Clin Pharmacokinet (2015) 54:691–708 DOI 10.1007/s40262-015-0264-4

REVIEW ARTICLE

Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Andre´ J. Scheen1,2

Published online: 25 March 2015 Ó Springer International Publishing Switzerland 2015

Abstract Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a

& Andre´ J. Scheen [email protected] 1

Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Lie`ge, Lie`ge, Belgium

2

Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Lie`ge, Lie`ge, Belgium

parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models.

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Key Points Pharmacokinetics of dapagliflozin, canagliflozin, empagliflozin and ipragliflozin are only mildly altered in patients with chronic kidney disease (CKD), leading to a modest increase in exposure to the parent active drug. Renally excreted metabolites are essentially inactive Pharmacodynamics of sodium-glucose cotransporters type 2 (SGLT2) inhibitors, as assessed by urinary glucose excretion, are impaired according to the degree of reduction in the estimated glomerular filtration rate Clinical efficacy as assessed by a reduction in glycosylated haemoglobin is maintained in the presence of mild (stage 2) CKD but decreases in patients with moderate (especially stage 3b) CKD and almost vanishes in patients with severe (stage 4) CKD Overall safety profile appears almost similar in patients with mild to moderate CKD as compared to that in patients with mild renal dysfunction, but caution is required in fragile patients with more advanced CKD Preclinical data in animals and preliminary observations in humans suggest that SGLT2 inhibitors may exert renoprotective effects and further studies are required to evaluate possible beneficial effects of this new class on the development of diabetic nephropathy

1 Introduction Type 2 diabetes mellitus (T2DM) affects more than 350 million people worldwide, and its overall prevalence is rapidly increasing. Despite a large armamentarium of drugs already available for the management of hyperglycaemia, glucose-lowering agents are not effective in maintaining long-term glycaemic control in the majority of patients with T2DM, even when used in combination [1]. Furthermore, many anti-hyperglycaemic agents are associated with adverse events such as hypoglycaemia and/or weight gain, which exert counterproductive effects and hamper adherence to treatment. Thus, there is a medical need for improving pharmacological therapy of T2DM [2, 3]. Sodium-glucose cotransporters type 2 (SGLT2) inhibitors are new glucose-lowering agents with an original

A. J. Scheen

insulin-independent mode of action [3–6]. They specifically target the kidney by blocking the reabsorption of filtered glucose, thus leading to increased urinary glucose excretion (UGE), especially when hyperglycaemia is present [7, 8]. They also exert indirect metabolic effects beyond increased glucosuria [9]. This mechanism of action holds promise for patients with T2DM not only in terms of improvements in glycaemic control, with a limited risk of hypoglycaemia, but also considering the potential benefits of weight loss resulting from increased glucosuria and arterial blood pressure reduction associated with the osmotic diuretic effect [7, 8]. SGLT2 inhibitors may be used as monotherapy in diet-treated patients or in combination with any other glucose-lowering agent, including insulin [10– 13]. Pharmacokinetic characteristics of SGLT2 inhibitors show an excellent oral bioavailability, a rather long halflife (t‘) allowing once-daily administration, a low accumulation index, no active metabolites and a limited renal excretion [14]. Furthermore, these agents share a negligible risk of drug–drug interactions [15]. Currently, there are three SGLT2 inhibitors marketed in Europe and the USA (dapagliflozin [16–18], canagliflozin [19–21] and empagliflozin [22–24]), a few others are commercialized or approved by the regulatory agency in Japan (ipragliflozin [25], luseogliflozin [26], tofogliflozin [27]) and several others are in the late phase of clinical development (among which ertugliflozin and remogliflozin are the most advanced) [12, 13]. Chronic kidney disease (CKD) is rather prevalent in patients with T2DM, especially in the older population, and the use of most glucose-lowering agents is quite challenging in these patients [28]. Not surprisingly, the glucuretic effect of SGLT2 inhibitors decreases according to the reduction of the estimated glomerular filtration rate (eGFR), leading to a partial reduction of the glucose-lowering effect. Furthermore, safety concerns have been raised in this more fragile population with a possible higher risk of bone fractures and volume depletion events [29]. Consequently, the use of SGLT2 inhibitors is subject to restrictions in patients with CKD although they may be used in patients with mild CKD (stage 2: eGFR 60–90 mL/min/ 1.73 m2) and some may be used in patients with moderate CKD (stage 3a: eGFR 45–60 mL/min/1.73 m2). SGLT2 inhibitors have the potential to reduce arterial blood pressure, especially in hypertensive patients [30]. Based on current data, the reduction in blood pressure observed with SGLT2 inhibitors is partially due to a combination of diuresis, nephron remodelling, reduction in arterial stiffness and weight loss [30]. Correction of hypertension could contribute to reduce the progression of diabetic nephropathy. Furthermore, and interestingly enough, early tubular cell proliferation and increased sodium-glucose cotransport, as triggered by the diabetic

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD

milieu, enhance proximal tubular reabsorption and make the glomerular filtration rate (GFR) supranormal through the physiology of tubule-glomerular feedback [31, 32]. Experimental data in diabetic disease models suggest that the tubular system may play a role in the pathophysiology of the diabetic kidney [31, 32]. Therefore, the potential effects of SGLT2 inhibitors on renal function itself, and whether they may influence the development of diabetic/ hypertensive nephropathy in patients at risk, are of major clinical interest [33]. The aim of this review is to provide an updated analysis of the pharmacokinetics, pharmacodynamics, efficacy and safety profile of SGLT2 inhibitors in patients with mild to moderate CKD, with a special focus on dapagliflozin [34], canagliflozin [35], empagliflozin [36] and ipragliflozin [25]. Tofogliflozin and luseogliflozin (only commercialized in Japan) will not be considered extensively in this review in the absence of published dedicated studies in patients with CKD. To identify relevant studies, an extensive literature search in MEDLINE was performed from January 2008 to February 2015, with the following MESH terms: SGLT2 inhibition, canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin and luseogliflozin on the one hand, and CKD, renal impairment or renal insufficiency, on the other hand. No language restrictions were imposed. Reference lists of original studies, narrative reviews, previous systematic reviews and abstracts of the 2014 meetings of the American Diabetes Association and the European Association for the Study of Diabetes were also carefully examined.

2 Dapagliflozin 2.1 Pharmacokinetics Clinical pharmacokinetics and pharmacodynamics of dapagliflozin in the general population have been extensively reviewed [17]. Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-0-glucuronide (D30G; this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (\2 % of dose is recovered in urine as parent drug). In contrast, D30G elimination occurs mainly via renal excretion, with 61 % of a dapagliflozin dose being recovered as this metabolite in urine (Table 1). A single 50-mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups of subjects: healthy non-diabetic subjects; patients with T2DM and normal kidney function, and patients with T2DM and mild, moderate or severe CKD based on

693

eGFR [37]. Following a single 50-mg dose of dapagliflozin, maximum plasma concentrations (Cmax) of dapagliflozin and its inactive metabolite D3OG were incrementally increased with declining kidney function (Table 2) [37]. Total exposure (area under the concentration-time curve from zero to infinity or AUC?) was likewise higher in patients with CKD (Table 2). Values for the elimination t‘ were *3–6 h longer in patients with T2DM and CKD, but were not well correlated with the degree of CKD. Renal clearance (CLR) of dapagliflozin was correlated with the degree of CKD; however, the extent of urinary excretion, expressed as a percentage of the administered dose, indicated that urinary excretion represents a minor elimination route for dapagliflozin (0.5–1.6 % of dose), and is not well correlated with CKD. Some patients with T2DM participated in a multipledose study and received once-daily 20 mg dapagliflozin on days 4–10 [37]. Results obtained with the first dose of dapagliflozin 20 mg were comparable to those observed with the previous 50-mg single-dose study, with an increased exposure to dapagliflozin and its main metabolite according to the decline of renal function (Table 2). There were no marked differences in the steady-state pharmacokinetics of dapagliflozin and D3OG on day 10 compared with the first 20-mg dose on day 4. Modest accumulation of dapagliflozin (\40 %) from the first dose to the steadystate (seventh dose) was observed that was correlated with the degree of CKD. As observed in the single-dose study, at steadystate, both dapagliflozin and D3OG showed incrementally higher exposure with greater degrees of CKD [see the geometric mean ratios (GMRs) in the footnote of Table 2] [37]. Overall, these results indicate that the kidney, besides the liver, significantly contributes to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. 2.2 Pharmacodynamics Compared with patients with normal renal function, 24-h UGE was reduced in patients with decreased GFR after a single dose of 50 mg dapagliflozin (Table 3). These results were confirmed both after a first dose of 20 mg dapagliflozin (Table 3) and after 7 days of treatment with 20 mg dapagliflozin (steadystate). Steady-state renal glucose clearance was reduced by 42, 83 and 84 % in T2DM patients with mild, moderate or severe CKD, respectively, leading to a progressive attenuation of the glucose-lowering effect [37]. These findings are consistent with the observation of reduced efficacy in terms of glycosylated haemoglobin (HbA1c) reduction in this patient population with CKD, as discussed below.

Extensively metabolized by O-glucuronidation to two major inactive metabolites (M5 and M7) \1 % eliminated as unchanged drug in urine

1–2

118

91 12.2

Extensive glucuronidation to inactive conjugates (primarily dapagliflozin 3-0 glucuronide)

\2 % eliminated as unchanged drug in urine (primarily inactive metabolites)

tmax (h)

Volume of distribution (L)

Plasma protein binding (%) t‘ (h)

Hepatic metabolism

Urinary elimination

NA not available, SGLT2 sodium-glucose cotransporters type 2

98 11–13

119

1–2

Not clinically relevant

Not clinically relevant

Food effect

28.6 % excreted unchanged in urine

Extensively metabolized by glucuronidation, and to a lesser extent, oxidation to six inactive metabolites

86 12.4

74

1

Not clinically relevant

B1 % eliminated as unchanged drug in urine (primarily inactive metabolites)

Extensively metabolized by glucuronidation to two major inactive metabolites (M2 and M4)

NA 10–13

NA

1–2

NA

25, 50 NA

10, 25 [60 %

Suglat (Japan)

Ipragliflozin [25]

100, 300

Jardiance (Europe and USA)

Empagliflozin [22, 36]

&65

5, 10

78

Invokana (Europe and USA)

Oral bioavailability (%)

Farxiga (USA)

Forxiga (Europe)

Canagliflozin [21, 35]

Tablets (mg)

Trade name

Dapagliflozin [16, 17, 34]

NA

NA

NA 10–12

39

1–2

Not clinically relevant

NA

2.5, 5

Lusefi (Japan)

Luseogliflozin [67]

About 76 % of the dose excreted in urine mainly as metabolites (mean portion of 16.1 % as the unchanged parent drug)

Metabolism predominantly oxidative with minor glucuronide conjugates

83 6.8

50

0.75

NA

97.5

20

Apleway, Deberza (Japan)

Tofogliflozin [27, 64, 65]

Table 1 Main pharmacokinetic parameters of SGLT2 inhibitors. No clinically relevant pharmacokinetic drug–drug interactions were reported with these compounds [15]

694 A. J. Scheen

Single dose 50 mg

Kasichayanula et al. [37]

AUC0? (ngh/mL)

GMR (90 % CI)

22.7 ± 10.3a 0.67 ± 0.23a

17.4 ± 5.41a 1.50 ± 1.13a

t‘ (h)

CLR (mL/min)

0.50 ± 0.35a

21.7 ± 10.9a

1.75 (1.0–5.0)

0.17 ± 0.12a

21.6 ± 9.2a

1.5 (1.0–5.0)

NA

17.2 ± 4.9 (post)

21.4 ± 12.0a (pre)

2.0 (1.5–5.0) (post)

2.25 (1.0–6.0) (pre)

1.022 (0.727–1.436) (post) 3.5 (1.5–5.0)

1.289 (0.960–1.730)

1.75 (0.5–5.0)

1.286 (0.958–1.726)

tmax (h)

1433 ± 509a (pre)

0.989 (0.785–1.246 (post)

0.940 (0.686–1.287) (pre)

1834 ± 732

a

13,587 ± 3216a (post) 0.953 (0.770–1.179) (pre)

14,205 ± 3648a (pre)

1.125 (0.838–1.510)

1773 ± 439

a

1.505 (1.222–1.854)

21,596 ± 5485a

ESRD/haemodialysis n=8

NA

NA

NA

GMR (90 % CI)

1574 ± 482

a

1.631 (1.324–2.009)

23,311 ± 5475a

Severe CKD n=8

1.42 [30]b

NA

1.0 (0.5–2.0)

NA

NA

NA

NA

ESRD/haemodialysis

NA

NA

NA

NA

NA

NA

NA

ESRD/haemodialysis

1287 ± 277a (post)

1475 ± 669

a

1.174 (0.953–1.447)

16,719 ± 3721a

14,345 ± 3605a

Moderate CKD n=8

2.54 [71]b

NA

NAc

330 [6]b

NAc

1920 [26]b

Severe CKD n=3

0.84 [46]

b

15.0 ± 4.2a

1.17 (0.75–1.5)

1.36 (1.12–1.63)

772 [11]b

1.75 (1.49–2.07)

4884 [10]b

Severe CKD n=4

(ng/mL)

Cmax

GMR (90 % CI)

Single dose 200 mg

AUC? (ngh/mL)

Devineni et al. [46]

Dosing reference

Canagliflozin

Mild CKD n=8

2.37 [54]b

5.22 [38]b

CLR (mL/min) No CKD n=8

NA

NA

1.0 (0.5–1.0)

1.0 (1.0–6.0)

1.0 (0.5–1.5)

tmax (h)

t‘ (h)

Cmax (ng/mL) NAc

NA

NAc

249 [21]b

NA

c

1807 [31]b

GMR (90 % CI)

Kasichayanula et al. [37]

GMR (90 % CI)

c

1428 [38]b

864 [11]b

Moderate CKD n=6

2.06 [81]

466 [21]b

Single dose 20 mg

AUCtau (ngh/mL)

Mild CKD n=4

2.85 [55]

No CKD n=4

3.43 [47]

b

17.9 ± 3.4a

1.00 (0.5–3.0)

1.26 (1.09–1.45)

897 [41]b

1.52 (1.35–1.72)

5182 [38]b

Moderate CKD n=8

410 [23]b

Dosing reference

Dapagliflozin

CLR (mL/min)

b

18.4 ± 8.2a

11.9 ± 5.7a

t‘ (h) b

1.14 (1.05–1.24) 1.25 (0.5–2.0)

1.25 (0.5–2.0)

tmax (h)

902 [35]b

1.28 (1.19–1.37)

4018 [26]b

2504 [30]b 647 [37]b

Mild CKD n=8

No CKD n = 12

GMR (90 % CI)

Cmax (ng/mL)

Dosing reference

Dapagliflozin

Table 2 Key pharmacokinetic parameters of SGLT2 inhibitors in subjects with various degrees of CKD (according to eGFR) compared with subjects with normal renal function (no CKD)

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD 695

Single dose 100 mg

Inagaki et al. [47]

AUC?

