SAT-632 - Use of SGLT2 Inhibitors in Type A Insulin Resistance

Background
Germline pathogenic variants in the insulin receptor gene (INSR) are a cause of severe insulin resistance. More severe, biallelic variants cause Rabson-Mendenhall syndrome, while milder, monoallelic variants cause type A insulin resistance. Patients often have difficult to control diabetes with high insulin requirements and are prone to both hypoglycemia and ketoacidosis. Use of SGLT2 inhibitors has not been well studied in this population. SGLT2 inhibitors offer a potential mechanism to improve glycemic control, without escalation of insulin dosing.

Methods
We retrospectively reviewed the charts of six patients with INSR pathogenic variants who were managed at the NIH Clinical Center and were treated with SGLT2 inhibitors. Demographics, genetic variants, comorbidities, vital signs, diabetes treatment regimen and insulin requirements, continuous glucose monitor use, and adverse events (AEs) were collected.

Results
Six patients used an SGLT2 inhibitor (canagliflozin only in three, empagliflozin only in two, both drugs at different times in one).
Safety: SGLT2 was discontinued due to AEs in 3/6 patients (all taking canagliflozin). Two patients discontinued within a few days of initiation due to increased vulvovaginal pruritus in one and large urine ketones in the other. The third patient discontinued canagliflozin after 7 months due to diabetic ketoacidosis that occurred in the context of insulin underdosing and rationing due to lack of supply. The mean A1c among patients who discontinued canagliflozin due to adverse events was 14. 5%. Among patients who did not discontinue SGLT2 inhibitors due to AEs, small ketones and nocturia were reported in the two patients taking empagliflozin.
Efficacy: Two patients had data available to assess glycemia control before and after >=three weeks of SGLT2 inhibitor use. One patient showed rapid improvement in glycemia within three weeks of starting empagliflozin 10 mg daily based on CGM readings, with reduction in estimated HbA1c from 11.6 to 7.6%. At follow up at one year, however, HbA1c increased to 11.9%. The second patient had reduction in HbA1c from 8.9 to 8.1% after 1 year of canagliflozin 100 mg daily. However, due to unavailability of canagliflozin for almost a year, the patient was initiated on empagliflozin 25 mg daily, which led to reduction in HbA1c from 10.8 to 8.9%.

Interpretation/Conclusion
Based on limited data, SGLT2 inhibitors can be a useful adjunct in treating patients with INSR pathogenic variants, without significant risk of hypoglycemia. However, ketonuria was frequently observed, with one case of diabetic ketoacidosis, thus close ketone monitoring is warranted. There is limited long term efficacy and safety data, including cardiac and renal protection.

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