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Dapagliflozin in patients with type 1 diabetes: A post hoc analysis of the effect of insulin dose adjustments on 24‐hour continuously monitored mean glucose and fasting β‐hydroxybutyrate levels in a phase IIa pilot study
Author(s) -
Henry Robert R.,
Dandona Paresh,
Pettus Jeremy,
Mudaliar Sunder,
Xu John,
Hansen Lars
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12882
Subject(s) - dapagliflozin , insulin , medicine , endocrinology , type 2 diabetes , diabetes mellitus , placebo , type 1 diabetes , ketoacidosis , ketosis , pharmacodynamics , pharmacokinetics , pathology , alternative medicine
Aims To investigate the effects of total daily insulin dose ( TDD ) reductions on 24‐hour continuously monitored mean glucose and fasting β‐hydroxybutyrate (a marker for diabetic ketosis/ketoacidosis [ DKA ]) levels, using patient‐level data from a 14‐day, pilot study of dapagliflozin in type 1 diabetes ( T1DM ). Methods A post hoc exploratory correlation analysis was performed to determine the relationship between change in TDD and (1) 24‐hour mean glucose, assessed by continuous glucose monitoring, and (2) fasting β‐hydroxybutyrate, in 70 patients with T1DM receiving insulin and dapagliflozin (1, 2.5, 5 or 10 mg) or placebo. The pharmacodynamic effect of dapagliflozin was estimated as a virtual “insulin dose” using 24‐hour urinary glucose excretion values and a recognized insulin‐to‐carbohydrate counting technique. Results Trends for correlations were observed between change in TDD and 24‐hour glucose (day 7: r = −0.264, P = .056) and β‐hydroxybutyrate (day 7: r = −0.187, P = .133; day 14: r = −0.274, P = .047). The pharmacodynamic effect of dapagliflozin 5 or 10 mg was estimated as equivalent to ~20% of baseline TDD . Higher mean and maximum β‐hydroxybutyrate levels were observed on days 7 and 14 in patients with a TDD reduction >20% vs ≤20%. Conclusions Over 14 days, decreasing the insulin dose diminished the glucose‐lowering effect of dapagliflozin–insulin combination therapy and increased levels of β‐hydroxybutyrate. While insulin dose adjustments should always be individualized, these analyses suggest that, as a general rule, TDD reduction in dapagliflozin‐treated patients with T1DM should not exceed 20%, to ensure glycaemic control does not deteriorate and to mitigate the potential for an increased risk of DKA .