248 Diabetes Volume 68, February 2019

Sodium–Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease

Radica Z. Alicic,1,2 Joshua J. Neumiller,3 Emily J. Johnson,1 Brad Dieter,1 and Katherine R. Tuttle1,2,4,5

Diabetes 2019;68:248–257 | https://doi.org/10.2337/dbi18-0007

Diabetic kidney disease (DKD) is now the principal cause complications is also rapidly escalating. Approximately of chronic kidney disease leading to end-stage kidney half of individuals with type 2 diabetes (T2D) and one- disease worldwide. As a primary contributor to the ex- third of people with type 1 diabetes (T1D) develop diabetic cess risk of all-cause and cardiovascular death in di- kidney disease (DKD), a microvascular complication that is abetes, DKD is a major contributor to the progressively now the leading cause of chronic kidney disease (CKD) and expanding global burden of diabetes-associated mor- end-stage kidney disease (ESKD) in the world (4–6). bidity and mortality. Sodium–glucose cotransporter For people with diabetes, development of kidney dis- 2 (SGLT2) inhibitors are a newer class of antihypergly- ease increases the risk of death by five- to sixfold (7–9). cemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials Tragically, approximately 90% of patients with DKD die of SGLT2 inhibitors have consistently demonstrated before requiring kidney replacement therapy (KRT). reduction of albuminuria and preservation of kidney Among those who reach ESKD, the risk of death is 10- function. In particular, SGLT2 inhibitors lower risk of to 100-fold higher than for individuals with normal kidney congestive heart failure, a major cardiovascular compli- function (10). Depending on the country, only 10%–50% cation in DKD. This Perspective summarizes proposed of those who need KRT will ever receive it (10). Thus, in mechanisms of action for SGLT2 inhibitors, integrates many parts of the world, ESKD equates to a virtual death these data with results of recent cardiovascular out- sentence (10–12). Although survival rates for patients comes trials, and discusses clinical applications for receiving KRT have improved modestly over the past patients with DKD. The American Diabetes Association/ PERSPECTIVES IN DIABETES few decades, the increased risk of death remains unac- European Association for the Study of Diabetes Consensus ceptably high, as one-third of those treated by mainte- Report published online in October 2018 recommends nance dialysis die within 3 years of initiation (13). SGLT inhibitors as preferred add-on therapy for patients Achieving glycemic control with conventional blood with type 2 diabetes and established cardiovascular – disease or chronic kidney disease, if kidney function is glucose lowering therapies early in the course of T1D or adequate. Results of the ongoing and just completed T2D reduces, but does not eliminate, the risk of developing clinical trials conducted in patients with established DKD DKD (11,14,15). Therefore, agents that control hypergly- will facilitate further refinement of current guidelines. cemia safely while also preventing or treating DKD are urgently needed. Over the past three decades, discovery and elucidation of the role of sodium symporters in glu- The impact of the current diabetes pandemic is rapidly cose reabsorption, and thereby glucose homeostasis, have approaching that of the Great Plague (1,2). Its prevalence pointed to sodium–glucose cotransporter 2 (SGLT2) in- has nearly quadrupled since the 1980s, and 1 in 10 adults, hibition as a viable therapeutic target (16–19). In cardio- or 642 million people worldwide, are now projected to have vascular disease (CVD) outcomes trials conducted for diabetes by the year 2040 (3). As the number of people safety, SGLT2 inhibitors actually have demonstrated clear living with diabetes rises, the prevalence of diabetic benefits on CVD and CKD. This Perspective highlights

1Providence Health Care, Washington State University, Spokane, WA Received 13 August 2018 and accepted 7 November 2018 2 University of Washington School of Medicine, Seattle, WA © 2019 by the American Diabetes Association. Readers may use this article as 3 College of Pharmacy and Pharmaceutical Sciences, Washington State University, long as the work is properly cited, the use is educational and not for profit, and the Spokane, WA work is not altered. More information is available at http://www.diabetesjournals 4 Kidney Research Institute, University of Washington, Seattle, WA .org/content/license. 5Institute of Translational Health Sciences, University of Washington, Seattle, WA Corresponding author: Radica Z. Alicic, [email protected] diabetes.diabetesjournals.org Alicic and Associates 249 postulated mechanisms that may underlie clinical effects of filtered glucose (Fig. 1). SGLT1 is expressed on the of SGLT2 inhibition and provides guidance for use of these luminal surface of the epithelial cells of the late proximal antihyperglycemic agents in patients with T2D and CKD. tubule and reabsorbs most of the remaining ;10% of filtered glucose (21–23). THE ROLE OF THE KIDNEY IN GLUCOSE In humans, glycosuria occurs when blood glucose HOMEOSTASIS: SODIUM–GLUCOSE reachesathresholdofabout180mg/dL(10mmol/L).How- COTRANSPORTERS ever, this threshold can range approximately 100– Under normoglycemic to mildly hyperglycemic conditions, 240 mg/dL (5.5–13 mmol/L) (24–27). Diabetes increases the kidney reabsorbs almost all glucose in the glomerular the glycosuric threshold to 200–240 mg/dL (11–13 mmol/L) filtrate (19). Glucose reabsorption occurs against its con- and, in this way, exacerbates hyperglycemia. The exact centration gradient and is driven by sodium symporters mechanism behind this response is unclear but most likely expressed in the proximal tubule (20). Of these, SGLT2 and includes increased expression of SGLTs. In studies of sodium–glucose cotransporter 1 (SGLT1) are the principal mouse and rat models of T2D, SGLT1 and SGLT2 expres- known contributors. The complementary glucose transport sion are increased in the diabetic kidney (28–30). Corre- kinetics of these two transporters permit almost complete spondingly, tubular epithelial cells freshly isolated from resorption of filtered glucose (21). Experimental data in- the urine of humans with T2D exhibit increased expression dicate that SGLT2 is expressed on the luminal surface of the of SGLT2, and kidney tissue from patients with T2D epithelial cells of the proximal convoluted tubule and is displays higher expression of SGLT1 protein and mRNA a low-capacity, high-affinity (Km ;1– (31, 32). In sum, higher glucose reabsorptive capacity of 4 mmol/L for glucose) with 1:1 Na+/glucose stoichiometry. the diabetic kidney likely results from increased expression As such, SGLT2 is responsible for the reabsorption of ;90% of SGLTs (33) (Fig. 1).

