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Table S1. Studies included in the placebo-controlled double-blind analysis up to 24 weeks of dapagliflozin*

Description / Duration for: short term/total study (weeks) / Inclusion criteria / Renal function exclusion criteria† / ClinicalTrials.gov number(Reference)
Age (yr) / C-peptide (ng/mL) / BMI (kg/m2) / Entry HbA1c range (%, mmol/mol)
Phase 2b
Monotherapy / 12/12 / 18–79 / >1 / ≤40 / ≥7.0≤10.0, ≥53≤86 / Women: >1.4;
Men: >1.5 / NCT00263276 (9)
Phase 2b
Monotherapy
Japanese patients / 12/12 / 18–79 / ≥1 / ≤40 / ≥7.0≤10.0, ≥53≤86 / Women: >1.4;
Men: >1.5 / NCT00972244 (21)
Phase 2b
Added-on to insulin / 12/12 / 18–75 / ≥0.8 / ≤45 / ≥7.5≤10.0, ≥58≤86 / Women: >1.4;
Men: >1.5 / NCT00357370 (15)
Phase 3
Monotherapy / 24/24 / 18–77 / ≥1 / ≤45 / ≥7.0≤10.0, ≥53≤86 / Women: >1.4;
Men: >1.5 / NCT00736879 (22)
Phase 3
Initial combination with metformin / 24/24 / 18–77 / ≥1 / ≤45 / ≥7.5≤12.0, ≥58≤108 / Women: >1.4;
Men: >1.5 / NCT00643851 (24)
Phase 3
Initial combination with metformin / 24/24 / 18–77 / ≥1 / ≤45 / ≥7.5≤12.0, ≥58≤108 / Women: >1.4;
Men: >1.5 / NCT00859898 (24)
Phase 3
Added-on to sulfonylurea* / 24/48 / ≥18 / ≥1 / ≤45 / ≥7.0≤10.0, ≥53≤86 / Women: >1.4;
Men: >1.5 / NCT00680745 (12)
Phase 3
Added-on to thiazolidinedione* / 24/48 / ≥18 / ≥1 / ≤45 / ≥7.0≤10.5, ≥53≤91 / ≥2.0 or CrCL <50 mL/min / NCT00683878 (14)
Phase 3
Monotherapy* / 24/102 / 18–77 / ≥1 / ≤45 / Group 1: ≥7.0≤10.0, ≥53≤86
Group 2: ≥10.1≤12.0, ≥87≤108 / Women: >1.4;
Men: >1.5 / NCT00528372 (11)
Phase 3
Added-on to metformin* / 24/102 / Women: 55–77
Men:
30–77 / - / ≥25 / ≥6.5≤8.5, ≥48≤69 / Women: >1.4;
Men: >1.5 or CrCL <60 mL/min / NCT00855166 (23)
Phase 3
Added-on to metformin* / 24/102 / 18–77 / ≥1 / ≤45 / ≥7.0≤10.0, ≥53≤86 / Women: >1.4;
Men: >1.5 / NCT00528879 (10)
Phase 3
Added-on to insulin* / 24/104 / 18–80 / - / ≤45 / ≥7.5≤10.5, ≥58≤91 / >2.0‡ or CrCL <50 mL/min / NCT00673231 (16)

*All studies were included in the analysis up to 24 weeks, studies with the asterisks were included in the analysis up to 102 weeks.

†Serum creatinine (mg/dL) unless noted; CrCL was calculated by Cockcroft-Gault formula.

‡Or serum creatinine >1.4 mg/dL for women and >1.5 mg/dL for men receiving metformin.

Abbreviations: PBO, placebo.

Table S2. Urinary albumin to creatinine ratio shift analysis (X/N#) from baseline to Week 24 by baseline eGFR

Baseline eGFR / Up to Week 24
PBO
N=1393 / DAPA 2.5 mg
N=814 / DAPA 5 mg
N=1145 / DAPA 10 mg
N=1193
≥30 and <60 mL/min/1.73m2 / 11/107 (10.3) / 6/73 (8.2)
(p=0.6434) / 5/107 (4.7)
(p=0.1198) / 6/88 (6.8)
(p=0.3950)
≥60 and < 90 mL/min/1.73m2 / 45/748 (6.0) / 24/431 (5.6)
(p=0.7526) / 50/595 (8.4)
(p=0.0902) / 35/616 (5.7)
(p=0.7938)
≥90 mL/min/1.73m2 / 27/519 (5.2) / 24/299 (8.0)
(p=0.1078) / 33/421 (7.8)
(p=0.1003) / 29/469 (6.2)
(p=0.5057)

Data are n (%) and include data after rescue.

