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

Abstract

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 (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 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/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL 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 AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (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.

Trial registration: Clinicaltrials.gov NCT01392560.

Conflict of interest statement

Competing Interests: BAP has received speaker honoraria from Medtronic Inc., Johnson and Johnson, Roche, GlaxoSmithKline Canada, Novo Nordisk and Sanofi; has received research grant support from Medtronic and Boehringer Ingelheim; and serves as a consultant for Neurometrix. DZC has received speaker honoraria from Merck, Boehringer Ingelheim, Janssen, and research funding from Astellas Pharma and Boehringer Ingelheim. HP has received speaker honoraria from Janssen, Boehringer Ingelheim and AstraZeneca. BZ has received research support and or consulting honoraria from Boehringer Ingelheim, Janssen, AstraZeneca, Eli Lilly, Novo Nordisk, Merck and Sanofi. RM received research support from Boehringer Ingelheim and honoraria for speaking from Sanofi and Abbott Diabetes Care. None of the above awards or honoraria are directly associated with this specific study. JL and HT have no conflicts of interest to declare. NS, NF, SK, HJW, UCB and OEJ are employees of Boehringer Ingelheim. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow chart for study participants.

Fig 2. Average Hourly Glycemic Exposure According to Nighttime, Daytime, and Total Hours.

Hourly glycemic exposure was evaluated by area under the median curve according to time of day: AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am. P>0.05 for all comparisons except for those significant differences indicated. 25(64%) participants saw a reduction in AUCTOTAL from baseline to end-of-treatment, while 14(36%) saw an increase. 28(72%) participants saw a reduction in AUCNIGHT from baseline to end-of-treatment, while 11(28%) saw an increase.