Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

Literature - Petrykiv S, Sjöström DC, Greasley PJ, et al. - Clin J Am Soc Nephrol 2017; published online ahead of print

Background

Dapagliflozin, an SGLT2 inhibitor, improves glycaemic control by decreasing renal glucose re-absorption in the kidneys and increasing urinary glucose excretion. This additionally leads to decreases in body weight, blood pressure, uric acid and albuminuria [1,2]. However, in patients with a reduced estimated glomerular filtration rate (eGFR) the increase in urinary glucose excretion and the decrease of hemoglobin A1c (HbA1c) is lowered compared with patients with preserved renal function [3,4]. This has led to a recommendation not to use SGLT2 inhibitors in patients with impaired renal function, although it is not clear whether effects of SGLT2 inhibition on other renal and cardiovascular risk markers also depend on eGFR.

In this pooled analysis of 11 randomised, controlled phase 3 clinical trials of 24-week duration, the effect of dapagliflozin on multiple renal and cardiovascular risk markers as a function of eGFR was evaluated in patients with type 2 diabetes. Moreover, it was assessed whether changes in systolic blood pressure (SBP) and body weight during dapagliflozin treatment were parallel to changes in HbA1c in patients with different eGFR levels.

Main results

• Out of 4404 patients, 1394 had an eGFR ≥90 ml/min per 1.73 m2, 2484 had an eGFR between ≥60 and<90 ml/min per 1.73 m2, and 526 had an eGFR between ≥45 and <60 ml/min per 1.73 m2.
• Patients with an eGFR between ≥45 and <60 ml/min per 1.73 m2 at baseline were older, more likely to be women, had a higher body weight and a longer duration of diabetes mellitus.
• After 24 weeks of therapy, the placebo-corrected reduction in urinary glucose-to-creatinine ratio with dapagliflozin was progressively smaller in patients with eGFR ≥45 and<60 ml/min per 1.73 m2 compared with patients with eGFR ≥60 and <90 ml/min per 1.73 m2 and patients with eGFR ≥90 ml/min per 1.73 m2.
• Compared with placebo, reductions in HbA1c after 24 weeks of treatment with dapagliflozin in the eGFR subgroups were 0.6%, 0.5% and 0.3% (P interaction <0.001).
• Compared with placebo, 24 weeks of treatment with dapagliflozin led to similar SBP changes in the eGFR subgroups: 23.4 mmHg (95% CI: 24.6 - 22.1), 22.6 mmHg (95% CI: 23.6 - 21.6), and 24.3 mmHg (95% CI: 26.8 - 21.8).
• Compared with placebo, reductions in albuminuria, haematocrit, bicarbonate, body weight, pulse pressure and uric acid were similar between eGFR subgroups.
• Compared with placebo, dapagliflozin caused an initial eGFR decrease in each subgroup. At week 4, the placebo-corrected changes in eGFR were 22.1 ml/min per 1.73m2 (95% CI: 23.5-20.7), 23.0 ml/min per 1.73m2 (95% CI: 23.7-22.2) and 22.9 ml/min per 1.73m2 (95% CI: 24.3-21.6).
• Weak correlations between changes in HbA1c and changes in SBP or body weight were observed in all eGFR subgroups.
• A higher overall rate of adverse events and serious adverse events was observed in patients in the lowest eGFR group, but this was true for both the placebo and dapagliflozin groups.

Conclusion

References

Find this article online at Clin J Am Soc Nephrol