Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes

Abstract

Aims: Sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-h blood pressure (BP), body weight, plasma volume and glomerular filtration rate (GFR).

Methods: In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12 weeks of treatment.

Results: Subjects' mean age was 56 years, type 2 diabetes mellitus (T2DM) duration 6.3 years, and haemoglobin A1c (HbA1c) 7.5%. Treatment with placebo, dapagliflozin or HCTZ resulted in changes from baseline in 24-h ambulatory mean systolic blood pressure (SBP) of -0.9 (95%CI -4.2, +2.4), -3.3 (95%CI -6.8, +0.2), and -6.6 (95%CI -9.9, -3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (-10.8%; 95%CI -14.6, -6.7) relative to placebo (-2.9%; 95% CI -6.9, +1.2) or HCTZ (-3.4%; 95%CI -7.3, +0.6).

Conclusions: Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-h BP, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycaemic control.

Keywords: HbA1c; blood pressure; dapagliflozin; renal function; type 2 diabetes.

© 2013 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Mean change in 24-h, day-time and night-time ambulatory systolic blood pressure, body weight, in-office systolic blood pressure and glomerular filtration rate over the course of the study in placebo, dapagliflozin and hydrochlorothiazide groups. Data are reported as mean (± 95% CI). P, placebo; D,  dapagliflozin; H, hydrochlorothiazide.

Figure 2

Median change in 24-h systolic blood pressure and median percentage change in plasma volume and red cell mass in substudy participating subjects in the placebo, dapagliflozin and hydrochlorothiazide groups. Because of the small sample size, data are reported as median (25th and 75th percentile) in order to exclude the influence of few extreme values that drive mean changes. In two patients plasma volume change could not be measured because an end of study measurement was not available. As a result, the sample size was too small to show 2.5–97.5% percentile. P, placebo; D, dapagliflozin; H, hydrochlorothiazide.

Figure 3

Mean change in haematocrit, haemoglobin, reticulocyte count and erythropoietin over the course of the study in placebo dapagliflozin, and hydrochlorothiazide groups. Data are reported as mean (±95% CI). Because of an extreme outlier, the median concentrations (25th and 75th percentile) in erythropoietin over time are reported in the figure. Excluding the outlier and calculating the mean value provided a similar picture (data not shown). P, placebo; D, dapagliflozin; H, hydrochlorothiazide.