(ngh/mL)

Single dose 200 mg

Inagaki et al. [47]

AUC? (ngh/mL)

GMR (90 % CI)

Single dose 50 mg Macha et al. [54]

AUC? (nmolh/L) GMR (90 % CI)

(mL/min)

28.5 [20.5]

18.6 [46.9]

b

b

0–96

24.6 [84.5]b

19.9 [58.8]b

t‘ (h)

CLR

1.188 (0.936–1.508) 2.5 (2.0–4.0)

1500 [29.4]b

1240 [23.5]b 1.0 (1.0–3.0)

12,700 [20.8]b 1.182 (0.962–1.454)

10,600 [16.4]b

tmax (h)

Mild CKD n=9

No CKD n=8

GMR (90 % CI)

Cmax (nmol/L)

Dosing reference

11.8 [69.6]

b

23.8 [87.9]b

2.0 (1.5–3.0)

1.023 (0.793–1.319)

1290 [37.9]b

13,000 [25.1]b 1.199 (0.963–1.495)

Moderate CKD n=7

11.73 ± 2.36a 0.97 ± 0.37a

14.43 ± 3.73a 1.33 ± 0.48a

t‘ (h) CLR (mL/min)

Empagliflozin

0.989 (0.827–1.182) 1.0 (1.0–2.0)

1.0 (1.0–6.0)

2333 ± 415a

tmax (h)

2416 ± 740a

1.216 (1.026–1.441)

17,835 ± 4434a

Moderate CKD n = 12

1.07 ± 0.35a

GMR (90 % CI)

Cmax (ng/mL)

No CKD n = 12

Dosing reference

Canagliflozin 14,815 ± 4162a

1.42 ± 0.62

CLR (mL/min)

15.50 ± 4.35a

12.58 ± 3.14a

t‘ (h) a

0.982 (0.821–1.173) 1.0 (1.0–3.0)

1197 ± 311a

1.258 (1.061–1.490)

8766 ± 2551a

Moderate CKD n = 12

1.0 (1.0–3.0)

Mild CKD

Mild CKD

tmax (h)

1214 ± 338a

6929 ± 1734a

No CKD n = 12d

GMR (90 % CI)

Cmax (ng/mL)

GMR (90 % CI)

Dosing reference

Canagliflozin

Table 2 continued

4.0 [30.6]

b

27.9 [76.8]b

2.0 (0.7–4.0)

1.207 (0.944–1.543)

1520 [31.6]b

17,700 [17.8]b 1.663 (1.344–2.057)

Severe CKD n=8

NA NA

NA

NA

NA

NA

NA

Severe CKD

NA

NA

NA

NA

NA

NA

NA

Severe CKD

0.5 [59.1]b

22.0 [74.3]b

2.5 (1.5–3.0)

1.038 (0.812–1.326)

1290 [27.5]b

16,600 [38.7]b 1.483 (1.199–1.834)

ESRD/haemodialysis n=8

NA NA

NA

NA

NA

NA

NA

ESRD/haemodialysis

NA

NA

NA

NA

NA

NA

NA

ESRD/haemodialysis

696 A. J. Scheen

Single dose 25 mg

Sarashina et al. [55]

AUC? (nmolh/L)

GMR (90 % CI)

NA

NA

1.213 (0.892–1.649) 1089 ± 223a 1.168 (0.853–1.599)

1045 ± 348a 1.122 (0.827–1.522)

4482 ± 1588

a

0.96 (0.77–1.19)

1626 ± 417a

1.40 (1.06–1.85)

10,506 ± 3165a

Moderate CKD n=8

13.2 [33.3]

0.936 (0.694–1.261)

8821 ± 1558

a

1.09 (0.88–1.36)

1456 ± 156a

1.26 (0.96–1.64)

8241 ± 1812a

7326 ± 2037a 1277 ± 360a

Mild CKD n=8

16.4 [23.8]

No CKD n=8

24.1 [25.3]

b

24.3 [39.2]b

2.50 (0.667–6.00)

0.922 (0.712–1.193)

1000 [26.4]b

1.438 (1.183–1.748)

10,800 [9.2]b

Moderate CKD n=8

1161 ± 358a NA

NA

5948 ± 2462

a

1.05 (0.85–1.31)

1448 ± 420a

1.47 (1.12–1.92)

12,404 ± 4906a

Severe CKD n=8

4.45 [47.4]

b

19.4 [44.7]b

3.25 (1.00–6.00)

0.940 (0.726–1.217)

1070 [42.3]

1.523 (1.253–1.852)

12,200 [40.1]b

Severe CKD n=8

NA NA

NA

NA

NA

1576 ± 404a

NA

12,687 ± 4840a

ESRD/haemodialysis n=8

NA

NA

NA

NA

NA

NA

NA

ESRD/haemodialysis

Mean [% CV]

Mean ± SD

d

Mixed group combining patients with no or mild CKD

GMR (90 % CI) only available on steady state (after 7 days of dapagliflozin 20 mg once daily): for AUCtau: 1.32 (1.14–1.52), 1.60 (1.25–2.06) and 1.87 (1.34–2.62), respectively, for mild, moderate and severe CKD vs no CKD; for Cmax: 1.04 (0.92–1.17), 1.06 (0.87–1.30) and 1.09 (0.83–1.42), respectively, for mild, moderate and severe CKD vs no CKD

c

b

a

AUC area under plasma concentration-time curve, AUC? AUC from time zero to infinity, AUCtau AUC during a dosing interval (T) at steady state, CI confidence interval, CKD chronic kidney disease, CLR renal clearance, Cmax maximum plasma concentration, CV coefficient of variation, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, GMR geometric mean ratio, NA not available, SD standard deviation, SGLT2 sodium-glucose cotransporters type 2, tmax time to reach maximum concentration, t‘ half-life

tmax values expressed as median (range)

Ferrannini et al. [62]

Cmax (ng/mL) GMR (90 % CI)

Ferrannini et al. [62]

GMR (90 % CI)

Single dose 50 mg

European subjects

Cmax (ng/mL)

Japanese subjects

100 mg

GMR (90 % CI)

GMR (90 % CI)

Single dose

AUC? (ngh/mL)

AUC? (ngh/mL)

Dosing reference

Ipragliflozin

(mL.min)

b

b

0–96 h

18.4 [33.7]b

19.1 [56.7]b

t‘ (h)

CLR

0.935 (0.722–1.210) 2.50 (1.00–4.00)

2.50 (1.00–2.50)

tmax (h)

1030 [34.4]b

1.288 (1.060–1.566)

9730 [14.7]b

7560 [14.9]b 1070 [18.1]b

Mild CKD n=8

No CKD n=8

GMR (90 % CI)

Cmax (nmol/L)

Dosing reference

Empagliflozin

Table 2 continued

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD 697

698

A. J. Scheen

Table 3 Pharmacodynamics assessed by urinary glucose excretion (UGE) of SGLT2 inhibitors in T2DM subjects with various degrees of chronic kidney disease (CKD; according to eGFR) compared with T2DM subjects with normal renal function (no CKD)