X is the number of patients with changing to a worse category (30−<300 mg/g (microalbuminuria); ≥ 300 mg/g (macroalbuminuria).

Includes only patients with non-missing albuminuria category at baseline and non-missing at post baseline.

The denominator is the number of treated patients in the corresponding baseline eGFR category with baseline/post baseline albuminuria category.

P-value for pairwise comparison versus placebo uses Cochran-Mantel-Haenszel test of those categories with ≥5 patients on average per group and study as stratum. In cases of <5 patients on average per group and study, but ≥5 per group, the stratum is dropped.

Abbreviations: DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo.

Table S3: Mean changes in serum creatinine (µmol/L) stratified by eGFR subgroups at 24 and 102 weeks

At 24 weeks / At 102 weeks
PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg / PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg
N* / 1393 / 814 / 1145 / 1193 / 785 / 625 / 767 / 859
Patients with baseline eGFR ≥30 and <60 mL/min/1.73m2
n* / 86 / 64 / 91 / 72 / 12 / 18 / 26 / 21
BL, mean / 103.52 / 104.67 / 105.46 / 107.58 / 105.28 / 104.75 / 108.91 / 107.05
SD / 17.91 / 18.26 / 19.18 / 20.60 / 19.09 / 18.34 / 19.63 / 21.09
Mean change / -4.60 / 0.44 / -2.65 / -5.48 / -4.86 / -2.83 / -6.90 / -11.49
SE / 1.43 / 1.95 / 1.74 / 1.99 / 3.72 / 3.40 / 3.64 / 2.70
Patients with baseline eGFR ≥60 and <90 mL/min/1.73m2
n* / 617 / 347 / 497 / 505 / 93 / 125 / 147 / 138
BL, mean / 79.91 / 80.00 / 80.44 / 79.65 / 80.18 / 80.53 / 80.89 / 79.47
SD / 12.78 / 12.40 / 12.88 / 12.68 / 12.92 / 12.40 / 12.93 / 12.63
Mean change / -1.33 / 0.00 / -0.53 / -0.18 / -2.74 / -1.24 / -2.12 / -1.50
SE / 0.36 / 0.48 / 0.40 / 0.38 / 0.96 / 0.81 / 0.80 / 0.77
Patients with baseline eGFR ≥90 mL/min/1.73m2
n* / 384 / 208 / 311 / 358 / 59 / 68 / 62 / 90
BL, mean / 63.29 / 63.47 / 62.32 / 62.50 / 63.12 / 63.47 / 62.50 / 62.23
SD / 10.36 / 10.48 / 10.47 / 10.25 / 10.26 / 10.25 / 10.63 / 10.03
Mean change / 1.86 / 2.56 / 1.41 / 1.68 / 2.12 / 3.36 / 0.71 / 1.24
SE / 0.46 / 0.45 / 0.40 / 0.40 / 0.98 / 0.96 / 0.92 / 0.85

Include data after rescue.
N* is the number of treated patients and n is the number of treated patients with non-missing baseline and week 24/102 values.
Abbreviations: BL, baseline; DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo; SD, standard deviation; SE, standard error.

Table S4. Marked laboratory abnormalities

Up to 24 weeks / Up to 102 weeks
PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg / PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg
N* / 1393 / 814 / 1145 / 1193 / 785 / 625 / 767 / 859
n* / 1381 / 814 / 1132 / 1178 / 778 / 625 / 756 / 846
Creatinine
≥1.5 times baseline / 22 (1.6) / 11 (1.4) (p=0.6532) / 22 (1.9)
(p=0.5053) / 21 (1.8)
(p=0.7100) / 17 (2.2) / 15 (2.4)
(p=0.7888) / 19 (2.5)
(p=0.6713) / 17 (2.0)
(p=0.8050)
≥221 µmol/L / 1 (0.1) / 0 (0) / 1 (0.1) / 1 (0.1) / 3 (0.4) / 0 (0) / 2 (0.3) / 2 (0.2)
BUN ≥60mg/dL or urea >21.4 mmol/L / 0 (0) / 0 (0) / 2 (0.2) / 2 (0.2) / 2 (0.3) / 0 (0) / 2 (0.3) / 2 (0.2)
Serum sodium
<130 mEq/L / 7 (0.5) / 10 (1.2)
(p=0.0625) / 7 (0.6)
(p=0.7087) / 3 (0.3)
(p=0.3082) / 5 (0.6) / 5 (0.8) / 6 (0.8) / 2 (0.3)
<120 mEq/L / 2 (0.1) / 1 (0.1) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0)
>150 mEq/L / 11 (0.8) / 13 (1.6)
(p=0.0816) / 6 (0.5)
(p=0.4175) / 15 (1.3)
(p=0.2307) / 11 (1.4) / 14 (2.2)
(p=0.2452) / 8 (1.1)
(p=0.5290) / 13 (1.5)
(p=0.8378)
Serum potassium
≤2.5 mEq/L / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0)
≥6 mEq/L / 36 (2.6) / 33 (4.1) (p=0.0606) / 32 (2.8)
(p=0.7352) / 34 (2.9)
(p=0.6658) / 31 (4.0) / 45 (7.2)
(p=0.1780) / 36 (4.8)
(p=0.7722) / 38 (4.5)
(p=0.5456)
Bicarbonate ≤13 mEq/L / 1 (0.1) / 0 (0) / 1 (0.2)† / 5 (0.4) / 0 (0) / 0 (0) / 2 (0.3) / 2 (0.2)
Serum magnesium
0.41 mmol/L / 4 (0.3) / 0 (0) / 2 (0.2) / 1 (0.1) / 4 (0.5) / 1 (0.2) / 1 (0.1) / 1 (0.1)
>1.64 mmol/L / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0)
Calcium
<1.88 mmol/L / 16 (1.2) / 9 (1.1) (p=0.9101) / 13 (1.1)
(p=0.9811) / 10 (0.8)
(p=0.4363) / 15 (1.9) / 15 (2.4)
(p=0.5437) / 18 (2.4)
(p=0.5411) / 14 (1.7)
(p=0.6780)
≥0.25 mmol/L from upper limit of normal
and ≥0.13 mmol/L from predose value / 5 (0.4) / 0 (0) / 1 (0.1) / 1 (0.1) / 3 (0.4) / 1 (0.2) / 1 (0.1) / 3 (0.4)
Inorganic phosphorus
≤0.58 mmol/L if age 17-65 yr or ≤0.68 mmol/L if age>66 yr / 2 (0.1) / 1 (0.1) / 1 (0.1) / 0 (0) / 3 (0.4) / 1 (0.2) / 1 (0.1) / 0 (0)
≥1.81 mmol/L if age 17-65 yr or ≥1.65 mmol/L if age>66 yr / 10 (0.7) / 8 (1.0)
(p=0.5163) / 17 (1.5)
(p=0.600) / 20 (1.7)
(p=0.0226) / 12 (1.5) / 9 (1.4)
(p=0.8753) / 20 (2.6)
(p=0.1308) / 20 (2.5)
(p=0.1800)

Data are n (%) and include data after rescue.

*N is the number of treated patients and n is the number of treated patients with non-missing baseline and week t values for the specific test

†n = 1131

Percentages are based on the number of patients with non-missing baseline and week t values for the specific test.

Abbreviations: DAPA, dapagliflozin; PBO, placebo.

Table S5. Adverse events related to renal function

Up to 24 weeks / Up to 102 weeks
PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg / PBO / DAPA
2.5 mg / DAPA
5 mg / DAPA
10 mg
N / 1393 / 814 / 1145 / 1193 / 785 / 625 / 767 / 859
Patients with at least one serious adverse event of renal impairment / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 2 (0.3) / 1 (0.2) / 1 (0.1) / 0 (0)
Patients with at least one event of renal impairment leading to discontinuation / 3 (0.2) / 2 (0.2) / 3 (0.3) / 5 (0.4) / 3 (0.4) / 5 (0.8)
(p=0.2996) / 7 (0.9)
(p=0.1917) / 8 (0.9)
(0.1726)
Total patients with adverse event related to renal function / 12 (0.9) / 11 (1.4)
(p=0.2743) / 15 (1.3)
(p=0.2731) / 11 (0.9)
(p=0.8701) / 13 (1.7) / 15 (2.4) (p=0.3201) / 14 (1.8)
(p=0.7988) / 16 (1.9)
(p=0.7507)
Blood creatinine increased / 7 (0.5) / 6 (0.7)
(p=0.4872) / 6 (0.5)
(p=0.9398) / 9 (0.8)
(p=0.4156) / 5 (0.6) / 8 (1.3)
(p=0.2096) / 6 (0.8)
(p=0.7330) / 9 (1.0)
(p=0.3654)
Urine flow decreased / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 3 (0.3)
Renal failure / 3 (0.2) / 0 (0) / 2 (0.2) / 1 (0.1) / 2 (0.3) / 1 (0.2) / 3 (0.4) / 2 (0.2)
Creatinine renal clearance
decreased / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1)
GFR decreased / 0 (0) / 0.1 (0.1) / 3 (0.3) / 1 (0.1) / 1 (0.1) / 1 (0.2) / 1 (0.1) / 1 (0.1)
Renal impairment / 1 (0.1) / 2 (0.2) / 2 (0.2) / 0 (0) / 2 (0.3) / 2 (0.3) / 2 (0.3) / 1 (0.1)
Urine output decreased / 1 (0.1) / 1 (0.1) / 0 (0) / 0 (0) / 1 (0.1) / 1 (0.2) / 0 (0) / 1 (0.1)
Cystatin C increased / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 0 (0)
Renal failure acute / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 1 (0.2) / 1 (0.1) / 0 (0)
Renal function test abnormal / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0)
Anuria / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0)
Oliguria / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.2) / 0 (0) / 0 (0)
Obstructive uropathy / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0)
Blood creatinine abnormal / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0)
Patients with at least one adverse event of renal function by baseline eGFR*
≥90 mL/min/1.73m2 / 2 (0.4) / 1 (0.3) / 1 (0.2) / 0 / 2 (0.8) / 2 (1.0) / 0 / 0
≥60 and < 90 mL/min/1.73m2 / 4 (0.5) / 2 (0.5) / 7 (1.1) / 4 (0.6) / 6 (1.4) / 3 (0.8)
(p=0.4965) / 7 (1.6)
(p=0.7737) / 7 (1.5)
(p=0.8576)
≥30 and <60 mL/min/1.73m2 / 6 (5.6) / 8 (10.8) (p=0.1989) / 7 (6.5) (p=0.7753) / 7 (7.9) (p=0.5282) / 5 (6.5) / 10 (13.9)
(p=0.1351) / 7 (8.0)
(p=0.7193) / 9 (12.0)
(p=0.2421)
Patients with at least one adverse event of renal function by baseline age group
< 65 years / 9 (0.8) / 5 (0.8) / 10 (1.1) / 6 (0.6) / 8 (1.5) / 6 (1.3) / 9 (1.5) / 9 (1.4)
≥ 65 years / 3 (1.1) / 6 (3.1) / 5 (2.3) / 5 (2.5) / 3 (1.9) / 9 (5.9) / 5 (3.1) / 6 (4.5)
Patients with at least one renal related event of interest
Urinary stones / 12 (0.9) / 6 (0.7)
(p=0.7540) / 5 (0.4)
(p=0.1918) / 6 (0.5)
(p=0.2744) / 12 (1.5) / 7 (1.1)
(p=0.5087) / 9 (1.2)
(p=0.5449) / 9 (1.0)
(p=0.3859)
Pyelonephritis / 1 (0.1) / 2 (0.2) / 1 (0.1) / 0 (0) / 0 (0) / 2 (0.3) / 1 (0.1) / 0 (0)
Volume depletion total events / 5 (0.4) / 10 (1.2)
(p=0.0165) / 7 (0.6)
(p=0.3564) / 9 (0.8)
(p=0.1720) / 6 (0.8) / 10 (1.6)
(p=0.1412) / 8 (1.0)
(p=0.5616) / 13 (1.5)
(p=0.1559)
Hypotension / 2 (0.1) / 6 (0.7) / 5 (0.4) / 5 (0.4) / 1 (0.1) / 7 (1.1) / 4 (0.5) / 5 (0.6)
Syncope / 1 (0.1) / 0 (0) / 0 (0) / 2 (0.2) / 3 (0.4) / 0 (0) / 2 (0.3) / 4 (0.5)
Urine flow decrease / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 3 (0.3)
Urine output decreased / 1 (0.1) / 1 (0.1) / 0 (0) / 0 (0) / 1 (0.1) / 1 (0.2) / 0 (0) / 1 (0.1)
Blood pressure decrease / 1 (0.1) / 0 (0) / 0 (0) / 0 (0) / 1 (0.1) / 0 (0) / 0 (0) / 0 (0)
Orthostatic hypotension† / 0 (0) / 1 (0.1) / 2 (0.2) / 0 (0) / 0 (0) / 1 (0.2) / 2 (0.3) / 0 (0)
Dehydration / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 2 (0.3) / 0 (0) / 0 (0)

Data are n (%) and include data after rescue.

N is the number of treated patients. *Ns are in Table 1.

Percentages are based on the number of treated patients per treatment group.

†Defined as decrease from supine to standing of >20 mmHg in systolic blood pressure or >10 mmHg in diastolic blood pressure.

Abbreviations: DAPA, dapagliflozin; PBO, placebo.

Table S6. List of preferred terms for urinary stones (MedDRA version 13.0)

AE / Preferred term
Urinary stones / Calculus bladder, calculus urethritis, calculus urethral, calculus urinary, renal colic, urate nephropathy, nephrocalcinosis, nephrolithiasis, stag horn calculus, renal stone removal, urinary stone removal.