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Objective: Use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) is associated with ketosis. On the other hand, insulin treatment inhibits lipolysis, hepatic ketogenesis, and promotes ketone oxidation in the peripheral tissues. Here, we investigated the effects of insulin therapy on circulating ketone levels in patients with type 2 diabetes (T2DM) receiving SGLT2i. Research Design and Methods: 150 patients with T2DM on SGLT2i (51.3% on concomitant insulin therapy) and 100 not on SGLT2i were recruited from Diabetes Clinic. Fasting serum levels of β-hydroxybutyrate (βOHB)and free fatty acids (FFA) were measured by colorimetric assays. Results: Participants on SGLT2i had significantly better glycemic control than those not on SGLT2i (HbA1c 7.7±1.2% and 8.8±1.5%, respectively; p <0.001). However, serum βOHBlevels were significantly higher in participants on SGLT2i compared with those who were not (347 uM [228-507] vs. 196 [151-274], respectively, p <0.001), despite similar age, body mass index (BMI), duration of diabetes and serum FFA levels (111 uM [81-148] vs. 108 [88-143]). In the group of participants on SGLT2i, those on insulin therapy had significantly higher BMI and HbA1c than those not on insulin therapy (BMI: 30.3±5.5 kg/m2vs. 27.5±5.5, respectively, p=0.002; HbA1c: 8.1±1.3% vs. 7.4±1.0%, respectively, p=0.001) but the duration of diabetes was similar. The median total daily dose of insulin was 50 units. Despite the concomitant use of insulin, serum βOHBlevels were comparable between participants on SGLT2i with or without insulin therapy (347 uM [220-485] vs. 347 [230-523], respectively), and were similar even after adjustments for BMI and HbA1c levels. Conclusions: Serum ketone levels were increased in patients with T2DM on SGLT2i, and concomitant insulin therapy did not suppress the increase in circulating ketone levels. Further prospective studies or randomized controlled trials are required to confirm the above findings. Disclosure: C. Lee: None. J.K. Lam: None. A.C. Lee: None. D.T. Lui: None. H. Fong: None. Y. Woo: None. K.S. Lam: None. K.C. Tan: None. [ABSTRACT FROM AUTHOR]