Dapagliflozin

Dosing reference

No CKD

Mild CKD

Moderate CKD

Severe CKD

Single dose 50 mg

n = 12

n=8

n=8

n=4

Kasichayanula et al. [37]

85 ± 45

51 ± 29

18 ± 18

11 ± 7a,c

Single dose 20 mg

n=4

n=4

n=6

n=3

Kasichayanula et al. [37]

63 ± 31a,c

49 ± 40a,c

20 ± 13a,c

18 ± 13a,c

Canagliflozin

Single dose 200 mg

n=3

n = 10

n=9

n = 10

n=8

UGE g/24 h

Devineni et al. [46]

50.7 ± 10.0a

26.1 ± 10.0a

10.9 ± 10.0a

4.7 ± 10.0a

NA

Single dose 100 mg Inagaki et al. [47]

n = 12 87 ± 17a

n = 12 61 ± 19a

NA

NA

Single dose 200 mg

n = 12

n = 12

Inagaki et al. [47]

103 ± 19a

71 ± 18a

NA

NA

Single dose 50 mg

n=8

n=7

n=8

UGE g/24 h

Empagliflozin UGE g/24 h UGE g/24 h

a,c

Macha et al. [54]

102.13 ± 22.40

a,c

a,c

ESRD/haemodialysis

n=9 a

a

65.75 ± 21.93

a

56.64 ± 45.30

NA NA

n=8 a

19.22 ± 11.40

2.93 ± 3.62a

Single dose 25 mg

n=8

n=8

n=8

n=8

Sarashina et al. [55]

78.0 ± 21.6a

66.5 ± 20.0a

58.7 ± 13.0a

21.7 ± 11.64a

Ipragliflozin

Single dose 100 mg

n=8

n=8

n=8

n=8

UGE g/24 h

Ferrannini et al. [62]

64.8 [37.4]b

77.8 [64.8]b

18.7 [21.6]b

11.5 [10.1]b

NA

NA

NA

NA

Caucasian subjects UGE g/24 h

Single dose 50 mg

n=8

n=9

n=8

Ferrannini et al. [62]

110.9 [106.6]b

63.4 [31.7]b

40.3 [25.9]b

Japanese subjects CV coefficient of variation, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, NA not available, SD standard deviation, SGLT2 sodium-glucose cotransporters type 2, T2DM type 2 diabetes mellitus, UGE urinary glucose excretion a

Mean ± SD

b

Median [interquartile range]

c

Approximate values calculated from available data derived from a figure in supplementary materials [37]

2.3 Clinical Efficacy Dapagliflozin reduced hyperglycaemia in patients with T2DM and normal or mildly impaired renal function [16]. The primary efficacy endpoint of trials in monotherapy or as add-on therapy was the change from baseline in HbA1c after 24 weeks, although various other outcomes were also evaluated, including the proportion of patients achieving target HbA1c and the changes from baseline in fasting plasma glucose levels, body weight and blood pressure [16, 18]. The efficacy of dapagliflozin has been evaluated in a randomized placebo-controlled clinical trial as add-on therapy to usual care in 252 T2DM patients with moderate CKD (&90 % of patients with stage 3CKD: eGFR C30 to \60 mL/min/1.73 m2) [29]. The mean change in HbA1c was not statistically different from placebo after 24 weeks (-0.41 and -0.44 % for 5- and 10-mg doses, respectively, and -0.32 % for placebo) (Table 4). The mean weight change from baseline was -1.54 and -1.89 kg for the 5and 10-mg doses, respectively, and ?0.21 kg for placebo. The mean systolic and diastolic blood pressure decreased

in the dapagliflozin groups compared with placebo. Thus, in patients with moderate CKD, dapagliflozin did not improve glycaemic control, but reduced body weight and blood pressure (Table 4). Currently, dapagliflozin is not recommended in T2DM patients with eGFR \60 mL/min/ 1.73 m2 [34]. 2.4 Overall Safety in Patients with CKD Overall, the tolerance and safety of dapagliflozin appear good. The most frequent adverse event associated with the SGLT2 inhibitor is the occurrence of mycotic genital infections, especially in women, resulting from the glucuretic effect [16, 18]. The tolerance and safety profile was almost similar in diabetic patients with CKD as that reported in the overall diabetic population. Nevertheless, concern about a possible higher risk of bone fractures has been raised. In an extension follow-up up to 104 weeks, 13 (7.7, 5 % at 5 mg and 8 % at 10 mg) patients with moderate CKD receiving dapagliflozin and no patients receiving placebo experienced bone fracture. Of the 13 patients reporting fracture, five had stage 3a CKD (C45 to \60 mL/min/1.73 m2) and

Stage 3 CKD eGFR: C30 to\50 mL/min/ 1.73 m2

Yale et al. [51]

Stage 3 CKD eGFR: C30 to\50 mL/min/ 1.73 m2

Yale et al. [50]

Canagliflozin

C30 to \60 mL/min/1.73 m2)

(&90 % stage 3 CKD

Stage 2–4 CKD eGFR: \30 to \90 mL/ min/1.73m2

Kohan et al. [29]

Dapagliflozin

Study stage CKD

89

90

Placebo

90

100 mg qd

300 mg qd

90

Placebo

90

84

85

83

Patients (n)

89

52

26

24

Duration (weeks)

300 mg qd

100 mg qd

Placebo

10 mg qd

5 mg qd

Treatment (mg) (once daily)

8.0 ± 0.9

8.0 ± 0.8

7.9 ± 0.9

8.0 ± 0.9

8.0 ± 0.8

7.9 ± 0.9

8.53 ± 1.29

8.22 ± 0.97

8.30 ± 1.04

?0.07

p = NA

-0.41 (-0.68, -0.14)

Placebo-subtracted

-0.33

p = NA

-0.27 (-0.53, 0.001)

Placebo-subtracted

-0.19

-0.03

p \ 0.001

-0.44

p \ 0.05

-0.33

-0.32 ± 0.17

p = 0.435

-0.44 ± 0.17

p = 0.561

-0.41 ± 0.17

92.8 ± 17.4

90.2 ± 18.1

90.5 ± 18.4

92.8 ± 17.4

90.2 ± 18.1

90.5 ± 18.4

89.6 ± 20.1

93.3 ± 17.3

95.2 ± 20.9

-0.01

p = NA

-0.8 (-1.8, 0.2)

Placebosubtracted

-1.3

p = NA

-1.3 (-2.3, -0.3)

Placebosubtracted

-1.8

p = NA

?0.2 ± NA

p = NA

-1.4 ± NA

p = NA

-1.2 ± NA

?0.68 ± 0.45

p = NA

-1.72 ± 0.44

p = NA

-1.34 ± 0.43

Change from baseline

Baseline

Baseline

Change from baseline

Mean body weight (kg)

Mean HbA1c (%)

132.1 ± 13.6

136.7 ± 15.0

135.9 ± 13.1

132.1 ± 13.6

136.7 ± 15.0

135.9 ± 13.1

130.7 ± 14.1

133.7 ± 17.0

131.8 ± 17.9

Baseline

-0.01 ± 1.4

-6.7 (-10.5, -2.9)

Placebo-subtracted

-6.7 ± 2.4

p = NA

-5.5 (-9.3, -1.7)

Placebo-subtracted

-5.5 ± 2.0

-0.3 ± 1.5

p = NA

-6.4 ± 1.5

p = NA

-6.1 ± 1.5

-4.1 ± 1.5

p = NA

-2.5 ± 1.8

p = NA

-0.25 ± 2.0

Change from baseline

Mean systolic blood pressure (mmHg)

Table 4 Randomized placebo-controlled clinical trials investigating the efficacy of dapagliflozin, canagliflozin, empagliflozin and ipragliflozin as add-on therapy to usual care in patients with T2DM and various degrees of chronic kidney disease. Results are expressed as mean ± SD for baseline values and as mean ± SE or as mean (95 % CI) for changes from baseline. p-values correspond to differences vs placebo

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD 699

Stage 4 CKD eGFR: C15 to \30 mL/ min/1.73 m2

Barnett et al. [56]

Stage 3 CKD eGFR: C30 to \60 mL/ min/1.73 m2

Barnett et al. [56]

eGFR: C60 to \90 mL/min/1.73 m2

Stage 2 CKD

Barnett et al. [56]

Empagliflozin

Study stage CKD

Table 4 continued

187

25 mg qd

Placebo

37

37

25 mg qd

37 37

52

24

Placebo

25 mg qd

187

187

25 mg qd

Placebo

187

Placebo 52

95

Placebo 24

97

98

10 mg qd

25 mg qd

95

Placebo

98

Patients (n)

97

52

24

Duration (weeks)

25 mg qd

10 mg qd

Treatment (mg) (once daily)

8.16 ± 0.99

8.06 ± 1.05

8.16 ± 0.99

8.06 ± 1.05

8.09 ± 0.80

8.02 ± 0.84

8.09 ± 0.80

8.02 ± 0.84

8.09 ± 0.80

7.96 ± 0.73

8.02 ± 0.84

8.09 ± 0.80

7.96 ± 0.73

8.02 ± 0.84

-0.46 (-0.60 to -0.32)

-0.37 ± 0.79

NS

0.11 ± 1.48

-0.18 ± 0.77

NS

?0.04 ± 1.62

?0.12 (0.00 to 0.24)

p \ 0.0001

-0.32 (-0.44 to -0.20)

?0.05 (-0.05 to 0.15)

-0.37 (-0.47 to -0.27) p \ 0.0001

?0.06 (-0.10 to 0.22)

p \ 0.0001

-0.60 (-0.76 to -0.44)

p \ 0.0001

-0.57 (-0.73 to -0.41)

?0.06 (-0.08 to 0.20)

p \ 0.0001

-0.63 (-0.77 to -0.49)

p \ 0.0001)

84.1 ± 21.1

77.9 ± 16.4

84.1 ± 21.1

77.9 ± 16.4

82.5 ± 18.0

83.2 ± 19.5

82.5 ± 18.0

83.2 ± 19.5

86.0 ± 20.0

88.1 ± 21.7

92.1 ± 21.4

86.0 ± 20.0

88.1 ± 21.7

92.1 ± 21.4

0 ± 3.6

p = NA

-1.0 ± 3.3

-0.1 ± 1.9

p = NA

-1.4 ± 5.0

0.00 (-0.41 to 0.41)

p \ 0.0001

-1.17 (-1.58 to 0.76)

-0.08 (-0.43 to 0.27)

p = 0.0004

-0.98 (-1.33 to -0.63)

-0.44 (-1.07 to 0.19)

p \ 0.0001

-2.60 (-3.23 to -1.97)

p = 0.0006

-2.00 (-2.63 to -1.37)

-0.33 (-0.80 to 0.14)

p \ 0.0001

-2.33 (-2.70 to -1.88)

p \ 0.0001

-1.76 (-2.21 to -1.31)

Change from baseline

Baseline

Baseline

Change from baseline

Mean body weight (kg)

Mean HbA1c(%)

146.2 ± 22.0

145.0 ± 20.6

146.2 ± 22.0

145.0 ± 20.6

134.7 ± 17.0

137.4 ± 15.0

134.7 ± 17.0

-3.9 (-5.7 to -2.0)

137.4 ± 15.0

?1.0 ± 17.4

p = NA

-11.2 ± 15.7

?1.2 ±16.3

p = NA

-7.4 ± 16.9

(-2.8 to 1.2)

-0.8

p = 0.0023

(-7.1 to -3.1)

-5.1

(-1.4 to 2.2)

?0.4

p = 0.0013

?1.6 (-1.0 to 4.2)

p \ 0.0001

-6.2 (-8.8 to -3.7)

p = 0.0745

-1.7 (-4.3 to 0.9)

?0.7 (-1.7 to 3.0)

p = 0.0024

-4.5 (-6.8 to -2.2)

p = 0.0333

(-5.2 to 0.6)

-2.9

Change from baseline

134.7 ± 17.0

133.7 ± 17.7

137.4 ± 15.0

134.7 ± 17.0

133.7 ± 17.7

137.4 ± 15.0

Baseline

Mean systolic blood pressure (mmHg)

700 A. J. Scheen

p = 0.215

-0.09 ± 0.51 Stage 3 CKD eGFR C30 to \60 mL/min/ 1.73 m2

NA et al. [63]

23 Placebo

CI confidence interval, CKD chronic kidney disease, eGFR estimated glomerular filtration rate, NA not available, NS not significant, qd once daily, SD standard deviation, SE standard error, T2DM type 2 diabetes mellitus

-2.8 ± 9.8

p = NA

p = NA

134.3 ± 12.8 -0.07 ± 1.16

p \ 0.001

NA

-2.5 ± 10.6

-5.4 ± 16.4

133.8 ± 12.3

132.7 ± 14.1 -1.85 ± 1.43

-0.19 ± 1.75 NA

NA -0.28 ± 0.58

-0.26 ± 0.52 NA

NA 58

23

701

24 Placebo

50 mg qd

NA 60 24

Stage 2 CKD eGFR C60 to \90 mL/min/ 1.73 m2

Kashiwagi

-3.8 ± 16.1

p = NA

133.3 ± 10.8 -1.88 ± 1.73

p \ 0.001

NA 50 mg qd Kashiwagi et al. [63]

46

-0.56 ± 0.40

-0.17 ± 0.52 7.52 ± 0.54 Placebo Stage 2–3 CKD eGFR C30 to \90 mL/ min/1.73 m2

118 24 50 mg qd Kashiwagi

Ipragliflozin

p \ 0.001

-2.7 ± 10.1

p = NA

134.1 ± 12.4 -0.06 ± 1.47 66.5 ± 10.6

-4.6 ±16.2

p = NA

133.0 ± 12.5 -1.87 ± 1.58 69.1 ± 11.7 p = 0.004

7.52 ± 0.55

-0.42 ± 0.51

et al. [63]

Patients (n) Duration (weeks) Treatment (mg) (once daily) Study stage CKD

Table 4 continued

p \ 0.001

Change from baseline Baseline Change from baseline Baseline Baseline

Change from baseline

Mean body weight (kg) Mean HbA1c(%)

Mean systolic blood pressure (mmHg)

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD

eight had stage 3b CKD (C30 to \45 mL/min/1.73 m2) [29]. However, this imbalance in bone fractures between the dapagliflozin-treated group and the non-dapagliflozintreated group was not confirmed in a larger pooled data set of patients with renal impairment [38]. 2.5 Effects on Renal Function In patients with T2DM receiving SGLT2 inhibitors in phase II–III randomized controlled trials, pyelonephritis was rare and balanced among treatments [39]. In a pooled data analysis from 21 phase IIb/III trials in 9339 T2DM patients, dapagliflozin 10 mg was associated with a slight increase of renal adverse events, mostly transient creatinine changes, but not of renal severe adverse events, compared with placebo. The difference was primarily driven by the subgroup of patients with eGFR C30 to\60 mL/min/1.73 m2 at baseline [40]. Volume depletion events and urinary volume events were slightly more common with dapagliflozin than with placebo, predominantly in at-risk subjects (patients taking diuretics, older patients and patients with moderate CKD), but were mostly mild and did not lead to study discontinuation [41]. In patients with moderate CKD, the mean serum creatinine slightly increased with dapagliflozin 5 and 10 mg at 1 week, and did not change further after 104 weeks. Mean serum electrolytes did not change in any group, and there were fewer episodes of hyperkalaemia with dapagliflozin than placebo [29]. Dapagliflozin 10 mg does not appear to increase the risk of hyperkalaemia in a pooled data analysis from 13 placebo-controlled studies of up to 24 weeks’ duration and in a dedicated study in patients with renal impairment (eGFR C30 to \60 mL/min/1.73 m2) [42]. Dapagliflozin-induced SGLT2 inhibition for 12 weeks was associated with reductions in 24-h blood pressure, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower blood pressure in addition to beneficial effects on glycaemic control [43]. In a pre-specified pooled analysis of 12 placebo-controlled studies for 24 weeks, dapagliflozin 10 mg was associated with a mean change from baseline in systolic blood pressure of 4.4 mmHg and in diastolic blood pressure of 2.1 vs 0.9 and 0.5 mmHg, respectively, in the placebo group [44]. Reductions of hyperglycaemia and blood pressure, indirectly, may have benefits for the prevention of diabetic renal disease [30]. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT2, including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as to reduce the tubular toxicity of glucose [31, 32]. Some studies have demonstrated significant reductions in albumin excretion in various experimental models,

702

independent of the effects of SGLT2 inhibition on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress [45].

3 Canagliflozin 3.1 Pharmacokinetics The pharmacokinetics/pharmacodynamics and metabolism of canagliflozin have been recently reviewed [19, 20]. Canagliflozin undergoes O-glucuronidation. There are two major human metabolites, ether (O)-glucuronides M5 and M7. Both are chemically nonreactive and pharmacologically inactive with respect to SGLT2 and SGLT1 inhibition in vitro. Canagliflozin is extensively protein bound ([99 %). Excretion of canagliflozin and its metabolites occurs primarily in the faeces (60 %) and urine (32.5 %) (Table 1) [20]. An open-label, phase I, single-dose study evaluated the pharmacokinetics and pharmacodynamics of canagliflozin in non-diabetic Caucasian subjects with different degrees of CKD compared with healthy subjects [46]. Canagliflozin AUC? and Cmax were slightly higher in subjects with mild CKD and modestly higher in subjects with moderate to severe CKD, but not in patients with end-stage renal disease (ESRD), than in those with normal function (Table 2). Canagliflozin was negligibly removed by haemodialysis [46]. In Japanese patients with T2DM, there was no significant effect of moderate CKD on canagliflozin Cmax after a single administration of canagliflozin 100 and 200 mg (Table 2). Canagliflozin exposure (AUC?) was greater in those with moderate CKD than in those without, after both canagliflozin doses (Table 2). Thus, the pharmacokinetics of canagliflozin are affected by renal function, with slight decreases in renal clearance observed [47]. A phase I study evaluated the effects of hydrochlorothiazide (25 mg once daily for 28 days) on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin (300 mg once daily for 7 days) in healthy subjects. Canagliflozin AUC during a dosing interval (T) at steady state (AUCtau,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with hydrochlorothiazide, with GMRs (90 % confidence interval [CI]) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUCtau,ss and Cmax,ss for hydrochlorothiazide were similar with and without canagliflozin coadministration [48].

A. J. Scheen

3.2 Pharmacodynamics UGE after canagliflozin administration decreased as renal function declined (Table 3). Following canagliflozin treatment, the renal threshold for glucose was modestly higher in subjects with moderate to severe CKD than in subjects with normal function and mild CKD, and the pharmacodynamic response to canagliflozin declined with increasing severity of CKD [46]. Across all renal function groups (normal renal function, mild CKD, moderate CKD, severe CKD), canagliflozin treatment increased 24-h UGE relative to baseline. However, the extent of the increase in UGE from baseline progressively decreased with decreasing eGFR. In Japanese patients with T2DM, delta UGE24 h increased after administration of 100- and 200-mg canagliflozin doses, but in patients with moderate CKD, the increase was approximately 70 % of that in patients with normal renal function or mild CKD. Thus, CKD reduced the ability of canagliflozin to promote UGE (Table 3) [47]. Adding canagliflozin treatment to healthy participants on hydrochlorothiazide treatment had no notable pharmacodynamic drug–drug interactions [48]. 3.3 Clinical Efficacy In a post-hoc analysis of a pooled population (eight randomized placebo-controlled and active-controlled studies over 26–52 weeks) in T2DM patients who had a reduction in eGFR from C60 mL/min/1.73 m2 to C45 and \60 mL/ min/1.73 m2 at the last post-baseline follow up (n = 664 among a total of 9439 patients; 7 %), canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight and systolic blood pressure, consistent with the overall population [49]. The efficacy of canagliflozin has been evaluated in patients with moderate (stage 3) CKD [50, 51]. In this randomized, double-blind, placebo-controlled, phase III trial in T2DM subjects (n = 269), both 100- and 300-mg doses of canagliflozin reduced HbA1c from baseline compared with placebo at week 26 (Table 4). Numerical reductions in fasting plasma glucose and higher proportions of subjects reaching HbA1c \7.0 % were observed with canagliflozin 100 and 300 mg vs placebo (27.3, 32.6 and 17.2 %) [50]. At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (Table 4); placebosubtracted differences (95 % CI) were -0.27 % (-0.53, 0.001) and -0.41 % (-0.68, -0.14). In this study in patients with moderate CKD, canagliflozin also lowered fasting plasma glucose, body weight and blood pressure vs placebo [51].

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD

A post-hoc analysis used integrated data from four randomized, placebo-controlled, phase III studies that enrolled a proportion of patients with T2DM and stage 3 CKD: stage 3a CKD (eGFR C45 and \60 mL/min/1.73 m2) and stage 3b CKD (eGFR C30 and \45 mL/min/1.73 m2) [52]. Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47 %; p \ 0.001), body weight (-1.6 % and -1.9 %; p \ 0.001) and systolic blood pressure (-2.8 and -4.4 mmHg; p \ 0.01) were seen with canagliflozin 100 and 300 mg, respectively [52]. The maximum recommended dosage is canagliflozin 100 mg once daily in patients with moderate RI, but the drug is not recommended in those with eGFR of \45 mL/ min/1.73 m2 [35]. A recent paper highlighted the US Food and Drug Administration’s quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing of canagliflozin in patients with renal impairment [53]. 3.4 Overall Safety in Patients with CKD The overall tolerability and safety profile of canagliflozin is good. As explained by the mechanism of action of SGLT2 inhibition, the most frequently reported adverse events with canagliflozin 100 or 300 mg once daily in clinical trials were genital mycotic infections mainly in women and, to a lesser degree, mild urinary tract infections [21]. In subjects with T2DM and stage 3 CKD, slightly higher rates of urinary tract infections and adverse events related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with canagliflozin 100 mg and placebo [50]. 3.5 Effects on Renal Function In a pooled analysis of eight randomized controlled trials, canagliflozin was generally well tolerated with a low incidence of volume depletion-related adverse events [49]. In patients with normal renal function or mild CKD, canagliflozin 300 mg was associated with slightly increased incidence of rare renal-related adverse events compared with placebo [10]. In a pooled analysis of patients with stage 3a and 3b CKD, initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time [52]. Similarly, in a specific trial in subjects with T2DM and stage 3 CKD, transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin [50]. At 52 weeks, decreases in eGFR (-2.1, -4.0 and -1.6 mL/min/1.73 m2) were seen with canagliflozin 100 and 300 mg compared with placebo. However, canagliflozin 100 and 300 mg provided median

