report of Two Cases.

Introduction: Subcutaneous insulin resistance syndrome (SIRS) is a rare condition in which patients poorly respond to subcutaneous (SC) insulin but maintain a normal response to intravenous (IV) insulin. The underlying pathophysiology remains elusive. Several treatment regimens have been tested for the management of SIRS, none of which included a sodium-glucose cotransporter-2 inhibitor (SGLT-2).

Case presentation: Two cases of type 1 diabetes initially achieved adequate glycemic control with subcutaneous insulin. Both cases later progressed into recurrent diabetic ketoacidosis that would resolve following IV insulin administration. Further investigation revealed unresponsiveness to SC, but not IV, insulin and the clinical diagnosis of SIRS was established accordingly. HbA1c values for cases 1 and 2 were 11% on 400 units/day of SC insulin, and 12% on 350 - 400 units/day of SC insulin, respectively. The patients required very high doses of intramuscular (IM) insulin. Subsequently, dapagliflozin as adjunct therapy significantly reduced the patients' IM insulin requirements beyond the anticipated dose reduction. Ultimately, case 1 achieved an HbA1c of 7 - 8% on 90 units/day of IM insulin and 10 mg/day of dapagliflozin, and case 2 achieved an HbA1c of 7 - 8% on 120 units/day of IM insulin and 10 mg/day of dapagliflozin.

Conclusions: These are the first reported cases of SIRS in which dapagliflozin, an SGLT-2 inhibitor, was used. The substantial reduction in the IM insulin dose following the addition of dapagliflozin in our reported cases of SIRS suggests a possible novel mechanism for dapagliflozin beyond its glucosuric effects. In this report, we present a hypothetical basis for this possible novel mechanism.