Abstract
Introduction
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to reduce proteinuria and disease progression in people with chronic kidney disease (CKD), but data in Fabry disease (FD) are scant. This prospective, multicenter study evaluated the 12-month effects of dapagliflozin 10 mg/dL on albuminuria, proteinuria, and renal function in patients with FD and albuminuric CKD.
Methods
Adults with FD and albuminuric CKD (estimated glomerular filtration rate [eGFR] ≥ 25 ml/min) despite stable enzyme replacement therapy (ERT) or migalastat and maximally tolerated dose of renin-angiotensin system inhibitors (RAS-i) were included. Proteinuria, urinary albumin-to-creatinine ratio (UACR), eGFR, and blood pressure were assessed 12 months before dapagliflozin initiation (T0), at treatment initiation (T1), and at 12-month follow-up (T2).
Results
Sixteen patients were enrolled. After 12 months of dapagliflozin, UACR and 24-hour proteinuria decreased by 47.6% (300.1 [interquartile range, IQR: 106.5–856.1] mg/g [T1] vs. 142.5 [IQR: 60.7–415.7) mg/g [T2]; P = 0.01) and 22.2% (0.45 [IQR: 0.31–1.67] g/d [T1] vs. 0.35 [IQR: 0.18–1.42] g/d [T2]; P < 0.001), respectively. Mixed-effects model analysis confirmed the effect of dapagliflozin on reducing 24-hour proteinuria (P < 0.001), after adjustment for age, sex, eGFR, FD phenotype and ERT/migalastat treatments. eGFR remained stable (63.50 [SD: 25.13] ml/min per 1.73 m2 [T1] vs. 64.31 [SD: 26.40] ml/min per 1.73 m2 [T2]; P = 0.65), contrasting with annual decline (−5.63 [SE: 1.78] ml/min per 1.73 m2) during T0 to T1 period, adjusting for sex, age, FD phenotype, ERT/migalastat treatments and 24-hour proteinuria. Eight out of 9 fast renal progressor patients achieved an annual eGFR slope ≤ 3 ml/min during the T1 to T2 period.
Conclusion
this preliminary evidence shows that dapagliflozin was associated with reduction in albuminuria, proteinuria, and eGFR decline in patients with FD and albuminuric CKD receiving ERT or migalastat and RAS-i over 12 months.
Keywords: ERT, GFR, migalastat, proteinuria, RAS-i, SGLT2 inhibitors
Graphical abstract
FD is an X-linked lysosomal storage disorder caused by pathogenic mutations in the GLA gene, resulting in a deficiency of the enzyme alpha-galactosidase and progressive accumulation of globotriaosylceramide in multiple organs, including the kidneys.1 Renal involvement, characterized by reduced glomerular filtration rate and proteinuria, is a major clinical feature.2,3 Pathologically, globotriaosylceramide deposition in glomerular podocytes contributes to foot processes effacement,4 leading to urinary protein loss.5 Wanner et al.6 demonstrated that proteinuria is a key risk factor for the progression of kidney damage in both male and female patients with FD, emphasizing the need for effective management strategies
Disease-specific treatments, such as enzyme replacement therapy (ERT) and chaperone therapy, have shown limited efficacy in reducing proteinuria and preserving renal function in FD, particularly in patients with 24-hour proteinuria > 1 g.7,8 Notably, ERT has not consistently shown a significant impact on proteinuria.9
Supportive treatments, particularly RAS-i (i.e., angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), are the cornerstone of renal protection in CKD.10 More recently, SGLT2 inhibitors have emerged as an adjunctive therapy for proteinuria reduction and prevention of progressive eGFR loss across various CKD etiologies.11, 12, 13
Kidney Disease Improving Global Outcomes 2024 guidelines recommend the combined use of SGLT2 inhibitors and RAS-i in patients with CKD and proteinuria, irrespective of comorbidities (i.e., diabetes).14 However, clinical data on their use in patients with FD are scant.15, 16, 17
To address this gap, we investigated the effects of dapagliflozin, an SGLT2 inhibitor, in patients with FD and CKD not on dialysis, focusing primarily on albuminuria and proteinuria reduction and secondarily on kidney disease progression and clinical FD stability.
