Diurnal Glycemic Patterns during an 8-Week Open-Label Proof-of-Concept Trial of Empagliflozin in Type 1 Diabetes

Background We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM). Methods In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUC(TOTAL) 12:00am-11:55pm; AUC(DAY) 7:05am-10:55pm, AUC(NIGHT) 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (>= 70 to <= 140mg/dL). Results The 40 patients (26 on insulin pump) were aged 24 +/- 5 years and BMI 24.5 +/- 3.2 kg/m(2). Consistent with the observed HbA1c decrease (8.0 +/- 0.9% to 7.6 +/- 0.9%, p<0.0001), normalized AUC(TOTAL) CGM decreased from 153.7 +/- 25.4 to 149.0 +/- 30.2mg/dL.h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1 +/- 29.5mg/dL.h, p = 0.02). The numerical decrease in normalized AUC(NIGHT) (152.0 +/- 36.6 to 141.9 +/- 34.4mg/dL.h, p = 0.13) exceeded AUC(DAY) (154.5 +/- 24.5 to 152.6 +/- 30.4mg/dL.h, p = 0.65). Trends toward lower glycemic variability (83.1 +/- 18.9 to 75.6 +/- 28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8 +/- 3.6 to 10.3 +/- 4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3 +/- 19.3mg/dL, p = 0.04 and 11.8 +/- 3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2 +/- 11.9 to 43.1 +/- 13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects. Conclusions We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime.