J Nephrol (2016) 29:391–400 DOI 10.1007/s40620-016-0261-1

ORIGINAL ARTICLE

The effect of dapagliflozin on renal function in patients with type 2 diabetes Donald Elliott Kohan1 • Paola Fioretto2 • Kristina Johnsson3 • Shamik Parikh4 Agata Ptaszynska5 • Lisa Ying5

•

Received: 29 October 2015 / Accepted: 3 January 2016 / Published online: 19 February 2016 Ó Italian Society of Nephrology 2016

Abstract Background Dapagliflozin’s antihyperglycemic effects are mediated by inhibition of renal sodium-glucose cotransporter-2; therefore, renal safety of dapagliflozin was assessed. Methods Twelve double-blind, placebo-controlled, randomized clinical trials were analyzed up to 24 weeks

Electronic supplementary material The online version of this article (doi:10.1007/s40620-016-0261-1) contains supplementary material, which is available to authorized users. & Agata Ptaszynska [email protected] Donald Elliott Kohan [email protected] Paola Fioretto [email protected] Kristina Johnsson [email protected] Shamik Parikh [email protected] Lisa Ying [email protected] 1

Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA

2

Department of Medicine, University of Padua, Padua, Italy

3

Global Medical Affairs, AstraZeneca, Mo¨lndal, Sweden

4

Global Medical Affairs, AstraZeneca, Wilmington, DE, USA

5

Bristol-Myers Squibb, Research and Development, Route 206 and Provinceline Road, Princeton, NJ 08543, USA

(N = 4545). Six of the 12 studies included long-term data for up to 102 weeks (N = 3036). Patients with type 2 diabetes with normal or mildly impaired renal function [estimated glomerular filtration rate (eGFR) 60 to\90 mL/ min/1.73 m2] were treated with dapagliflozin (2.5, 5, or 10 mg/day) or placebo. Renal adverse events (AEs) were assessed. Results Mean eGFR showed small transient reductions with dapagliflozin at week 1, but returned to near baseline values by week 24 and remained stable to week 102. Mean eGFR changes were not very different for dapagliflozin 2.5, 5 and 10 mg versus placebo at 102 weeks: -0.74, 2.52 and 1.38 versus 1.31 mL/min/1.73 m2, respectively. Renal AEs were similar in frequency to placebo through 24 weeks (1.4, 1.3, 0.9, and 0.9 %, respectively) and 102 weeks (2.4, 1.8, 1.9 and 1.7 %, respectively). Few were serious (0.2, 0.1, 0 and 0.3 %, respectively, over 102 weeks). The most common renal event was serum creatinine increase. In subgroup analyses in patients C65 years of age or those with moderate renal impairment (eGFR 30 to \60 mL/min/ 1.73 m2), renal AEs occurred more frequently with dapagliflozin than placebo. No events of acute tubular necrosis were reported. Conclusion In patients with normal or mildly impaired renal function, dapagliflozin is not associated with increased risk of acute renal toxicity or deterioration of renal function. All trials included in this analysis are registered at ClinicalTrials.gov: NCT00263276, NCT00972244, NCT00528372, NCT00736879, NCT00528879, NCT00855166, NCT00357370, NCT00680745, NCT00683878, NCT00673231, NCT00643851, NCT00859898. Keywords

Dapagliflozin
Renal
Safety
SGLT2

123

392

Introduction The sodium-glucose cotransporter-2 (SGLT2) is located in the early proximal tubule and is responsible for the majority of glucose reabsorption in the kidney [1, 2]. Inhibition of SGLT2 is a novel mechanism to treat type 2 diabetes mellitus (T2DM) by lowering hyperglycemia via glucosuria [3]. Dapagliflozin is a potent and highly selective SGLT2 inhibitor [4]. Its glucose lowering effect is independent of insulin secretion or action [5], and is dependent on serum glucose concentration and glomerular filtration rate [6–8]. Komoroski et al. showed that dapagliflozin induces dosedependent glucosuria in healthy subjects [3]. In patients with T2DM, dapagliflozin induced dose-dependent, longterm, and stable glucosuria as demonstrated in clinical trials ranging in duration from 12 to 104 weeks [9–16]. These trials studied dapagliflozin as monotherapy [11] or in combination with metformin [10], sulfonylureas [12, 13], thiazolidinedione [14], or insulin [15, 16], and showed improved glycemic control and weight reduction via eliminating calories in the form of urinary glucose. In these trials, the changes in HbA1c ranged from -0.52 to -0.97 % (-5.7 to -10.6 mmol/mol) in the dapagliflozin groups versus -0.13 to -0.42 % (-1.4 to -4.6 mmol/mol) in the placebo group at 24 weeks; p \ 0.001 [9–16]. The changes in body weight ranged from -0.09 to -3.3 kg in the dapagliflozin groups versus ?0.4 to -0.9 kg in the placebo group at 24 weeks [9–16]. As SGLT2 is expressed almost exclusively in the kidney and patients with T2DM are particularly prone to chronic kidney disease, renal safety was of special interest in the dapagliflozin-treated patients [17]. This analysis describes the impact of dapagliflozin treatment on various indicators of renal function and related safety monitoring parameters in patients with normal renal function and mild-to-moderate renal impairment using data pooled from 12 phase 2b and 3 placebo-controlled clinical trials for up to 102 weeks. It is important to note that the data presented in this manuscript are longerterm and include a larger pool of patients compared with renal safety findings reported for other SGLT inhibitors [18–20].

Research design and methods The analyses herein were prespecified to be conducted on pooled patient data from placebo-controlled, randomised, phase 2b and 3 trials for dapagliflozin, with appropriate similarity across the trials with respect to design, conduct, and patient population.

123

J Nephrol (2016) 29:391–400

Patients with T2DM were treated with orally administered dapagliflozin (2.5, 5, or 10 mg/day) or placebo for 12, 24, 48, 102, or 104 weeks as monotherapy (four studies) [9, 11, 21, 22], as add-on combination therapy with a wide variety of other antidiabetic medication (six studies) [10, 12, 14–16, 23] or as initial combination with metformin (two studies) [24]. Institutional review boards or independent ethics committees approved each protocol, and each patient provided written informed consent. Twelve double-blind, placebo-controlled, randomized clinical trials consisting of three Phase 2b and nine Phase 3 studies were included in the analysis up to 24 weeks (supplement Table S1). Six of the 12 studies included longterm extensions beyond 24 weeks and were pooled for analysis labeled ‘‘up to 102 weeks’’; one trial (Phase 3 added-on to insulin study [16]) went up to 104 weeks as indicated in supplement Table S1. The pooled analysis up to 24 weeks provided the most comprehensive and bestcontrolled examination of the effects of dapagliflozin, minimizing confounding by rescue medications and dropouts, and the analysis up to 102 weeks allowed for understanding of the evolution of safety over time. The inclusion criteria were study specific for age, C-peptide, BMI, and entry hemoglobin A1c (HbA1c) range (supplement Table S1), with all patients having inadequate glycemic control at baseline. Key exclusion criteria included aspartate or alanine aminotransferases [3 times the upper limit of normal (ULN), creatine kinase [3 times ULN, urinary albumin:creatinine ratio [1800 mg/g, and studyspecific serum creatinine or creatinine clearance criteria (supplement Table S1). Patients who met prespecified glycemic criteria were allowed to use concomitant antidiabetic rescue therapy as indicated in each protocol. All data for safety evaluations were collected and reported according to good clinical practice guidelines. Data were collected on adverse events (AEs), clinical laboratory tests, and vital signs including electrocardiograms and blood pressure. A central laboratory was used to assess laboratory tests. Estimated glomerular filtration rate (eGFR) was calculated using the Abbreviated Modification of Diet in Renal Disease Study (MDRD) 4-variable equation [25]. Patients with eGFR \30 mL/min/1.73 m2 were excluded from all studies because of the expected lack of efficacy. Marked abnormalities for creatinine were defined as either 1.5 times baseline value or an absolute value of C221 lmol/L. AEs related to renal function and volume depletion (hypotension/hypovolemia/dehydration) were identified from investigator-reported AEs based on prespecified lists of 39 and of 36 referred terms, respectively, from the Medical Dictionary for Regulatory Activity (MedDRA). Examples of MedDRA preferred terms for

J Nephrol (2016) 29:391–400

393

renal AEs included azotemia, blood creatinine abnormal, GFR decreased, and acute renal failure, and preferred terms for volume depletion included terms such as hypotension, dehydration, blood osmolarity increase, and volume blood decrease.

3.5, 2.6 and 3.9 % in the dapagliflozin 2.5, 5, 10 mg and placebo groups, respectively) were concomitantly receiving loop diuretics in the short-term pool (up to 24 weeks).

Statistical analysis

In the dapagliflozin groups, mean eGFR decreased from baseline at week 1 (-2.83, -2.51, and -4.13 mL/min/ 1.73 m2 for dapagliflozin 2.5, 5, and 10 mg, respectively) and then returned to near- or above-baseline values by week 24 and remained stable up to week 102 (Fig. 1). As shown in Table 2, the point estimate for mean eGFR was slightly above baseline at weeks 24 and 102 in the placebo and dapagliflozin 5 and 10 mg groups. At weeks 24 and 102, no significant difference in the mean eGFR change from baseline between dapagliflozin 5 or 10 mg and placebo was observed (Table 2). In patients not using an ACE inhibitor and/or ARB, mean change from baseline to week 24 in eGFR was 0.75 mL/min/1.73 m2 with dapagliflozin 10 mg (n = 428) and 1.84 mL/min/1.73 m2 with placebo (n = 489). In patients who used an ACE inhibitor and/or ARB, mean change from baseline in eGFR was -0.02 mL/ min/1.73 m2 with dapagliflozin 10 mg (n = 507) and 0.04 mL/min/1.73 m2 with placebo (n = 598) at week 24. Mean urinary albumin:creatinine ratio data are given in Table 2. Over 90 % of patients remained in the normal albuminuria category (0 to \30 mg/g) across dapagliflozin and placebo groups at weeks 24 and 102. Within each subgroup of baseline eGFR category (normal renal function, and mild or moderate renal impairment), the proportion of patients shifting from normal to a worse albuminuria category [30 to \300 mg/g (microalbuminuria); C300 mg/g (macroalbuminuria)], and those with microalbuminuria (30 to \300 mg/g) shifting to macroalbuminuria (C300 mg/g) was similar for dapagliflozin and placebo groups at week 24 (Table S2). Overall, no effect of dapagliflozin on the albumin/creatinine ratio was observed. Small changes in mean serum creatinine levels from baseline to weeks 24 or 102 were observed in both dapagliflozin and placebo groups (Table 2). Mean changes in serum creatinine stratified by eGFR subgroups at 24 and 102 weeks are available in Table S3. Marked abnormalities for creatinine were reported in a small proportion of patients with no imbalance between treatment groups (supplement Table S4). The marked abnormalities for creatinine were consistent between the 24- and 102-week time periods (supplement Table S4). Small increases from baseline in mean BUN levels and mean serum albumin were observed with dapagliflozin versus placebo at week 102, consistent with the mild osmotic diuretic effect of the drug (Table 2). Marked abnormalities for BUN C60 mg/dL (C21.4 mmol/L) were reported in similar proportions (0–0.3 %) of patients in all

The formal statistical hypothesis-testing was not done for the pooled analysis presented here. As such, p-values were not routinely run for all parameters, and only selected p-values are provided. Safety analyses included data after the initiation of rescue therapy. Data for changes in renal function parameters including eGFR, serum creatinine, blood urea nitrogen (BUN), urinary albumin:creatinine ratio and serum albumin were analyzed using an analysis of covariance (ANCOVA) model with treatment group as an effect and baseline value as a covariate. P-values were not calculated for changes in serum electrolytes. P-value for pairwise comparison versus placebo for the proportions of patients changing to a worse category of albuminuria [30 to \300 mg/g (microalbuminuria); C300 mg/g (macroalbuminuria)] by baseline eGFR subgroups were derived using Cochran-Mantel– Haenszel test.

Results Demographics and baseline characteristics Baseline demographics (Table 1) were similar between placebo and dapagliflozin groups. Mean baseline eGFR ranged from 84.6–86.7 mL/min/1.73 m2 in the dapagliflozin groups and was 86.0 mL/min/1.73 m2 in the placebo group for the analysis up to 24 weeks. In the 12 placebocontrolled studies, approximately half (52.8–54.4 %) of the patients in each group had baseline eGFR values in the range of mildly impaired renal function (eGFR C60 to \90 mL/min/1.73 m2); and 7.5–9.3 % of the patients had baseline eGFR values in the range of moderate impairment (eGFR C30 to \60 mL/min/1.73 m2), 88 % of those were in the top half of this category (eGFR 45–59 mL/min/ 1.73 m2). As shown in Table 1, the proportion of patients in each albuminuria category was similar between the dapagliflozin and placebo groups with approximately 75 % of patients in the normal albuminuria category (0 to \30 mg/g). Patients concurrently receiving angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) antihypertensive agents were equally distributed between dapagliflozin and placebo groups (Table 1). Likewise, similar proportions of patients (4.5,

Renal function

123

394

J Nephrol (2016) 29:391–400

Table 1 Demographics and baseline characteristics Up to 24 week pool

Up to 102 week pool

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

Mean age, years (SD)

55.3 (10.5)

57.0 (10.1)

55.4 (10.4)

55.1 (10.1)

56.9 (10.2)

57.5 (9.9)

56.5 (10.1)

56.0 (9.9)

Female, n (%) Race, n (%)

677 (48.6)

400 (49.1)

581 (50.7)

598 (50.1)

387 (49.3)

313 (50.1)

388 (50.6)

447 (52.0)

Caucasian

1129 (81.0)

653 (80.2)

907 (79.2)

976 (81.8)

679 (86.5)

543 (86.9)

645 (84.1)

739 (86.0)

African American

38 (2.7)

15 (1.8)

33 (2.9)

35 (2.9)

17 (2.2)

9 (1.4)

21 (2.7)

20 (2.3)

Asian

201 (14.4)

127 (15.6)

181 (15.8)

152 (12.7)

73 (9.3)

59 (9.4)

81 (10.6)

74 (8.6)

Other

25 (1.8)

19 (2.3)

24 (2.1)

30 (2.5)

16 (2.0)

14 (2.2)

20 (2.6)

26 (3.0)

Geographic region, n (%) North America

443 (31.8)

221 (27.1)

362 (31.6)

384 (32.2)

192 (24.5)

152 (24.3)

228 (29.7)

232 (27.0)

Latin America

272 (19.5)

174 (21.4)

270 (23.6)

237 (19.9)

171 (21.8)

138 (22.1)

188 (24.5)

194 (22.6)

Europe

496 (35.6)

309 (38.0)

348 (30.4)

435 (36.5)

357 (45.5)

289 (46.2)

282 (36.8)

371 (43.2)

Asia/Pacific

182 (13.1)

110 (13.5)

165 (14.4)

137 (11.5)

65 (8.3)

46 (7.4)

69 (9.0)

62 (7.2)

2.90

4.40

3.30

4.20

5.65

6.40

5.70

5.30

Duration type 2 diabetes Median, years Mean HbA1c % (SD)

8.39 (1.16)

8.11 (0.87)

8.39 (1.09)

8.28 (1.05)

8.12 (0.92)

8.17 (0.86)

8.27 (0.95)

8.11 (0.93)

68 (12.7)

65 (9.5)

68 (11.9)

67 (11.5)

65 (10.1)

66 (9.4)

67 (10.4)

65 (10.2)

C90 mL/min/1.73 m2

528 (37.9)

300 (36.9)

429 (37.5)

474 (39.7)

266 (33.9)

198 (31.7)

239 (31.2)

317 (36.9)

C60 and \90 mL/min/1.73 m2

758 (54.4)

440 (54.1)

609 (53.2)

630 (52.8)

442 (56.3)

355 (56.8)

440 (57.4)

467 (54.4)

mmol/mol (SD) GFR category, n (%)

C30 and \60 mL/min/1.73 m

2

\30 mL/min/1.73 m2

107 (7.7)

74 (9.1)

107 (9.3)

89 (7.5)

77 (9.8)

72 (11.5)

88 (11.5)

75 (8.7)

0

0

0

0

0

0

0

0

Albuminuria category, n (%) Normal (0 \ 30 mg/g)

1055 (75.7)

623 (76.5)

862 (75.3)

910 (76.3)

591 (75.3)

474 (75.8)

567 (73.9)

654 (76.1)

Micro (30 \ 300 mg/g)

297 (21.3)

168 (20.6)

235 (20.5)

254 (21.3)

168 (21.4)

137 (21.9)

168 (21.9)

182 (21.2)

Macro (C300 mg/g)

39 (2.8)

15 (1.8)

41 (3.6)

26 (2.2)

26 (3.3)

14 (2.2)

31 (4.0)

22 (2.6)

Not reported

2 (0.1)

8 (1.0)

7 (0.6)

3 (0.3)

0

0

1 (0.1)

1 (0.1)

735 (52.8)

444 (54.5)

570 (49.8)

616 (51.6)

493 (62.8)

378 (60.5)

428 (55.8)

490 (57.0)

ACE inhibitor or ARB, n (% yes)

DAPA dapagliflozin, PBO placebo, NA not available

treatment groups, including patients using an ACE inhibitor and/or ARB. Renal adverse events No imbalance of renal AEs was observed between patients treated with dapagliflozin or placebo up to 24 weeks (supplement Table S5). In the analysis up to 102 weeks, these events were reported in a slightly higher proportion of dapagliflozin-treated patients (1.8–2.4 %) compared with placebo-treated patients (1.7 %), as shown in supplement Table S5. One patient in the dapagliflozin 2.5 mg group died due to renal failure precipitated by congestive heart failure. No serious AEs (requiring hospitalization or

123

otherwise considered medically important events by the investigator) of renal impairment or failure were reported in the analysis up to 24 weeks, occurred rarely in the analysis up to 102 weeks and were balanced between dapagliflozin and placebo: 1 (0.2 %), 1 (0.1 %), and 0 in the dapagliflozin 2.5, 5, and 10 mg groups, respectively, versus 2 (0.3 %) in the placebo group (supplement Table S5). Discontinuations due to renal AEs were uncommon and were balanced between dapagliflozin and placebo up to 24 weeks. The proportion of patients with renal events leading to discontinuation up to 102 weeks remained small (B1 %), though higher in the dapagliflozin groups compared with placebo group (supplement Table S5).

J Nephrol (2016) 29:391–400

395

Fig. 1 eGFR mean change from baseline for placebo, dapagliflozin 2.5, 5 and 10 mg over time. Including data after rescue up to 102 weeks (data up to 24 weeks are also shown as an inset figure). Data are from 6 studies used in the analysis up to 102 weeks with 2 of the 6 studies being 48 weeks in duration

The moderate renal impairment subgroup (eGFR C30 and \60 mL/min/1.73 m2) had the highest proportion of patients (dapagliflozin and placebo) with renal AEs up to 24 weeks (supplement Table S5). In this subgroup only, renal AEs were more common in dapagliflozin-treated patients than placebo, with no dose dependence. The analysis up to 102 weeks was consistent with this. In patients classified by age-groups, events of renal impairment or failure in patients \65 years of age were reported in similar proportions across treatment groups and were reported less frequently compared with the subgroup of patients C65 years of age (supplement Table S5). In patients C65 years of age, a higher proportion of patients in the dapagliflozin groups reported AEs of renal impairment or failure versus placebo group. The most commonly reported AEs of renal impairment or failure were increases in blood creatinine and renal failure; however, these were reported in \1 % of patients in any group. AEs reported in patients C65 years of age were mild or moderate in intensity except two severe AEs (increased blood creatinine and renal failure) reported for one (0.5 %) patient in the dapagliflozin 10 mg group. There were no reports of acute tubular necrosis. Urinary stones were reported in a lower proportion of dapagliflozintreated patients versus placebo as shown in supplement Table S4. Most AEs of urinary stones were reported as nephrolithiasis (0.8, 1.0, 0.7 and 0.5 % in the placebo, dapagliflozin 2.5, 5 and 10 mg groups, respectively) and

few were associated with renal colic (0.4, 0.3, 0.4 and 0.3 %, respectively). The MedDRA preferred terms for AEs of urinary stones are listed in supplement Table S6. Kidney infection or pyelonephritis was reported infrequently and was balanced among patients treated with dapagliflozin or placebo (supplement Table S5). Hypovolemia events Few AEs corresponding to volume depletion were reported in the analysis up to 24 weeks (supplement Table S5). Syncope occurred in 2 patients treated with dapagliflozin and in 2 patients treated with placebo. One patient, on a loop diuretic and dapagliflozin 10 mg, was discontinued because of an event of dehydration and pre-renal azotemia. Most volume depletion events (20/27) in patients treated with dapagliflozin were mild in intensity and were mostly associated with transient episodes of hypotension without sequelae. Serious AEs of volume depletion occurred in 2/2251 (\0.1 %) patients on dapagliflozin, and 2/785 (0.3 %) patients on placebo in the analysis up to 102 weeks. General laboratory parameters and blood pressure No mean changes from baseline in serum electrolytes (sodium, potassium, bicarbonate, or chloride) were observed in the dapagliflozin groups compared with

123

396

J Nephrol (2016) 29:391–400

Table 2 Change in renal function parameters 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

1393

814

1145

1193

785

625

767

859

n Baseline

1087 86.0 (20.1)

619 84.6 (20.3)

899 85.3 (21.0)

935 86.7 (20.7)

164 83.1 (19.0)

210 81.4 (18.9)

235 81.9 (19.5)

249 84.3 (18.8)

Mean change from baseline

0.85 [0.34]

-0.90 [0.42]

0.77 [0.41]

0.33 [0.41]

1.31 [0.89]

-0.74 [0.76]

2.52 [0.81]

1.38 [0.73]

P-value vs placebo

–

0.0006

0.7436

0.4386

–

0.0842

0.4493

0.7640

n

1087

619

899

935

164

211

235

249

Baseline

75.41 (16.80)

76.11 (17.15)

76.02 (18.03)

74.87 (17.59)

76.91 (17.77)

77.88 (17.68)

78.15 (18.83)

75.76 (18.21)

Mean change from baseline

-0.44 [0.27]

0.88 [0.35]

-0.09 [0.35]

0.09 [0.27]

-1.15 [0.71]

0.09 [0.62]

-1.94 [0.71]

-1.33 [0.62]

P-value vs placebo

–

0.0019

0.2989

0.2169

–

0.1447

0.7416

0.9179

n

1087

619

899

935

166

211

235

249

Baseline

5.43 (1.59)

5.50 (1.55)

5.53 (1.74)

5.46 (1.62)

5.64 (1.67)

5.64 (1.57)

5.78 (1.83)

5.60 (1.67)

Mean change from baseline

0.11 [0.04]

0.54 [0.06]

0.50 [0.05]

0.57 [0.05]

0.36 [0.11]

0.61 [0.10]

0.57 [0.12]

0.50 [0.09]

P-value vs placebo

–

\0.0001

\0.0001

\0.0001

–

0.0384

0.0217

0.0823

N eGFR (mL/min/1.73 m2)

Serum creatinine (lmol/L)

BUN (mmol/L)

a

Albumin:creatinine ratio (mg/g) n

1080

613

897

934

161

210

234

248

Baseline

49.3 (174)

39.3 (127)

58.6 (216)

36.8 (108)

57.4 (203)

43.5 (141)

68.3 (253)

40.5 (123)

Mean change from baseline

-5.9 [3.89]

-10.1 [3.95]

-14.3 [5.18]

-5.4 [2.86]

3.9 [8.54]

-10.3 [10.34]

9.2 [7.15]

-10.8 [7.95]

P-value vs placebo

–

0.0648

0.5122

0.2138

–

0.0924

0.7538

0.0982

Serum albumin (g/L) n

1087

619

900

936

164

211

235

249

Baseline

44.0 (2.90)

43.80 (2.90)

43.80 (2.90)

43.80 (2.90)

44.00 (2.90)

43.6 (2.90)

43.70 (2.90)

43.80 (2.90)

Mean change from baseline

-0.10 [0.07]

0.30 [0.10]

0.30 [0.09]

0.60 [0.09]

0.00 [0.21]

0.50 [0.17]

0.60 [0.17]

0.80 [0.16]

P-value vs placebo

–

0.0169

0.0002

\0.0001

–

0.0444

0.0225

0.0048

Data are baseline (standard deviation) or mean [standard error] change from baseline 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 Absolute change values have been provided instead of percent change values to avoid inflating the estimates of albuminuria change because most patients were normal with respect to albumin excretion; very small changes are likely to result in very large percent changes for these patients DAPA dapagliflozin, PBO placebo, NA not available a

Measured by ‘‘spot’’ urine samples

placebo, with the exception of small mean increases in serum phosphorus and magnesium (Table 3) in the analysis up to 24 weeks. These small mean increases were not sustained in the analysis up to 102 weeks. Overall, supplement Table S4 shows that marked abnormalities were reported in small proportions of patients, with no clear imbalances across the treatment

123

groups. Marked abnormalities of hyperkalemia (serum potassium C6 mmol/L) were reported in similar proportions of patients between dapagliflozin (5.3 %) and placebo (4.0 %) groups in the analysis up to 102 weeks. In the individual studies [10–15], serum uric acid decreased by approximately 17.8–59.5 lmol/L with dapagliflozin. The increase in urinary excretion of uric acid was

J Nephrol (2016) 29:391–400

397

Table 3 Laboratory parameters and blood pressure At 24 weeks

N

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

1393

814

1145

1193

785

625

767

859

Serum electrolytes Sodium (mmol/L) n

1089

619

901

937

164

211

234

250

Baseline

139.6 (3.10)

139.7 (2.90)

139.3 (2.81)

139.6 (3.02)

140.1 (3.00)

139.9 (2.92)

139.5 (2.78)

139.8 (3.00)

Mean change from baseline

0.4 [0.09]

0.5 [0.12]

0.7 [0.10]

0.8 [0.10]

0.2 [0.23]

0.3 [0.20]

0.7 [0.19]

0.7 [0.19]

n

1088

619

898

936

163

211

234

250

Baseline

4.37 (0.46)

4.39 (0.45)

4.38 (0.46)

4.38 (0.45)

4.41 (0.49)

4.44 (0.47)

4.42 (0.47)

4.39 (0.47)

-0.01 [0.013]

-0.02 [0.018]

-0.05 [0.015]

-0.03 [0.015]

-0.06 [0.041]

-0.04 [0.036]

-0.05 [0.028]

-0.08 [0.033]

n

1089

619

901

937

164

211

235

250

Baseline

102.0 (3.0)

102.4 (3.0)

102.0 (3.0)

102.1 (3.0)

102.3 (2.8)

102.3 (2.9)

102.0 (2.9)

102.2 (2.9)

Mean change from baseline

0.4 [0.09]

0.4 [0.13]

0.7 [0.10]

0.7 [0.10]

0.4 [0.25]

0.4 [0.21]

0.5 [0.21]

0.6 [0.23]

n

1087

612

899

938

162

212

236

250

Baseline

25.5 (2.6)

25.5 (2.5)

25.5 (2.7)

25.6 (2.8)

25.6 (2.6)

25.6 (2.4)

25.6 (2.6)

25.6 (2.8)

Mean change from baseline

0.0 [0.09]

0.1 [0.12]

-0.2 [0.10]

-0.2 [0.10]

0.0 [0.22]

-0.1 [0.18]

0.1 [0.18]

-0.3 [0.18]

n

1087

619

898

936

164

211

235

247

Baseline

0.86 (0.12)

0.87 (0.12)

0.86 (0.12)

0.86 (0.13)

0.85 (0.11)

0.85 (0.11)

0.85 (0.11)

0.85 (0.12)

Mean change from baseline

-0.02 [0.003]

0.03 [0.005]

0.04 [0.004]

0.04 [0.004]

-0.08 [0.010]

-0.03 [0.009]

-0.02 [0.008]

-0.03 [0.009]

n

1087

618

899

935

164

211

234

249

Baseline

2.38 (0.12)

2.37 (0.13)

2.37 (0.11)

2.38 (0.11)

2.37 (0.13)

2.37 (0.13)

2.37 (0.11)

2.37 (0.12)

Mean change from baseline

-0.01 [0.00]

0.00 [0.01]

0.00 [0.00]

0.00 [0.00]

-0.01 [0.01]

0.03 [0.01]

-0.01 [0.01]

0.01 [0.01]

Potassium (mmol/L)

Mean change from baseline Chloride (mmol/L)

Bicarbonate (mmol/L)

Magnesium (mmol/L)

Calcium (mmol/L)

Inorganic phosphate (mmol/L) n

1087

618

898

935

164

211

235

249

Baseline

1.16 (0.16)

1.15 (0.17)

1.16 (0.16)

1.16 (0.17)

1.15 (0.16)

1.15 (0.17)

1.16 (0.16)

1.15 (0.17)

Mean change from baseline

0.01 [0.01]

0.03 [0.01]

0.05 [0.01]

0.05 [0.01]

0.03 [0.02]

0.01 [0.01]

0.03 [0.01]

0.03 [0.01]

n

1096

621

908

949

163

215

240

253

Baseline

130.0 (15.4)

131.9 (17.0)

129.0 (15.8)

130.4 (16.2)

130.8 (15.8)

133.1 (17.2)

130.5 (16.2)

131.1 (16.3)

Mean change from baseline

-0.9 (13.1)

-4.0 (14.2)

-3.5 (13.4)

-4.4 (13.9)

0.7 (14.8)

-2.6 (15.9)

-2.0 (14.4)

-1.7 (15.5)

P-value vs placebo

–

0.0003

\0.0001

\0.0001

–

0.0682

0.0324

0.0829

n

1096

621

908

949

163

215

240

253

Baseline

79.8 (8.7)

79.6 (9.3)

79.2 (9.0)

79.2 (9.1)

79.6 (9.0)

79.8 (9.3)

79.5 (8.9)

79.1 (9.3)

Blood pressure Seated systolic (mmHg)

Seated diastolic (mmHg)

123

398

J Nephrol (2016) 29:391–400

Table 3 continued 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

Mean change from baseline

-0.5 (8.3)

-1.8 (8.5)

-2.1 (7.9)

-2.1 (8.4)

-1.0 (8.5)

-1.6 (8.4)

-2.0 (9.0)

-1.6 (9.3)

P-value vs placebo

–

0.0001

\0.0001

\0.0001

–

0.1451

0.1483

0.1569

Data are baseline (standard deviation) or mean [standard error] change from baseline 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 DAPA dapagliflozin, PBO placebo

not associated with an increase in reported urinary stones; compared with placebo, a lower proportion of patients treated with dapagliflozin experienced urinary stones. At week 24, mean decreases in seated systolic and diastolic blood pressure were noted with dapagliflozin versus placebo; the mean decreases were -4.4 versus -0.9 and -2.1 versus -0.5 mmHg, respectively, with nominal P-values of B0.0001 (Table 3). The mean decreases with dapagliflozin were apparent at week 1 (changes from baseline with placebo vs dapagliflozin 10 mg were -1.0 vs -3.9 mmHg for SBP and -0.7 vs -1.5 mmHg for DBP) and persisted up to 102 weeks (Table 3).