Methods
The DEFY (Dapaglifozin on albuminuria in ckd patiEnts with FabrY disease) study was a multicenter, prospective, observational study conducted across nephrology and internal medicine units in 7 Italian cities.18 Patients were enrolled between January 1 and April 30, 2023.
Inclusion criteria were as follows: (i) male or female subjects aged ≥ 18 years; (ii) with CKD not on dialysis, (iii) a confirmed genetic diagnosis of FD, (iv) persistent UACR (≥ 30 mg/g) and/or proteinuria (≥ 150 mg/24 h) for ≥ 6 months despite treatment with a stable dose of ERT or migalastat for ≥ 12 months, and (v) used angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to the maximum tolerated dosage for ≥ 6 months. Patients who used immunosuppressive therapy, with type 1 diabetes mellitus, eGFR < 25 ml/min per 1.73 m2, and recurrent urinary tract infections (≥ 3 within a year)19 were excluded.
This investigation was conducted according to the Helsinki Declaration and approved by the Hospital Ethics Committee of the University Hospital of Padova (Ref No. 5499/AO/22). Informed consent was obtained from all participants after providing them with adequate information about the study.
Dapagliflozin was taken orally at a dose of 10 mg/dL. Data were collected at 3 time points: 12 months prior to dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up).
At each time point, demographic data (i.e., age, sex), medical history (i.e., comorbidities, medications, underlying kidney disease), and clinical parameters (i.e., systolic and diastolic blood pressure, heart rate, height, weight, body mass index) were recorded.
Biochemical data (i.e., eGFR, creatinine, urea, hematocrit, hemoglobin, fasting glucose, sodium, potassium, calcium, phosphorus, uric acid, total proteins, vitamin D, parathormone, brain natriuretic peptide, troponin I, as well as the UACR from the first morning urine sample and the 24-hour urinary protein excretion) were collected.
Body mass index was calculated as weight (kg) divided by height squared (m2), whereas eGFR using the CKD-Epidemiology Collaboration equation. Kidney disease progression was defined as a decline in eGFR > 3 and 2.5 ml/min per 1.73 m2/yr in males and females, respectively.20
The Fabry Stabilization Index was calculated at follow-up. A Fabry Stabilization Index score < 20% indicates clinical stability by comparing changes in relevant clinical parameters between 2 consecutive multidisciplinary evaluations.21
Statistical Analysis
Statistical analyses were performed using SPSS Statistics version 29 (IBM Corp, Armonk, NY). Continuous variables were presented as means and SDs or medians and IQRs, depending on data distribution assessed using histograms and QQ plots. Categorical variables were expressed as counts and percentages. Paired t test or Wilcoxon signed-rank test, and 1-way repeated-measures analysis of variance, were used as appropriate to compare continuous variables across different time points (T0, T1, and T2). No formal a priori sample size calculation was performed because of the exploratory nature of the study and the rarity of FD.
A linear mixed-effects model analysis22 was employed to assess the impact of dapagliflozin on changes in eGFR and 24-hour proteinuria, measured as the logarithm of 24-hour proteinuria (log_24h_prot), among values at 3 time-points (T0,T1, and T2). In the first model, with log_24h_prot as the dependent variable, fixed effects included time adjusted for age, sex, ERT/migalastat treatment, FD phenotype, and eGFR. Random effects included a random intercept for each subject, modelled with a variance-components covariance structure. In the second model, with eGFR as the dependent variable, fixed effects included time adjusted for age, sex, ERT/migalastat treatment, FD phenotype and log_24h_prot. Random effects included a random intercept for each subject, modelled with a variance-components covariance structure. The Satterthwaite method was used for degrees of freedom approximation, and 95% confidence intervals were calculated. To assess the robustness of the mixed-effects models, a sensitivity analysis was performed by excluding potentially influential observations. High-leverage cases were identified through regression diagnostics using Cook’s distance > 1 and leverage values > 0.5. Mixed-effects models were reestimated after excluding these cases. Statistical significance was set at P < 0.05.