Figure 1—A and B: Glucose reabsorption via SGLT1 and SGLT2 in normal and diabetic kidney. Expressed apically in the epithelium of the proximal convoluted tubule, SGLT2 reabsorbs about 90% of glucose from the urinary filtrate. The remaining 10% is reabsorbed by SGLT1, a high-affinity and low-capacity transporter expressed apically in the epithelium of the straight descending proximal tubule. 250 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

SGLT2 INHIBITION AND DKD (hazard ratio compared with placebo was 0.56 in the – 2 – The BI 10773 (Empagliflozin) Cardiovascular Out- 45 60 mL/min/1.73 m group and 0.32 in the 30 2 come Event Trial in Type 2 Diabetes Mellitus Patients 45 mL/min/1.73 m group) (39). Ongoing cardiovas- (EMPA-REG OUTCOME) trial and the Canagliflozin Car- cular outcomes trials with two other SGLT2 inhibitors, fl fl diovascular Assessment Study (CANVAS) Program were dapagli ozin and ertugli ozin, will also report major the original large studies that demonstrated improve- CKD outcomes (40). fi ments in both CVD and CKD outcomes in over 17,000 Although the ndings from the EMPA-REG OUTCOME participants with T2D at high CVD risk (34–38). EMPA- and CANVAS trials provide a strong signal that SGLT2 REG OUTCOME enrolled approximately 7,000 partici- inhibition preserves kidney function and improves overall pants and followed them for a mean duration of 3.1 years. and kidney survival in T2D, results from two clinical trials Study participants were randomized to empagliflozin (10 mg primarily designed to evaluate CKD outcomes with SGLT2 fl or 25 mg) or placebo. The empagliflozin group experienced inhibition are keenly awaited. The Canagli ozin and Renal significantly lower rates of hospitalization for heart failure Endpoints in Diabetes with Established Nephropathy (35% relative risk reduction), death from CVD (38% Clinical Evaluation (CREDENCE) (ClinicalTrials.org iden- tifier NCT02065791) and A Study to Evaluate the Effect relative risk reduction), and death from any cause (32% of Dapagliflozin on Renal Outcomes and Cardiovascular relative risk reduction) compared with the placebo group Mortality in Patients With CKD (Dapa-CKD) (Clinical- (34). Importantly, these observed risk reductions were Trials.org identifier NCT03036150) trials are evaluating maintained across estimated glomerular filtration rate effects of canagliflozin or dapagliflozin on composite (eGFR) and albuminuria categories in more than 2,000 primary outcomes including ESKD, doubling of serum participants with eGFR ,60 mL/min/1.73 m2 and/or creatinine (CREDENCE), $50% sustained decline in macroalbuminuria (35). eGFR (Dapa-CKD), and kidney disease or CVD death in EMPA-REG OUTCOME also examined secondary kid- participants with established DKD (41). CREDENCE con- ney disease outcomes of incident or worsening nephrop- cluded early due to positive efficacy findings, and results athy: new-onset albuminuria or progression to urine are expected to be publicly released in early 2019 (42). albumin-to-creatinine ratio (UACR) .300 mg/g (macro- Dapa-CKD is expected to report in 2021 (Table 1). albuminuria), doubling of serum creatinine, initiation of Preservation of eGFR and albuminuria reduction are KRT, and death from kidney disease as a composite out- class effects of SGLT2 inhibitors. An initial effect observed come and individual outcomes (36). The relative risk of within the first few weeks of SGLT2 inhibition is the developing incident or worsening nephropathy was 39% reduction of eGFR by approximately 5 mL/min/1.73 m2, fl lower in the empagli ozin group compared with placebo followed by stabilization over time (36,43–49). This phe- P , (13% vs. 19%, 0.001) (36). A comparable relative nomenon has been observed in patients with eGFR as low risk reduction for nephropathy was observed in partic- as 30 mL/min/1.73 m2 (50). Compared with , ipants with CVD who underwent coronary artery bypass canagliflozin resulted in slower mean eGFR decline graft surgery (37). Notably, most participants in EMPA- (0.5 mL/min/1.73 m2 per year for canagliflozin 100 mg REG OUTCOME also received treatment with ACE inhibitors daily, 0.9 mL/min/1.73 m2 per year for canagliflozin or angiotensin receptor blockers, agents that have been 300 mg daily, and 3.3 mL/min/1.73 m2 per year with shown to reduce DKD progression and prevent ESKD. glimepiride, P , 0.01 for between-group comparisons), The CANVAS Program integrated data from two CVD despite achieving a similar level of glycemic control (46). outcome trials enrolling over 10,000 participants with Albuminuria reduction is also observed across levels of fl T2D, randomized to either canagli ozin or placebo and albuminuria and eGFR. Although it did not have a signif- followed for a mean duration of 3.6 years (38). The icant effect on development of new-onset albuminuria in primary composite outcome of death from CVD causes, EMPA-REG OUTCOME, empagliflozin produced a 38% nonfatal myocardial infarction, and nonfatal stroke oc- relative risk reduction in progression to severely increased curred at a significantly lower rate in the canagliflozin albuminuria (11% vs. 16%, P , 0.001) compared with group compared with placebo (14% relative risk reduction, placebo (36). Similarly, in the CANVAS Program, canagli- P , 0.001). The risk of progression to albuminuria was flozin produced a 27% reduction in progression to se- decreased by 27%, and the composite kidney disease out- verely increased albuminuria and 1.7-fold higher rate of come (40% eGFR decline, KRT, or death from kidney albuminuria regression (38). Among patients with base- causes) occurred 40% less frequently in the canagliflozin line UACR .100 mg/g, treatment with dapagliflozin group relative to placebo (38). The secondary analysis of decreased 24-h urine albumin excretion by 36% (P , the CANVAS Program showed that cardiovascular and 0.001), and among those with eGFR 30– kidney outcomes were consistent across the different 60 mL/min/1.73 m2, it decreased frequency of severely levels of kidney function (eGFR 30–45, 45–60, 60–90, increased albuminuria (UACR .1,800 mg/g) compared and $90 mL/min/1.73 m2); however, canagliflozin with placebo (44, 51). Among patients with eGFR $30 to treatment had greater benefits on fatal/nonfatal ,50 mL/min/1.73 m2, treatment with canagliflozin was strokes in groups with eGFR ,60 mL/min/1.73 m2 associated with greater decrease in UACR compared with 251

Table 1—Summary of clinical trials evaluating kidney outcomes with SGLT2 inhibition Study Intervention Inclusion criteria Main kidney outcomes EMPA-REG OUTCOME Empagliflozin c T2D c 39% relative risk reduction for incident or worsening nephropathy (NCT01131676) vs. placebo c High CVD risk (12.7% vs. 18.8%) Alicic and Associates (34,36) c eGFR .30 mL/min/1.73 m2 c 38% relative risk reduction for progression to albuminuria (11.2% vs. 16.2%) c 44% relative risk reduction of doubling of serum creatinine (1.5% vs. 2.6%) c 55% relative risk reduction of need for initiation of KRT (0.3% vs. 0.6%) CANVAS Program Canagliflozin c T2D c Decreased progression of albuminuria (hazard ratio 0.73; 95% CI 0.67–0.79) (NCT01032629, vs. placebo c High CVD risk c Decrease in composite outcome of a sustained 40% reduction in eGFR, NCT01989754) (38) c Mean eGFR of 76.5 mL/min/1.73 m2 KRT, or death from kidney causes (hazard ratio 0.60; 95% CI 0.47–0.77) DECLARE-TIMI Dapagliflozin c T2D Results pending: 58 (NCT01730534) vs. placebo c High CVD risk c Kidney composite end point (sustained $40% decrease in eGFR to (40) c eGFR $60 mL/min/1.73 m2 eGFR ,60 mL/min/1.73 m2 and/or ESKD and/or renal or CVD death) VERTIS CV Ertugliflozin c T2D Results pending: (NCT01986881) (90) vs. placebo c History of atherosclerosis of the coronary, cerebral, or c Kidney composite end point (kidney death, KRT, or doubling of serum peripheral vascular systems creatinine) CREDENCE Canagliflozin c T2D Results pending: (NCT02065791) (41) vs. placebo c eGFR $30 to ,90 mL/min/1.73 m2 c Kidney composite end point (ESKD, doubling of serum creatinine, and c UACR .300 to #5,000 mg/g kidney or CVD death) c Stabilization on maximum labeled or tolerated c Change in eGFR over time dose of an ACE inhibitor or angiotensin II receptor blocker c Change in albuminuria over time Dapa-CKD Dapagliflozin c T2D with DKD and nondiabetic kidney disease Results pending: (NCT03036150) (87) vs. placebo c eGFR $25 to #75 mL/min/1.73 m2 c Kidney composite end point ($ 50% sustained decline in eGFR, ESKD, or c UACR $200 to #5,000 mg/g kidney or CVD death) c Stabilization on maximum labeled c Change in eGFR over time or tolerated dose of an ACE inhibitor or c Change in albuminuria over time angiotensin II receptor blocker (unless contraindicated) EMPA-KIDNEY Empagliflozin c eGFR $20 to ,45 mL/min/1.73 m2 Results pending: (NCT03594110) vs. placebo OR eGFR $45 to ,90 mL/min/1.73 m2 with UACR c Composite outcome of time to first occurrence of: (91) $200 mg/g c Kidney disease progression (ESKD, sustained decline in eGFR c Clinically appropriate dose of an ACE inhibitor or to ,10 mL/min/1.73 m2, kidney death, or a angiotensin II receptor blocker unless not tolerated or sustained decline of $40% in eGFR from randomization), OR indicated c Cardiovascular death DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events trial. diabetes.diabetesjournals.org 252 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019 placebo (median percent reduction 230%, 221%, and Although blood glucose lowering is central to DKD pre- 28% in canagliflozin 100 mg daily, 300 mg daily, vention, there are also likely direct effects independent of and placebo groups, respectively) (48). When compared glycemia. with glimepiride treatment with canagliflozin 100 mg or One putative mechanism is normalization of glomerular 300 mg daily in patients with at least moderately increased hemodynamics through restoration of tubuloglomerular albuminuria (UACR $ 30 mg/g), decreased UACR by 32% feedback. Hyperfiltration with resulting hypertension in (P = 0.01) and 50% (P , 0.001), respectively, despite the glomerular capillary circulation is an early hemody- similar glycemic control (46). namic change observed in at least 75% of patients with T1D and 40% of those with T2D (Fig. 1) (52,53). Glomer- DIRECT EFFECTS OF SGLT2 INHIBITION ON THE ular hyperfiltration is driven by metabolic derangements DIABETIC KIDNEY including hyperglycemia and hyperaminoacidemia, as well Knowledge of the biological mechanisms behind the as increased proximal tubular reabsorption of glucose and kidney-protective effects of SGLT2 inhibition is evolving. sodium chloride via SGLT1 and SGLT2 (Fig. 2).