Conclusions and discussion Dapagliflozin’s mechanism of action is different from, and complementary to, the mechanisms of other available drugs, resulting in insulin-independent renal glucose excretion. Renal safety is of special interest in patients treated with dapagliflozin, as SGLT2 is expressed almost exclusively in the kidney, and, moreover, patients with T2DM are particularly prone to kidney disease [17]. Treatment with dapagliflozin resulted in a rapid, small mean decrease of eGFR in the first week (with more pronounced decreases in the dapagliflozin 10 mg group), and subsequent return to baseline. This early drop in eGFR was not associated with AEs. The mechanisms responsible for the initial fall in eGFR are speculative and may be associated with hemodynamic changes related to the mild proximal tubular diuretic effect of dapagliflozin. Furthermore, the fall in eGFR may partly be explained by the drop in renal perfusion pressure caused by a decrease in systemic blood pressure. Tubuloglomerular feedback [26] could be another possible mechanism with increased sodium delivery to the juxtaglomerular apparatus potentially driving the initial transient fall in GFR. Exposure to SGLT2 blockade with dapagliflozin reduced proximal tubular reabsorption of sodium by 24–27 % in two highly controlled rodent models [27]. This increased solute

123

delivery to the macula densa may activate the tubuloglomerular feedback mechanism leading to an initial lowering of GFR [26]. Over time, this process may reset such that GFR gradually returns to baseline, as seen in the clinical experience. Direct measurement of GFR is impractical where there are large patient populations, necessitating the use of estimating equations. Therefore, GFR was estimated in the studies included in this analysis using a serum creatininebased formula. The creatinine based equations used to evaluate and estimate renal function (Cockcroft-Gault, MDRD) have limitations. Both equations have a tendency toward systematic error at higher levels of renal function but are reasonable to measure change in renal function from baseline. This analysis used MDRD to determine eGFR; eGFR derived from the MDRD equation is biased toward underestimation when eGFR is C60 mL/min/ 1.73 m2 [28]. However, changes in MDRD still accurately reflect changes in eGFR over time (which is the analysis presented here). eGFR measurement in diabetes trials helps to more precisely address variations across broader populations that are expected to be treated. We measured creatinine clearance in a dedicated study in patients with moderate renal impairment (eGFR 30–59 ml/min/1.73 m2) [29], which has been reported previously. Few events of volume depletion were reported with dapagliflozin; this was expected based on dapagliflozin’s mild diuretic effect and was consistent with the modest blood pressure reductions observed with dapagliflozin. Clinically significant reductions in blood pressure were noted with dapagliflozin at week 24, which were sustained, although to a lesser extent, up to week 102. Stratified analyses of SBP changes according to baseline eGFR subgroups were not performed. However, reductions in SBP have been noted with dapagliflozin compared with placebo in the dedicated study in patients with T2DM and moderate renal impairment (mean changes -3.81, -6.73, and ?2.41 mmHg at 52 weeks and -0.25, -2.51 and ?4.14 mmHg at 104 weeks in the dapagliflozin 5, 10 mg and placebo groups, respectively) [29, 30]. An overall

J Nephrol (2016) 29:391–400

decrease in serum uric acid observed in the individual studies could be beneficial [31, 32]. A lower proportion of patients treated with dapagliflozin experienced urinary stones. A possible explanation could be an increase in urine volume. No adverse effect of dapagliflozin was seen on albuminuria, whether assessed as mean albumin:creatinine ratio or as shift in albuminuria category (normal, microalbuminuria, macroalbuminuria). Likewise, canagliflozin, another SGLT2 inhibitor, showed median percent reductions in urine albumin:creatinine ratio versus placebo (-16.4, -28.0 versus 19.7 % with canagliflozin 100 and 300 mg versus placebo, respectively) at 52 weeks in a placebo-controlled study in patients with T2DM and eGFR C30 and \50 mL/min/1.73 m2 [33]. It can be hypothesized that improved glycemic control, blood pressure lowering and renal safety noted with the use of dapagliflozin in patients with T2DM may have renal protective effects over the longer term; however, this should be balanced with the lower glycemic efficacy seen in patients with decreased GFR [29] due to the drug’s mechanism of action. In the present analysis, similar proportions of patients shifted to a worse category of albuminuria in the dapagliflozin and placebo dose groups, which suggested that dapagliflozin did not produce any negative effect on the renal health of patients included in this analysis. Furthermore, findings from pre-clinical studies of the SGLT2 inhibitor, empagliflozin have shown amelioration of early features of diabetic nephropathy associated with its use in diabetic mice [34, 35]. In addition, findings from a recently reported large, long-term study have shown significant improvements in renal outcomes with empagliflozin versus placebo in patients with T2DM. Such findings suggest that SGLT2 inhibitors may confer a renoprotective effect in patients with T2DM [36]. The present analysis has its limitations. As noted earlier, data at 24 weeks are more robust, minimally affected by rescue medications and dropouts. However, 24 weeks is too short a timeframe to assess chronic renal toxicity. Only small proportions of patients had baseline albuminuria of any degree; this contributed to the larger variability noted in smaller subgroups making it difficult to interpret results in these groups. Although both short-term (up to 24 week) and longer-term (up to 104 week) findings have been reported, it should be noted that not all of the studies comprising the short-term pool had longer-term data available for analysis at the 102-week time point and that the longer-term data are available for a smaller number of patients. Another limitation of the present analysis is that formal statistical hypothesis testing was not done. In summary, comparison of AEs and laboratory findings in [3000 dapagliflozin-treated patients in this pooled analysis showed renal AEs were similar between dapagliflozin and placebo up to 102 weeks. Most of those events