703

percent reductions in urine albumin to creatinine ratio vs placebo (-16.4, -28.0 and 19.7 %, respectively) [51]. Two specific trials are currently investigating the effects of canagliflozin on renal endpoints in adult participants with T2DM: CANVAS-R (ClinicalTrials.gov Identifier: NCT01989754) and CREDENCE (ClinicalTrials.gov Identifier: NCT02065791). These trials should confirm whether canagliflozin can slow the progression of diabetic nephropathy in T2DM as suggested by the effects of SGLT2 inhibitors in animal models [31, 32].

4 Empagliflozin 4.1 Pharmacokinetics The pharmacokinetic properties of empagliflozin have been reviewed [22]. Empagliflozin is rapidly absorbed with a mean t‘ of between 13 and 17 h. Glucuronidation is the major metabolic pathway for empagliflozin, and no major metabolites of empagliflozin were detected in human plasma. Approximately 11–19 % of the administered dose is excreted unchanged in urine (Table 1) [22, 23]. The effect of impaired kidney function on the pharmacokinetics of empagliflozin was investigated in Caucasian subjects with different degrees of CKD, who received a single dose of empagliflozin 50 mg [54]. The rate of absorption was slightly slower in subjects with CKD compared with those with normal renal function, with a median tmax of 2.0–2.5 and 1.0 h, respectively [54]. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion, which is consistent with previous reports in healthy subjects and patients with T2DM with normal kidney function [54]. Empagliflozin AUC values increased by approximately 18, 20, 66 and 48 % in subjects with mild, moderate, severe CKD and ESRD, respectively, in comparison to healthy subjects, which was attributed to decreased renal clearance (Table 2) [54]. There were also decreases in the mean fraction of the dose excreted in urine following drug administration with increasing CKD [54]. Because the increase in drug exposure remained rather limited, no dose adjustment of empagliflozin is required in patients with CKD. In Japanese patients with T2DM, exposure increased with the severity of CKD. Empagliflozin Cmax values were similar among all renal function groups. Adjusted GMRs for extent of exposure (AUC?) to empagliflozin vs normal renal function were rather modestly increased for patients with mild, moderate and severe CKD (Table 2). Decreases in renal clearance of empagliflozin correlated with eGFR. As for Caucasian patients, pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and CKD because increases in exposure were \2-fold [55].

704

4.2 Pharmacodynamics The cumulative UGE over 24 h decreased with increasing CKD (Table 3). The decrease in UGE followed the same pattern as the decreases in the empagliflozin renal clearance with increasing CKD [54]. Similarly, in Japanese patients with T2DM, UGE decreased with increasing renal impairment and correlated with eGFR (Table 3) [55]. 4.3 Clinical Efficacy In patients with T2DM and stage 2 or 3 CKD, empagliflozin as add-on to usual care reduced HbA1c (Table 4) [56]. In patients with stage 2 CKD, adjusted mean placebo-subtracted changes from baseline in HbA1c at week 24 were -0.52 % for empagliflozin 10 mg and -0.68 % for empagliflozin 25 mg (both p \ 0.0001). In patients with stage 3 CKD, the corresponding change was -0.42 % for empagliflozin 25 mg (p \ 0.0001). In patients with stage 4 CKD, no significant reduction in HbA1c was observed after empagliflozin 25 mg compared with placebo (Table 4).

A. J. Scheen

placebo and was well tolerated. Small decreases in eGFR were seen in the 25-mg empagliflozin group, which returned to baseline at follow-up [57]. In a post-hoc pooled analysis from 458 T2DM patients with pre-existing microalbuminuria, empagliflozin 10 and 25 mg significantly (p \ 0.01) reduced urinary albumin creatinine ratio by 30 and 25 %, respectively, compared with placebo at week 24. This effect was observed when empagliflozin was used as add-on to standard therapy including stable inhibition of the renin-angiotensin system [58]. Interestingly, short-term treatment with empagliflozin attenuated renal hyperfiltration in subjects with type 1 diabetes, likely by affecting tubular-glomerular feedback mechanisms [59]. These findings, although preliminary, suggest that SGLT2 inhibitors may have a role in diabetic CKD [33]. Further studies are required to investigate the long-term renal outcomes with SGLT2 inhibitors in patients with T2DM [45]. This issue will be evaluated as a secondary endpoint in an ongoing 4-year trial comparing empagliflozin and glimepiride in patients with T2DM inadequately controlled with metformin and diet/exercise [60].

4.4 Overall Safety in Patients with CKD

5 Ipragliflozin The overall safety profile of empagliflozin [24] is comparable to that of dapagliflozin and canagliflozin. In patients with T2DM and stage 2 or 3 CKD, empagliflozin was well tolerated [56]. In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87 %) taking placebo, 86 (88 %) taking empagliflozin 10 mg and 78 (80 %) taking empagliflozin 25 mg. In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83 %) taking placebo and 156 patients (83 %) taking empagliflozin 25 mg. In both stage 2 and stage 3 CKD patients, the incidence of severe and serious adverse events was similar in subjects treated with empagliflozin and in those receiving placebo. Again, as in T2DM patients with normal kidney function, the most commonly reported drug-related adverse event was mycoticgenital infections, with a rather low rate of urinary tract infections. The recommended maximum daily dose of empagliflozin in patients with stage 3 CKD is 10 mg and the drug should be discontinued when eGFR is persistently below 45 mL/min/1.73 m2 [36]. 4.5 Effect on Renal Function Patients (n = 825) with T2DM and hypertension were randomized to 10 or 25 mg empagliflozin or placebo once daily for 12 weeks. Empagliflozin was associated with significant reductions in blood pressure and HbA1c vs

Ipragliflozin (SuglatÒ, Japan) is the first SGLT2 inhibitor to be approved in Japan [25]. The clinical pharmacokinetics/pharmacodynamics of ipragliflozin have been recently discussed [61]. The majority of radioactivity in urine was excreted as metabolites, with B1 % of the dose excreted as unchanged ipragliflozin after a single oral dose of 100 mg ipragliflozin. The major metabolite in urine was M2 (20 -0-b-glucuronide of ipragliflozin), which contributed to 33.5 % of the dose excreted in the urine. None of the metabolites of ipragliflozin, including M2, is pharmacologically active (Table 1). 5.1 Pharmacokinetics In a study designed to investigate the effects of renal impairment on the pharmacokinetics of ipragliflozin in Japanese T2DM patients, Cmax and AUC? were 1.17 times and 1.21 times higher, respectively, in subjects with moderate CKD than in subjects with normal renal function (Table 2) [61, 62]. In another study performed in European T2DM patients with moderate and severe CKD, the AUC? of ipragliflozin was, respectively, 40 and 47 % higher compared with T2DM patients with normal renal function (Table 2) [62]. Considering these rather modest increases in total exposure, adjustment of the daily dose of ipragliflozin is not necessary in presence of CKD.

