To the Editor: There is a growing body of evidence that sodium-glucose co-transporter
2 (SGLT2) inhibition may confer a renoprotective effect. This beneficial renal effect
is thought to be achieved by mechanisms associated with reduced glucose and sodium
reabsorption in the proximal tubule leading to decreased intra-glomerular pressure
through the tubuloglomerular feedback mechanism [1]. In addition, reduced glucose
trafficking through the proximal tubular cells [2] may lead to decreased oxidative
stress, inflammation and tubulointerstitial fibrosis. Limiting proximal tubular reabsorption
and, thus, reducing hyperfiltration is an important therapeutic target, since glomerular
hyperfiltration is a potential driver of renal disease progression in type 2 diabetes
[1]. Furthermore, changes in albuminuria predict morbidity and mortality, as well
as cardiovascular and renal outcomes in patients with type 2 diabetes [3], and a short-term
beneficial effect of dapagliflozin on albumin excretion has been reported [4].
The efficacy and safety of dapagliflozin in 252 patients with type 2 diabetes and
moderate renal impairment has previously been assessed in a paper by Kohan and colleagues
[5] . We conducted a post hoc analysis of data from this study to examine the long-term
effects of dapagliflozin on urinary albumin/creatinine ratio (UACR) in patients with
UACR ≥3.4 mg/mmol (≥30 mg/g) at baseline. We also examined whether changes in UACR
occur independently of sex and changes in HbA1c, BP, uric acid and estimated GFR (eGFR).
Our post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD)
and increased albuminuria (≥3.4 mg/mmol). Patients were randomised to dapagliflozin
10 mg (n = 56), dapagliflozin 5 mg (n = 53) or placebo (n = 57). Institutional review
boards or independent ethics committees approved the protocol. Patients provided written
informed consent.
Percentage change in UACR (with/without adjustments for sex and changes in HbA1c,
systolic and diastolic BP, uric acid and eGFR), overall adverse events (AEs), AEs
of special interest (AEs of renal function and volume reduction based upon a predefined
list of preferred terms) and changes in eGFR, HbA1c, body weight and BP were assessed
up to Week 104 and included data after rescue. UACR was measured at each visit of
the 104-week treatment period using standard, fasting, untimed (‘spot’) morning urine
samples. All samples were handled using a central laboratory procedure (Quintiles
Laboratories, www.quintiles.com).
The analyses included all randomised patients with UACR ≥3.4 mg/mmol. Mean change
from baseline value and 95% CI were derived using the longitudinal repeated measures
mixed model with fixed terms for treatment, study week, strata (pre-enrolment anti-hyperglycaemic
therapy was defined as: insulin [INS] ± another anti-hyperglycaemic medication or
sulfonylurea [SU] ± anti-hyperglycaemic except INS or thiazolidinedione-based regimen
except SU or INS or any anti-hyperglycaemic agent[s] not previously described or no
background anti-hyperglycaemic medication) study week-by-treatment interaction as
well as the fixed covariates of baseline and baseline-by-week interaction. The model
also included an indicator variable to indicate if rescue had occurred at each visit.
UACR values were log transformed (using the natural log) and then exponentiated back
to the original scale. The shift in albuminuria status was assessed from baseline
to Week 104.
Adverse event data were summarised using descriptive statistics. All analyses for
both safety and efficacy variables also included data from patients who had received
glycaemic rescue therapy. Patients received open-label rescue therapy with an anti-hyperglycaemic
agent (except metformin) if pre-defined rescue criteria were exceeded. Changes in
antihypertensive medications were not controlled for in this study. Baseline characteristics
were largely comparable across groups (electronic supplementary material [ESM] Table
1). Median (range) UACR was 20.2 (3.6–541.5), 44.9 (3.5–561.6) and 20.3 (3.4–1046.6)
mg/mmol in the dapagliflozin 10 mg, 5 mg and placebo groups, respectively.
Placebo-corrected UACR reductions (95% CI) of −57.2% (−77.1, −20.1) and −43.8% (−71.0,
9.0) occurred in the dapagliflozin 10 mg and 5 mg groups, respectively, at 104 weeks
(Fig. 1a). UACR measurements were available for 29, 20 and 25 patients in the dapagliflozin
10 mg, 5 mg and placebo groups, respectively, at 104 weeks. After adjusting for sex
and changes in BP, HbA1c, eGFR and uric acid, placebo-corrected reductions (95% CI)
of −53.6% (−75.5, −12.1) and −47.4% (−73.7, 5.3) were observed in the dapagliflozin
10 mg and 5 mg, respectively (ESM Fig. 1), indicating that the renal effects of dapagliflozin
were largely independent of changes in these variables.