Figure 2—Effects of diabetes and SGLT2 inhibition on nephron hemodynamics. A: Increased reabsorption of glucose by SGLT2 in the proximal convoluted tubule decreases delivery of solutes to the macula densa. The resulting decrease in ATP release from the basolateral membrane of tubular epithelial cells reduces production of adenosine and produces a vasodilatation of the afferent arteriole. B: SGLT2 inhibitors restore solute delivery to the macula densa with resulting adenosine activation and reversal of vasodilation of the afferent arteriole. diabetes.diabetesjournals.org Alicic and Associates 253

Tubuloglomerular feedback is an adaptive mechanism mean difference was 20.4% (P , 0.001) (43). Pooled through which reabsorption of sodium and chloride in the analysis of phase III empagliflozin clinical trials con- macula densa promotes adenosine release (Fig. 2). Aden- firmed this finding with evidence of placebo-corrected osine, in turn, acts in paracrine manner to constrict the reductions in HbA1c decreasing with declining eGFR afferent arteriole. In diabetes, as a result of increased (64). Treatment with dapagliflozin reduced HbA1c be- reabsorption of sodium and chloride in the proximal tween 0.3% and 0.4% in patients with eGFR .45 2 tubule, delivery to the macula densa is decreased, leading and #60 mL/min/1.73 m .NoHbA1c reduction was to lower solute reabsorption and a consequent decrease in observed in patients with eGFR #40 mL/min/1.73 m2 adenosine production. By promoting relative afferent ar- (44). As such, the antihyperglycemic effects of SGLT2 teriolar vasodilation, this mechanism contributes to glo- inhibition seem less likely to confer kidney protection merular hyperperfusion, hypertension, and hyperfiltration in the setting of moderate-to-severe CKD. in diabetes (54). As body fat loss per se may decrease albuminuria and By blocking reabsorption of sodium chloride in the glomerular hyperfiltration, weight reduction effect of proximal tubule, SGLT2 inhibition restores solute delivery SGLT2 inhibition may indirectly protect the diabetic kid- to the macula densa and thereby restores normal tubulo- ney (44,55). In patients with normal kidney function, glomerular feedback (Fig. 2). A net effect is reversal of SGLT2 inhibition leads to a loss of 60–80 g of glucose afferent vasodilation and normalization of glomerular (240–320 calories) per day via glycosuria, with expected hemodynamics (55). This effect has been observed with weight loss of 2–3 lb (0.9–1.4 kg) per month (65). How- the nonspecific SGLT2 inhibitor in a T1D model ever, weight loss plateaus after about 6 months of treat- in rats and, more recently, with the selective SGLT2 ment, after achieving a total weight loss of 5–7 lb (2.3– inhibitor empagliflozin in a mouse T1D model (56,57). 3.2 kg) (63). After more than 2 years of dapagliflozin In humans with T1D and glomerular hyperfiltration, treatment in patients with T2D and a mean weight of treatment with empagliflozin decreased directly measured 225 lb (102 kg), experienced weight loss was 11 lb GFR (inulin clearance) by 33 mL/min/1.73 m2 (mean 6 SD (5 kg) with a concomitant decrease in waist circumference 172 6 23 mL/min/1.73 m2 to 139 6 25 mL/min/1.73 m2) (66,67). Notably, a recent pooled analysis of phase III in conjunction with decreased plasma flow to the kidney, empagliflozin trials and secondary analysis of the CANVAS lower plasma nitric oxide levels, and increased kidney Program found that the weight loss effects were main- vascular resistance. This effect was only observed in tained in patients with eGFR as low as 30 mL/min/1.73 m2 patients with diabetes with glomerular hyperfiltration (39, 64). (58). Antihypertensive effects are observed with empagliflo- SGLT2 inhibition may have additional anti-inflamma- zin, dapagliflozin, and canagliflozin. Each of them lower tory and antifibrotic actions that protect the kidney. In systolic blood pressure by approximately 5 mmHg and primary proximal tubular cells, SGLT2 inhibition sup- diastolic blood pressure by approximately 2 mmHg pressed the generation of a hyperglycemia-mediated in- (63,68–70). The systolic blood pressure reduction appears crease in reactive oxygen species (47,59). Experimental rat greatest within 3–4 months of initiation of treatment with and mouse models of diabetes have shown attenuation empagliflozin and dapagliflozin (34,66). In