399

were transient changes in renal function and laboratory parameters, consistent with alterations in fluid balance. Dapagliflozin was not associated with increased risk of acute renal toxicity or deterioration of renal function. A small increase in renal AEs was noted in patients with moderate renal impairment (chronic kidney disease stage III). Similar to patients with normal renal function or mildly impaired GFR, these events were primarily laboratory changes. This analysis showed that dapagliflozin is safe and well tolerated in patients with normal or mildly impaired renal function. Acknowledgments The study team would like to acknowledge the patients for their participation and commitment during the studies. We also thank the investigators and contributors from each study site. The authors thank Dr. Bruce Leslie for his involvement with this analysis, Dr James List for his contribution to the analysis and initial manuscript development, and Jennifer Sugg for her contribution to statistical analysis. Professional medical writing and editorial assistance was provided by Carolyn Carroll, PhD, an employee of BristolMyers Squibb at the time of the development of this manuscript and Shelley Narula, MBBS, of inScience Communications, Springer Healthcare. Funding The conduct and analyses of these trials were supported by Bristol-Myers Squibb and AstraZeneca. Compliance with ethical standards Conflict of interest DEK is a consultant for Bristol-Myers Squibb and AstraZeneca. PF is a consultant for Bristol-Myers Squibb and AstraZeneca, and participant in boards for Boehringer Ingelheim. KJ and SP are employees and shareholders of AstraZeneca. AP and LY are employees and shareholders of Bristol-Myers Squibb. Ethical approval The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. Informed consent participants.

Informed consent was obtained from all

References 1. Wood IS, Trayhurn P (2003) Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 891:3–9 2. Kanai Y, Lee WS, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na?/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93:397–404 3. Komoroski B, Vachharajani N, Boulton D et al (2009) Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 85:520–526 4. Meng W, Ellsworth BA, Nirschl AA et al (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51:1145–1149 5. Han S, Hagan DL, Taylor JR et al (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57:1723–1729

123

400 6. List JF, Whaley JM (2011) Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int Suppl 79:S20–S27 7. Mather A, Pollock C (2011) Glucose handling by the kidney. Kidney Int Suppl 79:S1–S6 8. Vallon V, Platt KA, Cunard R et al (2011) SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 22:104–112 9. List JF, Woo V, Morales E, Tang W, Fiedorek FT (2009) Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32:650–657 10. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF (2010) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, doubleblind, placebo-controlled trial. Lancet 375:2223–2233 11. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF (2010) Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 33:2217–2224 12. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S (2011) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 13:928–938 13. Nauck MA, Del Prato S, Meier JJ et al (2011) Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34:2015–2022 14. Rosenstock J, Vico M, Wei L, Salsali A, List JF (2012) Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 35:1473–1478 15. Wilding JP, Norwood P, T’Joen C, Bastien A, List JF, Fiedorek FT (2009) A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 32:1656–1662 16. Wilding JP, Woo V, Soler NG et al (2012) Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 156:405–415 17. Sharif A (2011) Current and emerging antiglycaemic pharmacological therapies: the renal perspective. Nephrol (Carlton) 16:468–475 18. Committee for Medicinal Products for Human Use European Public Assessment Report (EPAR) Canagliflozin European Medicines Agency 2013. http://www.ema.europa.eu/docs/en_ GB/document_library/EPAR_-_Public_assessment_report/ human/002649/WC500156457.pdf 19. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D et al (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 16:1016–1027 20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ et al (2014) Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2:369–384 21. Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N et al (2013) Efficacy and safety of dapagliflozin as a monotherapy

123

J Nephrol (2016) 29:391–400

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, doubleblind, placebo-controlled trial. Diabetes Obes Metab 15:432–440 Bailey CJ, Iqbal N, T’joen C, List JF (2012) Dapagliflozin monotherapy in drug-naı¨ve patients with diabetes: a randomizedcontrolled trial of low-dose range. Diabetes Obes Metab 14:951–959 ¨ , Kullberg J, Johansson L, Wilding J, Bolinder J, Ljunggren O Langkilde AM et al (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97:1020–1031 Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF (2012) Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Prac 66:446–456 National Kidney Foundation (2002) Part 4. Definition and classification of stages of chronic kidney disease. Am J Kidney Dis 39:S46–S75 Vallon V, Richter K, Blantz RC, Thomson S, Osswald H (1999) Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 10:2569–2576 Thomson SC, Rieg T, Miracle C et al (2012) Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302:R75–R83 Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 354:2473–2483 Kohan DE, Fioretto P, Tang W, List JF (2014) Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85:962–971 Kohan DE, Fioretto P, List J, et al (2011) Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment. Presented at the American society of nephrology kidney week 2011 annual meeting; Philadelphia, PA, November 8–13, 2011; abstract #TH-PO524 Fukui M, Tanaka M, Shiraishi E et al (2008) Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metabolism 57:625–629 Kodama S, Saito K, Yachi Y et al (2009) Association between serum uric acid and development of type 2 diabetes. Diabetes Care 32:1737–1742 Yale JF, Bakris G, Cariou B et al (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 16(10):1016–1027 Gembardt F, Bartaun C, Jarzebska N et al (2014) The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 307(3):F317– F325 Vallon V, Gerasimova M, Rose MA et al (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306(2):F194– F204 Wanner C, Lachin JM, Fitchett DH, et al. (2015) Empagliflozin and clinical outcomes in patients with type 2 diabetes and chronic kidney disease. In: American Society of Nephrology, San Diego, CA, pp abstract# HI-OR01