Fig. 1
Adjusted mean changes (95% CI) in (a) UACR, (b) HbA1c, (c) body weight and (d) systolic
BP, for dapagliflozin (DAPA) 10 mg, DAPA 5 mg and PBO, over 104 weeks. Mean change
from baseline data (95% CI) were derived using the longitudinal repeated measures
mixed model with fixed terms for treatment, study week, strata (pre-enrolment anti-hyperglycaemic
therapy) study week-by-treatment interaction, as well as the fixed covariates of baseline
and baseline-by-week interaction. The model also included an indicator variable to
indicate if rescue had occurred at each visit. (a) Adjusted mean change in UACR at
Week 104 for DAPA 10 mg: −43.9 (−64.3, −12.0); DAPA 5 mg: −26.4 (−55.0, 20.5) and
PBO: 31.0 (−19.0, 111.9). (b) Adjusted mean change in HbA1c at Week 104 for DAPA 10 mg:
−0.8 (−1.2, −0.4); DAPA 5 mg: −0.5 (−0.9, −0.1) and PBO: −0.4 (−0.8, 0.0). (c) Adjusted
mean change in body weight at Week 104 for DAPA 10 mg: −1.6 (−3.5, 0.4); DAPA 5 mg:
−1.0 (−2.9, 0.8) and PBO: 2.8 (0.8, 4.8). (d) Adjusted mean change in systolic BP
at Week 104 for DAPA 10 mg: −7.6 (−13.3, −1.9); DAPA 5 mg: 0.1 (−6.6, 6.3) and PBO:
0.6 (−5.6, 6.9). Blue triangles, dapagliflozin 10 mg; red squares, dapagliflozin 5 mg;
grey circles, placebo. BL, baseline; DAPA, dapagliflozin; PBO, placebo; SBP, systolic
blood pressure
Compared with placebo, more patients in the dapagliflozin 10 mg and 5 mg groups shifted
to a lower UACR category (33.9 and 39.6%, respectively, vs 15.8% with placebo) and
fewer progressed to a higher UACR category (14.7% and 4.3% respectively, vs 27.3%
with placebo) (ESM Fig. 2). Overall, 17.8%, 18.9% and 7.0% of patients improved to
normoalbuminuria status in the dapagliflozin 10 mg, 5 mg and placebo groups, respectively.
There was an initial decrease in eGFR within the first 4 weeks of dapagliflozin therapy
with no further decline over the 104 weeks, whereas the placebo-treated patients showed
a gradual decline over the entire study period (ESM Fig. 3).
Dapagliflozin 10 mg and 5 mg groups showed placebo-corrected HbA1c reductions (95%
CI) of −0.43% (−0.95, 0.10) (−4.7 mmol/mol [−10.4, 1.1]) and −0.11% (−0.65, 0.42)
(−1.2 mmol/mol [−7.1, 4.6]), respectively, at 104 weeks (Fig. 1b). Dapagliflozin 10 mg
and 5 mg groups also showed placebo-corrected reductions (95% CI) of −3.9 kg (−6.4,
−1.3) and −4.4 kg (−7.0, −1.8) in weight (Fig. 1c). Placebo-corrected reductions (95%
CI) in systolic BP were numerically greater with dapagliflozin 10 mg (−8.3 mmHg [−16.2,
−0.3]) vs dapagliflozin 5 mg (−0.8 mmHg [−9.2, 7.7]) (Fig. 1d). Placebo-corrected
reductions (95% CI) in uric acid were −12.5 (−47.0, 22.0) and −35.1 (−70.8, 0.6) μmol/l
in the dapagliflozin 10 mg and 5 mg groups, respectively (data not shown).
Renal AEs were more common in the dapagliflozin 10 mg treated patients (10.7%) vs
those on dapagliflozin 5 mg (1.9%) or placebo (3.5%); these events were mostly associated
with increased creatinine (ESM Table 2). There was no increase in serious AEs of renal
function in the dapagliflozin 10 mg and 5 mg groups (1.8% and 1.9%, respectively)
vs placebo (1.8%) (ESM Table 2). AEs of volume reduction were balanced across groups
(8.9%, 9.4% and 7.0% in the dapagliflozin 10 mg, 5 mg and placebo groups, respectively).
One serious AE of volume reduction (syncope) was reported in the dapagliflozin 10 mg
group. The most common AEs leading to discontinuation were related to hyperkalaemia,
with a greater frequency noted with placebo vs dapagliflozin (ESM Table 2).
A limitation of this analysis is that it is a post hoc analysis with a relatively
small sample size. Nevertheless, reductions in albuminuria, along with an indication
of a long-term delay in worsening eGFR suggest that dapagliflozin may have a favourable
effect on preventing/delaying progression of renal disease. Moreover, recently published
data have shown dapagliflozin-induced reductions in albuminuria at 12 weeks in patients
receiving renin-angiotensin system blockade therapy [4]. This hypothesis is further
supported by a recent empagliflozin trial, that showed significant improvements in
hard renal outcomes in patients with type 2 diabetes, cardiovascular disease and various
degrees of CKD [6].
In conclusion, dapagliflozin reduced UACR over two years in individuals with type
2 diabetes and stage 3 CKD, without increases in serious renal AEs. The efficacy and
safety of dapagliflozin in individuals with type 2 diabetes, albuminuria and moderate
renal impairment is being further evaluated in an ongoing study (NCT02547935). Other,
long-term trials of SGLT2 inhibitors exploring renal endpoints (NCT01989754, NCT02065791,
NCT01730534) are underway to help to further characterise their potential renal benefits
in type 2 diabetes.
Trial registration: ClinicalTrials.gov NCT00663260
Funding: This study was funded by AstraZeneca
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM
(PDF 165 kb)