Results
Patient Characteristics
Out of 51 patients with FD screened, 16 met the inclusion criteria (Figure 1). The characteristics of this cohort are summarized in Table 1. Briefly, the mean age was 54.8 (SD: 10.58) years, with 56.3% male (n = 9). Fifteen families with 12 distinct GLA mutations were represented. Most patients (n = 12) exhibited the classic Fabry phenotype,1 characterized by multiple-organ involvement in addition to nephropathy (Table 2).
Figure 1.
Flow chart of patient selection. eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; RAS-i, renin-angiotensin system inhibitors.
Table 1.
Clinical and biochemical characteristics of the sample (n = 16) at SGLT2 inhibitor (T1) initiation
| Clinical variables | Biochemical variables | ||
|---|---|---|---|
| Age, yrs | 54.8 (± 10.58)a | Serum creatinine, mg/dl | 1.31 (± 0.56)a |
| Enzymatic activity, nmol/ml/h | 7.92 (± 9.33)a | eGFR, ml/min per 1.73 m2 | 63.50 (± 25.13)a |
| Lyso-Gb3, ng/ml | 10.44 (± 8.03)a | Serum urea, mg/dl | 43.91 (± 16.61)a |
| Male, % | 56.3 | Serum hemoglobin, g/l | 13.63 (± 1.58)a |
| Caucasic, % | 93.8 | Hematocrit, % | 41.0 (± 4.15)a |
| Smoke, % | 12.5 | Serum glucose, mg/dl | 85.40 (± 10.96)a |
| Hypertension, % | 81.3 | Serum sodium, mEq/l | 140.19 (± 1.83)a |
| Diabetes, % | 6.3 | Serum potassium, mEq/l | 4.34 (± 0.35)a |
| BMI, kg/m2 | 24.51 (± 3.93)a | Serum calcium, mg/dl | 9.43 (± 0.47)a |
| Agalsidase alfa/beta, % (n) | 18.7 (3) / 75.1 (12) | Serum phosphate, mg/dl | 3.12 (± 0.83)a |
| Migalastat, % (n) | 6.2 (1) | Serum acid uric, mg/dl | 6.27 (± 1.16)a |
| Supportive therapy, % | 25-OH-vitamin D, ng/ml | 20.48 (± 5.77)a | |
| - ACE-I | 44.4 | Parathormone, pg/ml | 57.78 (± 23.56)a |
| - ARBs | 55.6 | pro-BNP, pg/ml | 489.0 (67.75 - 1141.75)b |
| Antihypertensive drugs (n) | 1.62 (± 1.02)a | Troponin I, ng/l | 32.7 (14.62 - 60.22)b |
ACE-I, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; BMI, body mass index; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate (according to Chronic Kidney Disease-Epidemiology Collaboration formula); SGLT2, sodium-glucose cotransporter 2.
Mean (± Standard Deviation).
Median (interquartile range).
Table 2.
