SGLT2-Inhibition in Patients With Alport Syndrome

Abstract

Introduction: Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts.

Methods: This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i. The study's primary end point was change of albuminuria in albumin/g creatinine from the start of therapy.

Results: Compared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (aged 38 ± 14 years) and had a better estimated glomerular filtration rate (eGFR, 63 ± 35 ml/min per 1.73 m²; n = 98). Maximum follow-up was 32 months. Compared to baseline, at the first 3 follow-up visits (months 1 to 3, 4 to 8, and 9 to 15) after initiation of SGLT2i therapy, a significant reduction of albuminuria in mg albumin/g creatinine (>30%) was observed. Mean loss of eGFR was 9 ± 12 ml/min per 1.73 m² almost 1 year after initiation of SGLT2i therapy (n = 35). At a total of 71 patient-years at risk, 0.24 adverse events (AEs) per patient-year on SGLT2i were reported.

Conclusion: This study indicates that, additive to renin-angiotensin system (RAS)-inhibition (RASi), SGLT2i have the potential to reduce the amount of albuminuria in patients with AS. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with AS to assess whether the observed reduction in albuminuria translates to a delay in kidney failure (KF).

Keywords: Alport syndrome; COL4; albuminuria; dapagliflozin; empagliflozin; kidney failure.

Graphical abstract

Figure 1

Albuminuria and eGFR at V1 (months 1–3). (a) Albuminuria before initiation of SGLT2i therapy (baseline; blue) and after a mean follow-up of 2 ± 1 months (V1; red) of SGLT2i therapy (P = 0.002, n = 30; geometric mean with 95% CI). (b) eGFR before initiation of SGLT2i therapy (baseline; blue) and after mean follow-up of 2 ± 1 months (V1, red) (P = 0.004, n = 62; mean with 95% CI). CI, confidence interval; eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

Figure 2

Albuminuria and eGFR at V2 (months 4–8). (a) Albuminuria before initiation of SGLT2i therapy (baseline; blue) and after a mean follow-up of 6 ± 1 months (V2; red) (P = 0.01, n = 33, geometric mean with 95% CI). (b) eGFR before initiation of SGLT2i therapy (baseline, blue) and after a mean follow-up of 6 ± 1 months (V2; red) (P < 0.001, n = 72, mean with 95% CI). CI, confidence interval; eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

Figure 3

Albuminuria and eGFR at V3 (months 9–15). (a) Albuminuria before initiation of SGLT2i therapy (baseline; blue) and after a mean follow-up of 12 ± 2 months (V3; dark red) (P = 0.032, n = 22, geometric mean with 95% CI). (b) eGFR before initiation of SGLT2i therapy (baseline; blue) and after a mean follow-up of 12 ± 2 months (V3; dark red) (P < 0.001, n = 35, mean with 95% CI). CI, confidence interval; eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

Figure 4

Correlation between amount of albuminuria at baseline and the change in eGFR after initiation of SGLT2i. Pearson’s correlation between amount of albuminuria at baseline and absolute change in eGFR at a mean follow-up of 11 ± 2 months (r = 0.821; P = <0.01; n = 20). eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

Figure 5

Change in eGFR over time after initiation of SGLT2i therapy. eGFR at baseline, V1 (months 1–3), V2 (months 4–8) and V3 (months 9–15) in 16 patients, who completed every visit from V1 to V3. eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

Figure 6

Frequency of adverse events and discontinuation of SGLT2i therapy. (a) Number of patients with observed adverse events (AEs) (white) and patients without observed AEs (dark grey) (n = 89). (b) Number of patients without (therapy continued; white) and with discontinuation of therapy with SGLT2i (therapy discontinued; dark grey) (n = 106). (c) Time to discontinuation of SGLT2i therapy in months. The reason for discontinuation in 1 patient after 7 months was not reported. SGLT2i, sodium-glucose cotransporter-2 inhibitors.