Effects of Dapagliflozin on 24-Hour Glycemic Control in Patients with Type 2 Diabetes: A Randomized Controlled Trial

Robert R Henry, Poul Strange, Rong Zhou, Jeremy Pettus, Leon Shi, Sergey B Zhuplatov, Traci Mansfield, David Klein, Arie Katz, Robert R Henry, Poul Strange, Rong Zhou, Jeremy Pettus, Leon Shi, Sergey B Zhuplatov, Traci Mansfield, David Klein, Arie Katz

Abstract

Background: Glycated hemoglobin (HbA1c) and measures of short-term glycemia do not fully capture daily patterns in plasma glucose dynamics. This study evaluated 24-h glycemic profiles in patients with type 2 diabetes (T2D) initiated on dapagliflozin treatment using continuous glucose monitoring (CGM).

Methods: This randomized double-blind placebo-controlled multicenter parallel-design 4-week study compared dapagliflozin (10 mg/d; n = 50) with placebo (n = 50) in adult patients with T2D uncontrolled (HbA1c 7.5%-10.5%) on either stable doses of metformin monotherapy (≥1500 mg/d) or insulin (≥30 U/d with or without up to two oral antidiabetes drugs). CGM was used to measure 24-h glycemic profiles for 7 days pretreatment and during week 4 of treatment. The primary outcome was change from baseline in 24-h mean glucose (MG) at week 4.

Results: The 24-h MG decreased 18.2 mg/dL with dapagliflozin and increased 5.8 mg/dL with placebo (P < 0.001). The proportion of time spent in the target glucose range (70-180 mg/dL) increased significantly with dapagliflozin versus placebo (69.6% vs. 52.9%; P < 0.001), with a small (0.3%) increase in time spent in the hypoglycemic range (<70 mg/dL), driven by those on background insulin therapy. Dapagliflozin reduced postprandial glucose and significantly decreased overall glucose variability. Few events of symptomatic hypoglycemia occurred. The most common adverse event was urinary tract infection (6% in each treatment arm).

Conclusions: Compared with placebo, dapagliflozin improved measures of glycemic control and variability as assessed by CGM. Glycemic improvements were more pronounced in the group on background metformin than those receiving basal insulin.

Trial registration: ClinicalTrials.gov NCT02429258.

Keywords: Continuous glucose monitoring; Daily glycemic variability; Dapagliflozin; SGLT2 inhibitor.

Conflict of interest statement

R.R.H. has served on advisory panels for AstraZeneca, Boehringer Ingelheim, Elcelyx Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Janssen Pharmaceuticals, and Sanofi-Aventis; has served as a consultant for Alere and Intarcia Therapeutics; and has received research support from AstaMed, Eli Lilly and Company, Hitachi, Lexicon, and ViaCyte. P.S. has served as a consultant for AstraZeneca. R.Z., L.S., and D.K. have nothing to disclose. J.P. has served as a consultant for Dexcom, Insulet, Mannkind, Novo Nordisk, Sanofi, and Valeritas. S.B.Z. and T.M were employees of AstraZeneca at the time this research was conducted and also held stock/shares in AstraZeneca. A.K. was an employee of AstraZeneca at the time of this research.

Figures

FIG. 1.
FIG. 1.
Changes from baseline. (A) 24-h mean (SE) glucose, with treatment difference for LSM change from baseline (mg/dL) in the ITT population. (B) Comparison of change from baseline in mean 24-h glucose profile at week 4 as shown by MADz in the overall population (time 0 to 24 h means midnight to midnight; the black line represents the treatment DAPA–PBO difference; when the difference between the two groups' change from baseline [blue and green lines for DAPA and PBO, respectively] is outside the MADz red lines [95th percentiles], the two treatments are statistically different at that time of day). (C) Change from baseline in time spent (%) in plasma glucose ranges from baseline to week 4 in the ITT population. The arrows denote the percentages of time with glucose <70 mg/dL. CI, confidence interval; DAPA, dapagliflozin; ITT, intention-to-treat; LSM, least-squares mean; MADz, maximum absolute deviation from zero; PBO, placebo; SE, standard error.
FIG. 2.
FIG. 2.
ITT population changes from baseline for the metformin and insulin strata. (A) 24-h mean (SE) glucose for the strata, with treatment difference for LSM change from baseline (mg/dL). (B) Comparison of change from baseline in mean 24-h glucose profile at week 4 as shown by MADz. CI, confidence interval; DAPA, dapagliflozin; ITT, intention-to-treat; LSM, least-squares mean; MADz, maximum absolute deviation from zero; PBO, placebo; SE, standard error.
FIG. 3.
FIG. 3.
Change from baseline in time spent (%) in plasma glucose ranges from baseline to week 4 in the ITT population. (A) Metformin stratum. (B) Insulin stratum. The arrows denote the percentages of time with glucose <70 mg/dL. DAPA, dapagliflozin; ITT, intention-to-treat; PBO, placebo.

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