Genetic and phenotypic characteristics of the cohort (n = 16) at initiation of SGLT2 inhibitors (T1)
| ID | Age (gender) | Mutations | Phenotype | Clinical FD manifestations | Treatment (yrs) | |
|---|---|---|---|---|---|---|
| 1 | 49 (F) | c.115delG | p.Tyr39Argfs∗60 (T39RfsX60) | Classic | CVA, CKD CW, LVH | Algasidasi alfa (16) |
| 2 | 72 (F) | c.779G>A | p.Gly260Glu (G260E) | Classic | CVA, CKD, LVH | Algasidasi beta (20) |
| 3 | 57 (F) | c.928G>C | p.Ala310Pro (A310P) | Classic | CVA, CKD, CW, LVH | Algasidasi beta (6) |
| 4 | 63 (M) | c.644A>G | p.Asn215Ser (N215S) | Late-onset | LVH, CKD | Migalastat (6) |
| 5 | 58 (F) | c.790G>T | p.Asp264Tyr (D264Y) | Classic | CVA, CKD, CW | Algasidasi beta (10) |
| 6 | 52 (F) | c.644A>G | p.Asn215Ser (N215S) | Late-onset | ANG, CVA, CKD, LVH | Algasidasi beta (3) |
| 7 | 53 (M) | c.103G>C | p.Thr35Pro (T35P) | Classic | ANG, CW, CKD, LVH | Algasidasi beta (3) |
| 8 | 63 (M) | c.644A>G | p.Asn215Ser (N215S) | Late-onset | LVH, CKD | Algasidasi alfa (3) |
| 9 | 52 (M) | c.1066C>G | p.Pro356Arg (P356R) | Classic | ANG, CVA, CW | Algasidasi beta (10) |
| 10 | 48 (M) | c.740C>G | p.Thr247Arg (T247R) | Classic | ANG, CKD, CW | Algasidasi alfa (22) |
| 11 | 53 (M) | c.740C>G | p.Thr247Arg (T247R) | Classic | ANG, CVA, CKD CW | Algasidasi beta (22) |
| 12 | 44 (M) | c.1066C>G | p.Pro356Arg (P356R) | Classic | ANG, CVA, CKD, CW | Algasidasi beta (9) |
| 13 | 41 (M) | c.508G>A | p.Gly170Ser (G170S) | Classic | ANG, CW | Algasidasi beta (4) |
| 14 | 77 (F) | c.159delC | p.Val53Serfs | Classic | CVA, CKD, LVH | Algasidasi beta (3) |
| 15 | 60 (F) | c.299G>A | p.Arg100Lys (R100K) | Classic | CW, LVH | Algasidasi beta (2) |
| 16 | 38 (M) | c.427G>A | p.Ala143Thr (A143T) | Late-onset | ANG, CKD, CVA | Algasidasi beta (5) |
ANG, angiokeratomas; CKD, chronic kidney disease; CVA, cerebrovascular accident; CW, corneal whirls; F, female; LVH, left ventricular hypertrophy; M, male; SGLT2, sodium-glucose cotransporter 2.
Data Before Initiation of Dapagliflozin (T1)
Patients were treated with a stable dose of agalsidase alfa (18.7%), agalsidase beta (75.1%), or migalastat (6.2%) for a mean duration of 9 (SD: 7.12) years (median: 6 years). Therapy was started after a mean of 0.93 years (SD: 0.99) following FD diagnosis. All patients received stable RAS-i therapy, with 44.4% on angiotensin-converting enzyme inhibitors and 55.6% on angiotensin receptor blockers.
Individual values of 24-hour proteinuria, eGFR, serum creatinine, and systolic or diastolic blood pressure at pretreatment (T0), at treatment initiation (T1), and at the end of the follow-up period (T2) are shown in Supplementary Table S1, Figure 2, Figure 3, Table 3, and Table 4.
Figure 2.
Log (24-h proteinuria) levels for individual patients (n = 16) at 12 months before dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up). Each patient is shown as an individual regression line.
Figure 3.
eGFR levels for individual patients (n = 16) at 12 months prior to dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up). Each patient is shown as an individual regression line. eGFR, estimated glomerular filtration rate.
Table 3.
Mixed-effects model estimates of change in log 24-h proteinuria over time (T0, −12 months; T1, dapagliflozin initiation; T2, +12 months), adjusted for age, sex, FD phenotype, ERT/migalastat treatment, and eGFR
| Parameter | Estimate means | Std. Error | df | Sig. | 95% CI |
|
|---|---|---|---|---|---|---|
| LB | UB | |||||
| Time 0–1 | 0.06 | 0.10 | 39.32 | 0.593 | −0.15 | 0.26 |
| Time 0–2 | 0.39 | 0.11 | 45.38 | < 0.001a | 0.17 | 0.61 |
| Time 1–2 | 0.34 | 0.10 | 35.02 | 0.001a | 0.14 | 0.53 |
Dependent variable: log 24-h proteinuria.
CI, confidence interval; eGFR, estimated glomerular filtrate rate; ERT, enzime replacement therapy; FD, Fabry Disease; LB, lower bound; UB, upper bound.
Statistically significance.
Table 4.