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and CKD

5.2 Pharmacodynamics In the latter study, ipragliflozin increased glucosuria in direct linear proportion to the GFR and the degree of hyperglycaemia. Although absolute glucosuria (UGE) decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) was maintained in patients with severe CKD [62]. 5.3 Clinical Efficacy and Safety A cohort of Japanese patients with T2DM and mild to moderate CKD and poor glycaemic control, despite diet/ exercise therapy alone or in combination with an oral hypoglycaemic agent, were randomized in a double-blind manner to 50 mg ipragliflozin or placebo once daily for 24 weeks [63]. Ipragliflozin significantly decreased HbA1c and fasting plasma glucose levels and body weight from baseline to week 24 compared with placebo in all patients with CKD. However, the decreases in HbA1c and fasting plasma glucose levels were statistically significant in patients with mild CKD, but not in patients with moderate CKD (Table 4). Ipragliflozin significantly reduced body weight in both CKD groups. The improvements in glycaemic control were maintained in an open-label 28-week extension period. Ipragliflozin was associated with no clinically significant safety concerns, and its safety profiles were not influenced by the severity of CKD [63]. Thus, ipragliflozin is a valid treatment option for patients with mild renal impairment but not those with moderate renal impairment.

6 Other SGLT-2 Inhibitors Published data regarding other SGLT2 inhibitors commercialized in Japan or still in development, especially in patients with CKD, are scarce [12]. The metabolism and the mass balance of tofogliflozin was evaluated following administration of a single oral dose of 20 mg [14C]-tofogliflozin to Japanese healthy subjects [64]. Tofogliflozin was completely absorbed with subsequent predominate metabolic clearance and a small contribution of direct urinary elimination. Approximately, 76 % of the dose was excreted in urine and 20 % in faeces within 72 h. The phenyl acetic acid metabolite M1 was the major component excreted in urine and faeces, accounting for more than half of the dose [64]. In another study, the main route of elimination of the total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose) [65]. The observed CLR was higher than the product of the eGFR and fraction unbound in plasma, indicating the

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presence of net active tubular secretion in the renal elimination of tofogliflozin. Tofogliflozin exhibited favourable pharmacokinetic properties as demonstrated by its high bioavailability, low total clearance and a low volume of distribution at steadystate (Table 1) [27, 65]. An active tubular secretion of tofogliflozin ensured a high exposure of the medication to the target region of the kidney (i.e., proximal tubule) [65]. However, CLR contributed only 15.5 % to the total clearance of tofogliflozin, suggesting that reductions in CLR by renal impairment will not significantly affect systemic exposure to tofogliflozin [65]. Indeed, CKD did not have a significant effect on systemic exposure to tofogliflozin in 36 patients with T2DM with varying degrees of renal function (preliminary data only available in abstract form) [66]. Patients had eGFRs ranging from 8 to [90 mL/min. Impaired renal function did not affect systemic exposure of tofogliflozin significantly. No significant relationship between oral clearance and eGFR was observed. Although lower UGE correlated with lower eGFR, the inhibition of renal glucose reabsorption was constant across all renal function groups. This may indicate that tofogliflozin reached its target in the kidney independent of renal function [27]. The safety, pharmacokinetics and pharmacodynamics of luseogliflozin were investigated in Japanese healthy male subjects [67]. After administration of a single oral dose of luseogliflozin, its Cmax and AUC increased in a dose-dependent manner. The mean Tmax ranged from 0.667 to 2.25 h and the mean plasma t‘ averaged &10 h (Table 1). UGE increased in a dose-dependent manner, ranging from 18.9 to 70.9 g [67]. The influence of renal function on the efficacy and safety of luseogliflozin was analyzed in pooled data from four, 52-week, phase III studies in Japanese patients with T2DM and various levels of renal function. Mean HbA1c changes from baseline at week 52 were -0.67, -0.55 and -0.32 % in normal renal function, mild CKD and moderate CKD, respectively. Luseogliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and moderate renal impairment [68]. The disposition of ertugliflozin (PF-04971729) was studied after a single 25-mg oral dose of [14C]-ertugliflozin given to healthy human subjects [69]. Ertugliflozin is well absorbed and eliminated largely via glucuronidation. No data are available yet in patients with CKD. A dose-escalation study with remogliflozin etabonate was performed in healthy subjects and in subjects with T2DM, showing that the drug is rapidly absorbed and rapidly eliminated (mean t‘ around 120 min) [70]. No data about renal clearance of the drug were reported in this study.

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7 Conclusion In contrast to all other glucose-lowering medications, SGLT2 inhibitors specifically act in the kidney. Therefore, special attention should paid to patients with CKD or those who are susceptible of developing diabetic nephropathy. Impaired renal function may interfere with the pharmacokinetic/pharmacodynamic parameters of SGLT2 inhibitors and it may alter their glucose-lowering efficacy/ safety profile. Because the renal clearance of available SGLT2 inhibitors (dapagliflozin, canagliflozin empagliflozin, ipragliflozin) is low, CKD only marginally affects pharmacokinetic parameters and exposure to the parent drug; most metabolites eliminated in the urine are inactive and thus do not interfere with the pharmacological effects of the medications. According to reported changes in systemic exposure, the daily dose of dapagliflozin and empagliflozin should not be reduced in patients with moderate CKD whereas the maximum dose recommended for canagliflozin is 100 mg in the case of moderate CKD instead of 300 mg in patients with normal renal function or mild CKD. Pharmacodynamic changes associated with SGLT2 inhibitors are dependent on renal function and UGE progressively decreases with the degree of CKD, leading to a progressive attenuation of the glucose-lowering effects in T2DM patients. Nevertheless, despite the reduction in UGE in proportion to decreased GFR, the glucose-lowering efficacy of SGLT2 inhibitors was demonstrated in patients with mild to moderate degree of CKD. Furthermore, SGLT2 inhibitors have been shown to be safe in diabetic patients with mild to moderate CKD. All drugs that may decrease GFR may also reduce the glucose-lowering effects of SGLT2 inhibitors. In clinical practice, renal function should be regularly monitored in diabetic patients treated with SGLT2 inhibitors, especially in patients with mild/moderate CKD and in the older population, and all agents that may interfere with kidney function should be used with caution. The approved SGLT2 inhibitors have limited use based on kidney function and should be prescribed only in those with an eGFR [60 mL/min/1.73 m2 for dapagliflozin and C45 mL/min/ 1.73 m2 for canagliflozin, empagliflozin and most probably ipragliflozin. Dose adjustment and special caution may be recommended in patients taking loop diuretics, especially in older people, if there are concerns or symptoms of volume depletion-related adverse effects. Finally, clinical data supporting nephroprotective effects of SGLT2 inhibitors currently are limited compared with the more extensive experimental literature in favour of such a positive action. Ongoing controlled clinical studies should provide further evidence to support this concept.

A. J. Scheen Funding and conflict of interest No sources of funding were used to assist in the preparation of this manuscript. No conflicts of interest are directly relevant to the content of this manuscript. A. J. Scheen has received lecture/advisor fees from AstraZeneca/ BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi-Aventis and Takeda.

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