contrast to of glomerulosclerosis and tubulointerstitial fibrosis with blood glucose lowering, the magnitude of blood pressure SGLT2 inhibition (60–62). Decreased urinary excretion reduction is maintained, or perhaps increased, in patients of markers of kidney tubular injury (e.g., kidney injury with low eGFR (39). For example, in patients with T2D, the molecule 1) and inflammatory markers (e.g., interleukin-6) mean placebo-corrected changes in systolic blood pressure have been observed in humans with T2D treated with among those treated with empagliflozin were 23 mmHg dapagliflozin (47). with eGFR $90 mL/min/1.73 m2, 24 mmHg with eGFR 60–89 mL/min/1.73 m2, 26 mmHg with eGFR 30–59 EFFECTS OF SGLT2 INHIBITION ON RISK FACTORS mL/min/1.73 m2, and 27 mmHg with eGFR ,30 FOR DKD mL/min/1.73 m2 (64). The mechanisms underlying blood Glycemic control is known to decrease risk of DKD onset, pressure reduction are likely multiple and may include particularly if implemented early in the course of diabetes natriuresis, weight loss, and improved endothelial function (14,15). In patients with diabetes and preserved kidney and vascular compliance (71–76). function, SGLT2 inhibition reduces HbA1c by approxi- The natriuretic effect may be enhanced in diabetes due mately 1% (63). Due to the intrinsic mechanism of action, to greater proximal tubular sodium reabsorption related to the glycemic-lowering effects of SGLT2 inhibitors are blunted increased expression of SGLT2 and SGLT1 (77, 78). An- in patients with low eGFR (36,39,43,44,48,63,64). For in- other postulated mechanism for the natriuretic effect of stance, the adjusted mean treatment difference in HbA1c SGLT2 inhibition is “cross talk” with other solute trans- was 20.7% (P , 0.001) in patients with eGFR .60 porters, including the Na+/H+ exchanger 3 (NHE3). NHE3 and #90 mL/min/1.73 m2 who received empagliflozin is responsible for much of the sodium reabsorption from when compared with placebo, and in those with the glomerular filtrate (79). In rats, SGLT2 and NHE3 eGFR .30 and #60 mL/min/1.73 m2,theadjusted colocalize in the membrane of proximal tubular cells (80). 254 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

SGLT2 inhibition with phlorizin inhibits sodium bicar- Though both empagliflozin and canagliflozin have now bonate reabsorption by NHE3, though the specific been approved by the FDA for the indication of reducing mechanism of this effect remains unclear (81). the risk of cardiovascular events and cardiovascular death in adults with T2D and established CVD, to date, SGLT2 CLINICAL USE OF SGLT2 INHIBITORS inhibitors have not been recommended for the express purpose of improving CKD outcomes (85,86). The current Since the U.S. Food and Drug Administration (FDA) ap- recommendations to limit use of SGLT2 inhibitors by proval of canagliflozin for the treatment of T2D in 2013, eGFR criteria may change once results of CREDENCE the SGLT2 inhibitor class has quickly gained usage. Ma- jor guidelines and consensus statements, such as the and other ongoing clinical trials with primary CKD out- comes are reported (Table 2) (41,42,87). American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinol- CONCLUSIONS ogy (ACE) algorithm for the comprehensive management SGLT2 inhibitors show great promise for prevention of people with T2D, recommend SGLT2 inhibition because and treatment of DKD. Trials with empagliflozin have of the combined effects on glycemia, weight, and blood demonstrated, for the first time, a reduction in all-cause pressure in people with preserved eGFR (82–84). Based and cardiovascular mortality in patients with T2D and largely on results of the EMPA-REG OUTCOME and CKD. The mortality risk in this population has hereto- CANVAS clinical trials, the consensus report from the fore been unacceptably high and largely unmitigated; ADA and European Association for the study of Diabetes thus, the importance of improving survival while main- (EASD) recommends use of SGLT2 inhibitors as an add-on taining kidney function in patients with DKD is of urgent antihyperglycemic therapy of choice in patients who have and utmost importance. Research is needed to inform CVD or CKD (84). Dosing recommendations (eGFR the use of SGLT2 inhibitors in the setting of T1D and .30 mL/min/1.73 m2 for dapagliflozin, canagliflozin, perhaps for indications outside of diabetes, such as CKD and ertugliflozin and .45 mL/min/1.73 m2 for empagli- without diabetes. Progress on these fronts is already flozin), which are based on the limited antihyperglycemic under way. For example, the dual SGLT1/2 inhibitor efficacy of SGLT2 inhibition in patients with lower eGFR, sotagliflozin is currently under study for use in patients are not changed. with T1D (88,89). Empagliflozin will soon be studied