Mixed-effects model estimates of change in eGFR over time (T0, −12 months; T1, dapagliflozin initiation; T2, +12 months), adjusted for age, sex, FD phenotype, ERT/migalastat treatment and 24-h proteinuria
| Parameter | Estimate means | Std. error | df | Sig. | 95% CI |
|
|---|---|---|---|---|---|---|
| LB | UB | |||||
| Time 0–1 | 5.65 | 1.78 | 39.81 | 0.003a | 2.03 | 9.26 |
| Time 0–2 | 4.83 | 2.35 | 47.99 | 0.045a | 0.12 | 9.55 |
| Time 1–2 | −0.81 | 2.04 | 40.83 | 0.692 | −4.93 | 3.31 |
Dependent Variable: eGFR
CI, confidence interval; eGFR, estimated glomerular filtrate rate; ERT, enzime replacement therapy; FD, Fabry Disease; LB, lower bound; UB: upper bound.
Statistically significance.
Compared with enrolment (T0), there was a statistically significant decline in eGFR (69.43 [SD: 24.57] ml/min per 1.73 m2 [T0] vs. 63.50 [SD: 25.13] ml/min per 1.73 m2 [T1], P = 0.002), with an annual least-squares mean (± SE) eGFR slope of −5.63 (± 1.78) ml/min per 1.73 m2 during the pretreatment period. At T1, 9 of 16 patients (56.3%) met the criteria for renal progression.
No significant change was observed in 24-hour proteinuria (0.50 [IQR: 0.32–1.40] g/d [T0] vs. 0.45 [IQR: 0.31–1.67] g/d [T1]; P = 0.84) with a stable annual least-squares mean (± SE) change in log_24h_prot (6.52 ± 0.20 g/d [T0] vs. 6.46 ± 1.98 g/d [T1]; P = 0.59).
Follow-Up Data (T2) After Dapagliflozin Therapy
After 12 months of add-on dapagliflozin therapy, a significant reduction in 24-hour urinary protein excretion was observed, from 0.45 [IQR: 0.31–1.67] g/d at T1 to 0.35 [IQR: 0.18–1.42] g/d at T2 (P < 0.001). Mixed model analysis showed that dapagliflozin significantly reduced the annual change in log_24h_prot (P = 0.001) over 12 months, independent of eGFR, sex, age, FD phenotype and ERT/migalastat treatment (Table 3). UACR decreased by 120.1 [IQR: 239.5–33.1] mg/g, from 300.1 [IQR: 106.5–856.1] mg/g at T1 to 142.5 [IQR: 60.7–415.7] mg/g at T2 (P = 0.01).
Serum creatinine showed a slight, nonsignificant increase (from 1.25, SD: 0.41 [T1] to 1.27, SD: 0.52 mg/dl [T2]; P = 0.64). Similarly, eGFR remained stable over the 12 months (T1: 63.50, SD: 25.13 ml/min per 1.73 m2 vs. T2: 64.31 SD: 26.40 ml/min per 1.73 m2; P = 0.65).
The least-squares mean (± SE) eGFR slope from T1 to T2 (1.12 ± 1.78 ml/min per 1.73 m2/yr) was less negative than from T0 to T1 (−5.63 ± 1.78 ml/min per 1.73 m2/yr) after adjustment for age, sex, FD phenotype, ERT/migalastat treatment and 24-hour proteinuria (Table 4), resulting in a between-period difference of 6.75 [SD: 12.55] ml/min per 1.73 m2/yr (95% confidence interval: [0.06–13.44]; P < 0.05).
Sensitivity analysis excluding high-leverage cases confirmed the robustness of the mixed-model results for eGFR slope and log_24h_proteinuria.
Furthermore, no significant changes were observed in systolic blood pressure (129.68 [SD: 15.96] [T1] vs. 127.81 [SD: 12.77] [T2] mm Hg; P = 0.25) or diastolic blood pressure (78.12 [SD: 9.63] [T1] vs. 76.87 [SD: 7.50] [T2] mm Hg; P = 0.62) were found with no reduction dose in RAS-i therapy.
Clinical stability was further confirmed by Fabry Stabilization Index scores, which remained < 20% in all patients throughout follow-up. Dose of ERTs or migalastat remained stable over time. One patient reported a urinary tract infection, but no patients required discontinuing dapagliflozin therapy during the 12-month observational period.
