Abstract Background Fournier's gangrene (FG) is a form of necrotizing fasciitis characterized by polymicrobial infection of the perineal, perianal or genital areas; risk factors include diabetes mellitus and male gender. Dapagliflozin is one of four sodium-glucose cotransporter 2 (SGLT2) inhibitors FDA-approved for the treatment of Type 2 diabetes mellitus (T2DM). SGLT2 inhibitors decrease serum glucose and increase glycosuria by binding to renal tubular SGLT2 receptors, and inhibiting reabsorption of glucose from urine in the proximal convoluted tubule. Since their introduction in 2013, SGLT2 inhibitors have been shown to protect against decline in GFR, to improve LVEF in HFrEF, and to improve survival in T2DM. However, due to associated glycosuria, SGLT2 inhibitors are commonly associated with candidiasis, and are rarely associated with life-threatening adverse effects including FG, and euglycemic diabetic ketoacidosis. | Clinical case: A 57-year-old male with T2DM, diabetic neuropathy and hypertension presented to the ED with left testicular swelling, penile discharge and dysuria of several days duration. He was afebrile and vital signs were in normal ranges. Examination disclosed left-sided scrotal swelling surrounding a 1 cm black eschar, induration, erythema and discharge. WBC 15.1 with 79% neutrophils and HbA1c 10.4%. Dapagliflozin 4 mg daily had been added to insulin degludec one month earlier. He denied previous history of scrotal/genital infections. Ultrasound of the scrotum showed wall thickening on the left, a small hydrocele and heterogenous echogenicity suggesting an abscess. Pelvic CT scan with contrast revealed multiple small air bubbles in the scrotal wall. Findings were consistent with FG. He was treated promptly with IV piperacillin / tazobactam and vancomycin. Urological debridement of necrotic scrotal skin was carried out the morning after admission; cultures obtained at surgery grew Gram neg rods and Diphtheroids. Tissues within the scrotum were not gangrenous. Primary closure with a Penrose drain was attempted, but the skin surrounding the sutures necrosed and a second urological procedure was done to remove the sutures and allow the scrotal wall to heal by secondary intention. He was discharged after 5 days and I. V. ampicillin/sulbactam was continued for a total of 14 days with resolution of infection and healing of the skin. Conclusion SGLT2 inhibitors decrease mortality and increase quality of life in T2DM compared to older treatments with exogenous insulin and its secretagogues. Optimal utilization of SGLT2 inhibitors in the management of patients with T2DM will entail 1) quantifying risk specifically attributable to SGLT2 inhibitors since T2DM is a known risk factor for FG, and 2) routinely informing/reminding patients with T2DM to promptly report skin infections of the groin, perineum or perianal region. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.