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Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal
function
C.D. Sjöström1, P.J. Greasley1, J. Xu2, H.J.L. Heerspink3;
1
AstraZeneca, Gothenburg, Sweden, 2AstraZeneca, Gaithersburg, USA, 3Department of Clinical
Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen,
Netherlands.
Background and aims: Sodium glucose co-transporter 2 inhibition with dapagliflozin decreases HbA1c,
body weight, blood pressure and albuminuria (urine albumin-to-creatinine ratio [UACR]). Dapagliflozin
is also associated with small, predictable increases in haematocrit, likely related to osmotic diuresis. Prior
studies suggest that the HbA1c lowering effects of dapagliflozin attenuate at lower estimated glomerular
filtration rate (eGFR). However, effects on other cardiovascular risk factors at different eGFR levels are
incompletely understood.
Materials and methods: This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c,
body weight, systolic blood pressure, haematocrit and UACR with placebo (N=2,178) or dapagliflozin 10
mg (N=2,226) over 24 weeks in patients with type 2 diabetes, according to baseline eGFR (eGFR ≥45 to
<60; eGFR ≥60 to <90; eGFR ≥90 mL/min/1.73m2).
Results: The HbA1c lowering effects of dapagliflozin were smaller at lower baseline eGFR levels
(Table). However, the effects of dapagliflozin on body weight and systolic blood pressure were similar
regardless of baseline eGFR. Moreover, among individuals with baseline UACR of ≥30 mg/g, the greatest
reduction in UACR was observed in patients with an eGFR of ≥45 to <60 mL/min/1.73m2, despite similar
median values at baseline. Furthermore, dapagliflozin-induced volume contraction (as estimated by
changes in haematocrit) was equal across eGFR subgroups, despite lower urinary glucose excretion in
patients with low renal function. Adverse events occurred more frequently in the lowest eGFR subgroup;
this was true for both dapagliflozin and placebo treated patients.
Conclusion: In conclusion, dapagliflozin was associated with favourable effects on a number of renal and
cardiovascular risk factors, including reductions in body weight, systolic blood pressure and UACR,
regardless of baseline eGFR. These effects, in conjunction with the finding of similar volume contraction
independent of renal function, suggest that effects of dapagliflozin are partly mediated via non-glucosuria
dependent mechanisms. Such a mechanism could potentially be an increase in sodium excretion.
Collectively, these results suggest that dapagliflozin may confer renal and cardiovascular protection in
subjects with type 2 diabetes and low eGFR.
Clinical Trial Registration Number: NCT 00528372, NCT00528879, NCT00683878, NCT00859898,
NCT00680745, NCT00673231, NCT00984867, NCT00855166, NCT01031680, NCT01042977,
NCT00663260
Supported by: AstraZeneca
Disclosure: C.D. Sjöström: Employment/Consultancy; AstraZeneca. Stock/Shareholding; AstraZeneca.