Discussion
This prospective multicenter study describes the significant effects of the SGLT2 inhibitor, dapagliflozin, on albuminuria, 24-hour proteinuria, and renal function in patients with FD and albuminuric CKD already receiving ERT or migalastat and maximally tolerated doses of RAS-i.
Over a 12-month follow-up period, dapagliflozin was associated with a 22.2% reduction in 24-hour proteinuria, regardless of baseline eGFR, and a 47.6% decrease in albuminuria. These reductions in proteinuria and albuminuria appeared independent of blood pressure effects, because no significant changes were observed. Together with other reports on the effects of SGLT2i in FD,15,16,23 our findings are consistent with the strong evidence obtained in broader cohorts of people with diabetic and nondiabetic CKD.11, 12, 13
The approximately 50% reduction in UACR observed in our FD cohort was consistent with the percentage reduction observed in the 4-month follow-up in patients with CKD enrolled in the DAPA-CKD trial.12 By comparison, our study had a lower mean basal UACR than DAPA-CKD (UACR: ∼520 mg/g vs. ∼950 mg/g, respectively). Notably, a 30% UACR reduction has been approved by the US Food and Drug Administration as a surrogate end point for clinically meaningful drug effects in people with CKD and is predictive of long-term benefits on kidney function and damage.24,25
Similarly, a recent real-world Italian study involving 1724 patients with a low basal albuminuria (500 mg/d [IQR: 225–1425]) reported a 25.1% reduction in albuminuria (320 mg/d [IQR: 100–900]) with dapagliflozin over a follow-up of 4.1 (SD: 1.4) months.11 In line with these results, the EMPA-KIDNEY trial reported a 19% reduction in albuminuria with empagliflozin in a large CKD population with a lower baseline median UACR (∼331 mg/g).13
These results suggest that dapagliflozin may provide additive antiproteinuric effects when combined with RAS blockade, even in CKD secondary to FD. Mechanistically, RASi decreases intraglomerular pressure by vasodilation of the efferent arteriole, whereas SGLT2 inhibitors restore tubulo-glomerular feedback and reduce hyperfiltration by vasoconstriction of the afferent arteriole.10 However, the comprehensive renal effects of dapagliflozin in patients with CKD remain incompletely defined. Beyond their established hemodynamic effects, SGLT2 inhibitors may exert additional renoprotective actions through modulation of oxidative stress and inflammation pathways.26 For instance, Zaibi et al.27 showed that dapagliflozin reduced reactive oxygen species generation in human proximal tubular epithelial cells. In FD, globotriaosylceramide accumulation promotes increased reactive oxygen species production, endothelial dysfunction, atherosclerosis, and chronic inflammation, all of which contribute to CKD progression.28 Dapagliflozin may partially counteract these mechanisms, thereby complementing disease-specific therapies.
A remarkable finding is that mean eGFR remained stable (1.12 [SE: 1.78] ml/min per 1.73 m2/yr) over the 12-month follow-up after starting dapagliflozin in patients who had a mean eGFR slope of −5.63 [SE: 1.78] ml/min per 1.73 m2 in the prior 12 months. Considering single cases, 8 out of 9 patients who fulfilled criteria for renal progression at T1,20 achieved stabilization at T2.
Compared with previous studies reporting an average eGFR slope of approximately −2 ml/min per 1.73 m2/yr in the FD population,29, 30, 31 our findings may be explained by the inclusion of patients with more advanced nephropathy and/or random variability due to the limited sample size. However, if confirmed in larger cohorts with longer follow-up, it may suggest a renal protection potential greater than expected that, until now, has been a prerogative of ERT in Fabry nephropathy.
Our data are consistent with those of a recent retrospective case-control study involving 10 patients with FD. Specifically, the annual eGFR decline significantly improved from −4.38 ml/min per 1.73 m2/yr (IQR: −10.57 to 0.59) to 1.25 (IQR: −4.16 to 9.74) after initiation of SGLT2 inhibitor therapy (P < 0.05).23 Notably, the initial eGFR decline (typically with SGLT2 inhibitor therapy in CKD) was not observed in this FD cohort.
Further, our findings align with DAPA-CKD,12 which reported a significantly slower annual eGFR decline with dapagliflozin than with placebo (−1.67 [SE: 0.11] and −3.59 [SE: 0.11] ml/min per 1.73 m2, respectively). Furthermore, Fabry Stabilization Index scores remained below the 20% threshold in all patients throughout the study, indicating clinical stability beyond renal end points.
Regarding safety, no patients discontinued dapagliflozin due to adverse effects such as ketoacidosis and hypoglycemia during the 12-month follow-up. Notably, only 1 patient reported an episode of urinary tract infection, which was successfully treated with oral antibiotics. Although this contrasts with the higher discontinuation rate reported in randomized controlled trials (12.7%) among CKD populations,12 it is more consistent with real-world studies (2%).11 This discrepancy may be explained by differences in follow-up duration, patient selection, and the close clinical monitoring provided in our study.
We wish to acknowledge some study limitations. First, the small sample size and the lack of a control group restrict the generalizability of our findings and the assessment of secondary end points such as body composition, oxidative stress, and inflammation, which may be affected by SGLT2 inhibitors.32, 33, 34 Propensity-matched or synthetic control analyses were not feasible because of the small and heterogeneous cohort, further limiting causal interpretation. Although randomized controlled trials are warranted to confirm our results, such trials are seldom feasible in rare diseases because of economic and logistical constraints. Second, the follow-up period was relatively short (12 months) and no intermediate eGFR, proteinuria, or albuminuria data between time points were recorded. However, a planned 24-month follow-up visit will provide additional longitudinal data. Third, cardiovascular data obtained from electrocardiography and echocardiography was not analyzed; however, a secondary analysis is ongoing. Finaly, several clinically relevant parameters, including renal ultrasound findings35,36 and physical activity levels,37, 38, 39 were not collected,40 although they may influence renal outcomes in FD.
Conclusion
This study provides preliminary evidence on the antiproteinuric efficacy of dapagliflozin when added to RAS blockade and specific treatment in patients with FD and albuminuric CKD over 12 months. Notably, the reduction in proteinuria was independent of blood pressure changes and baseline eGFR. Furthermore, dapagliflozin was associated with a slower progressive loss of kidney function.
These findings suggest that dapagliflozin may be a valuable adjunctive therapy in managing FD nephropathy and may encourage its broader use in clinical practice. However, larger, prospective studies are needed to identify the long-term renal (and potential nonrenal) benefits of SGLT2 inhibitors in the FD population.
Disclosure
All the authors declared no competing interests.
Data Availability Statement
The data that support the findings of this study are available from the corresponding authors upon reasonable request. Individual-level data and all relevant aggregated data are included within the manuscript and its supplementary materials.
Author Contributions
Conceptualization was by YB, NV, GM, and GC. The investigation was by FB, FC, LM, LFS, FKM, ST, ER, CC, LL, AS, LZ, and PE. Formal analysis was by YB. Writing—original draft preparation was by FB. Writing—review and editing was by YB. Supervision was by FV, NV, FN, GPF, DG, and AP. Validation was by GC, GG, and GM. All the authors have read and agreed to the published version of the manuscript.
Footnotes
Table S1. Individual modifications of estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure at 12 months before dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up).
STROBE Checklist.
Contributor Information
Giacomo Marchi, Email: giacomo.marchi@aovr.veneto.it.
Gianni Carraro, Email: gianni.carraro_01@aopd.veneto.it.
Supplementary Material
Table S1. Individual modifications of estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure at 12 months prior to dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up). STROBE Checklist.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Individual modifications of estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure at 12 months prior to dapagliflozin initiation (T0, pretreatment), at treatment initiation (T1, initiation), and 12 months after treatment initiation (T2, follow-up). STROBE Checklist.
Data Availability Statement
The data that support the findings of this study are available from the corresponding authors upon reasonable request. Individual-level data and all relevant aggregated data are included within the manuscript and its supplementary materials.