Table 2—Summary of dosing recommendations for FDA-approved SGLT2 inhibitors Agent Usual dosing recommendations Renal dosing recommendations Canagliflozin c The recommended starting dose is 100 mg once c Assess kidney function before initiating and periodically daily, taken before the first meal of the day. thereafter. c The dose can be increased to 300 mg once daily in c Limit the dose to 100 mg once daily in patients who have those who require additional glycemic control. an eGFR of 45 to ,60 mL/min/1.73 m2. c Initiation is not recommended in patients with an eGFR ,45 mL/min/1.73 m2. c Use is not recommended when eGFR is persistently ,45 mL/min/1.73 m2. c Use is contraindicated in patients with an eGFR ,30 mL/min/1.73 m2. Dapagliflozin c The recommended starting dose is 5 mg once c Assess kidney function before initiating and periodically daily, taken in the morning, with or without food. thereafter. c The dose can be increased c Initiation is not recommended in patients with an eGFR to 10 mg once daily in those tolerating the ,60 mL/min/1.73 m2. who require additional glycemic c Use is not recommended in patients with an eGFR control. persistently between 30 and ,60 mL/min/1.73 m2. c Use is contraindicated with an eGFR ,30 mL/min/1.73 m2. Empagliflozin c The recommended starting dose is 10 mg once c Assess kidney function before initiating. daily, taken in the morning, with or without food. c Initiation is not recommended if eGFR is c The dose can be increased to 25 mg once daily. ,45 mL/min/1.73 m2. c Discontinue if eGFR is persistently ,45 mL/min/1.73 m2. Ertugliflozin c The recommended starting dose is 5 mg once c Assess kidney function before initiating and periodically daily, taken in the morning, with thereafter. or without food. c Initiation is not recommended in patients with an eGFR of c The dose can be increased to 15 mg once daily in 30 to ,60 mL/min/1.73 m2. those tolerating the medication who need c Continued use is not recommended in patients with an additional glycemic control. eGFR persistently between 30 and ,60 mL/min/1.73 m2. c Use is contraindicated with eGFR ,30 mL/min/1.73 m2. diabetes.diabetesjournals.org Alicic and Associates 255 for primary CKD outcomes and cardiovascular deaths 20. Gerich JE. Role of the kidney in normal glucose homeostasis and in the among those with established diabetic and nondiabetic hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med 2010; CKD. Elucidation of the biological mechanisms underlying 27:136–142 the effects of SGLT2 inhibition is necessary to advance 21. Wright EM. Glucose transport families SLC5 and SLC50. Mol Aspects Med 2013;34:183–196 understanding and more fully optimize clinical applica- 22. Coady MJ, Wallendorff B, Lapointe JY. Characterization of the transport tions of these agents for the treatment of diabetes, CKD, activity of SGLT2/MAP17, the renal low-affinity Na+-glucose cotransporter. Am J and CVD. Physiol Renal Physiol 2017;313:F467–F474 References 23. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive 1. Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for mechanism for D-glucose. J Clin Invest 1994;93:397–404 diagnosed diabetes among adults aged 20 to 79 years, United States, 1980-2012. 24. Ruhnau B, Faber OK, Borch-Johnsen K, Thorsteinsson B. Renal threshold for JAMA 2014;312:1218–1226 glucose in non--dependent diabetic patients. Diabetes Res Clin Pract 1997; 2. Alchon SA. A Pest in the Land: New World Epidemics in a Global Perspective. 36:27–33 Diálogos series, 1st ed. Albuquerque, University of New Mexico Press, 2003 25. Johansen K, Svendsen PA, Lørup B. Variations in renal threshold for 3. International Diabetes Federation. IDF Diabetes Atlas, 7th edition [Internet], glucose in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1984;26: 2015. Available from http://diabetesatlas.org. Accessed 15 October 2018 180–182 4. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney 26. Rave K, Nosek L, Posner J, Heise T, Roggen K, van Hoogdalem EJ. Renal disease among US adults with diabetes, 1988-2014. JAMA 2016;316:602– glucose excretion as a function of blood glucose concentration in subjects with 610 type 2 diabetes–results of a hyperglycaemic glucose clamp study. Nephrol Dial 5. KDOQI. KDOQI clinical practice guidelines and clinical practice recom- Transplant 2006;21:2166–2171 mendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007;49 27. Alsahli M, Gerich JE. Renal glucose metabolism in normal physiological – (Suppl. 2):S12 S154 conditions and in diabetes. Diabetes Res Clin Pract 2017;133:1–9 6. Reutens AT. Epidemiology of diabetic kidney disease. Med Clin North Am 28. Freitas HS, Anhê GF, Melo KF, et al. Na(+) -glucose transporter-2 messenger 2013;97:1–18 ribonucleic acid expression in kidney of diabetic rats correlates with glycemic 7. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al.; Emerging Risk levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause- Endocrinology 2008;149:717–724 specific death. N Engl J Med 2011;364:829–841 29. Gallo LA, Ward MS, Fotheringham AK, et al. Once daily administration of the 8. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without im- mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24:302–308 proving albuminuria in diabetic db/db mice. Sci Rep 2016;6:26428 9. Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal 30. Stearns AT, Balakrishnan A, Rhoads DB, Tavakkolizadeh A. Rapid upre- disease, 20 year mortality risk in type 1 diabetes is comparable to that of the gulation of sodium-glucose transporter SGLT1 in response to intestinal sweet taste general population: a report from the Pittsburgh Epidemiology of Diabetes stimulation. Ann Surg 2010;251:865–871 Complications Study. Diabetologia 2010;53:2312–2319 31. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose 10. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic transporters in human renal proximal tubular cells isolated from the urine of kidney disease to the global burden of major noncommunicable diseases. Kidney patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427–3434 Int 2011;80:1258–1270 32. Norton L, Shannon CE, Fourcaudot M, et al. Sodium-glucose co-transporter 11. Levin A, Tonelli M, Bonventre J, et al.; ISN Global Kidney Health Summit (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic – participants. Global kidney health 2017 and beyond: a roadmap for closing gaps in subjects. Diabetes Obes Metab 2017;19:1322 1326 care, research, and policy. Lancet 2017;390:1888–1917 33. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal fl 12. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global di- glucose reabsorption in response to dapagli ozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 2013;36:3169–3176 mension and perspectives. Lancet 2013;382:260–272 34. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. 13. Storey BC, Staplin N, Harper CH, et al. Declining comorbidity-adjusted Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J mortality rates in English patients receiving maintenance renal replacement Med 2015;373:2117–2128 therapy. Kidney Int 2018;93:1165–1174 35. Wanner C, Lachin JM, Inzucchi SE, et al.; EMPA-REG OUTCOME Investigators. 14. Nathan DM; DCCT/EDIC Research Group. The Diabetes Control and Com- Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, plications Trial/Epidemiology of Diabetes Interventions and Complications study at established cardiovascular disease, and chronic kidney disease. Circulation 2018; 30 years: overview. Diabetes Care 2014;37:9–16 137:119–129 15. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up 36. Wanner C, Inzucchi SE, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. – of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577 Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 1589 2016;375:323–334 16. Heilig CW, Brosius FC 3rd, Henry DN. Glucose transporters of the glo- 37. Verma S, Mazer CD, Fitchett D, et al. Empagliflozin reduces cardiovascular merulus and the implications for diabetic nephropathy. Kidney Int Suppl. 1997; events, mortality and renal events in participants with type 2 diabetes after 60:S91–S99 coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOMEÒ 17. Witowski J, Breborowicz A. The role of cellular glucose transporters in randomised trial. Diabetologia 2018;61:1712–1723 pathogenesis of diabetic nephropathy. Przegl Lek 1999;56:793–799 [in Polish] 38. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative 18. Santos LL, Lima FJC, Sousa-Rodrigues CF, Barbosa FT. Use of SGLT-2 Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl inhibitors in the treatment of type 2 diabetes mellitus. Rev Assoc Med Bras (1992) J Med 2017;377:644–657 2017;63: 636–641 39. Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal outcomes with 19. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and canagliflozin according to baseline kidney function. Circulation 2018;138:1537– disease. J Intern Med 2007;261:32–43 1550 256 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

40. Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ 58. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of baseline characteristics. Diabetes Obes Metab 2018;20:1102–1110 sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. 41. Jardine MJ, Mahaffey KW, Neal B, et al.; CREDENCE Study Investigators. The Circulation 2014;129:587–597 Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy 59. Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a highly selective inhibitor of Clinical Evaluation (CREDENCE) study rationale, design, and baseline character- SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on istics. Am J Nephrol 2017;46:462–472 proximal tubular cells partly by suppressing oxidative stress generation. Horm 42. Janssen Global Services. Phase 3 CREDENCE renal outcomes trial of IN- Metab Res 2016;48:191–195 VOKANA (canagliflozin) is being stopped early for positive efficacy findings 60. Kawanami D, Matoba K, Takeda Y, et al. SGLT2 inhibitors as a therapeutic [Internet], 16 July 2018. Available from https://www.janssen.com/phase-3- option for diabetic nephropathy. Int J Mol Sci 2017;18:E1083 credence-renal-outcomes-trial-invokanar-canagliflozin-being-stopped-early- 61. Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an positive-efficacy. Accessed 15 October 2018 inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and anti- 43. Barnett AH, Mithal A, Manassie J, et al.; EMPA-REG RENAL Trial Investigators. fibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs- Efficacy and safety of empagliflozin added to existing antidiabetes treatment in receptor axis. Horm Metab Res 2015;47:686–692 patients with type 2 diabetes and chronic kidney disease: a randomised, double- 62. Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empa- blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014;2:369–384 gliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 44. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 2014;307: 2 diabetes and moderate renal impairment shows that dapagliflozin reduces F317–F325 weight and blood pressure but does not improve glycemic control. Kidney Int 2014; 63. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose co- 85:962–971 transporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. 45. Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the Ann Intern Med 2013;159:262–274 urinary albumin-to-creatinine ratio in patients with type 2 diabetes and es- 64. Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of phase III trials tablished cardiovascular disease: an exploratory analysis from the EMPA-REG indicate contrasting influences of renal function on blood pressure, body weight, OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol and HbA1c reductions with empagliflozin. Kidney Int 2018;93:231–244 2017;5:610–621 65. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose co- 46. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. transporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev Canagliflozin slows progression of renal function decline independently of gly- 2011;32:515–531 cemic effects. J Am Soc Nephrol 2017;28:368–375 66. Wilding J, Bailey C, Rigney U, Blak B, Kok M, Emmas C. Dapagliflozin therapy 47. Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, for type 2 diabetes in primary care: changes in HbA1c, weight and blood pressure Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and over 2 years follow-up. Prim Care Diabetes 2017;11:437–444 tubular injury markers. Diabetes Obes Metab 2018;20:1988–1993 67. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body 48. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in weight, total fat mass, and regional adipose tissue distribution in patients with type subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2 diabetes mellitus with inadequate glycemic control on . J Clin En- 2013;15:463–473 docrinol Metab 2012;97:1020–1031 49. Seidu S, Kunutsor SK, Cos X, Gillani S, Khunti K; Primary Care Diabetes 68. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Europe. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: renal impairment: a systematic review and meta-analysis. Prim Care Diabetes a systematic review and meta-analysis. J Am Soc Hypertens 2014;8:262–275. 2018;12:265–283 e9 50. Fioretto P, Stefansson BV, Johnsson E, Cain VA, Sjöström CD. Dapagliflozin 69. Liu XY, Zhang N, Chen R, Zhao JG, Yu P. Efficacy and safety of sodium- reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of ran- renal impairment. Diabetologia 2016;59:2036–2039 domized controlled trials for 1 to 2years. J Diabetes Complications 2015;29: 51. Petrykiv SI, Laverman GD, de Zeeuw D, Heerspink HJL. The albuminuria- 1295–1303 lowering response to dapagliflozin is variable and reproducible among individual 70. Yang XP, Lai D, Zhong XY, Shen HP, Huang YL. Efficacy and safety of patients. Diabetes Obes Metab 2017;19:1363–1370 canagliflozin in subjects with type 2 diabetes: systematic review and meta- 52. Premaratne E, Verma S, Ekinci EI, Theverkalam G, Jerums G, MacIsaac RJ. analysis. Eur J Clin Pharmacol 2014;70:1149–1158 The impact of hyperfiltration on the diabetic kidney. Diabetes Metab 2015;41:5–17 71. Luzardo L, Noboa O, Boggia J. Mechanisms of salt-sensitive hypertension. 53. Tuttle KR. Back to the future: glomerular hyperfiltration and the diabetic Curr Hypertens Rev 2015;11:14–21 kidney. Diabetes 2017;66:14–16 72. Tanaka H, Takano K, Iijima H, et al. Factors affecting canagliflozin-induced 54. Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardio- 2017;34:436–451 vascular and kidney effects, potential mechanisms, and clinical applications. 73. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin Circulation 2016;134:752–772 a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. 55. Škrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the Diabetes Obes Metab 2013;15:853–862 potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens 74. Cooper JN, Buchanich JM, Youk A, et al. Reductions in arterial stiffness with 2015;24:96–103 weight loss in overweight and obese young adults: potential mechanisms. Ath- 56. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin erosclerosis 2012;223:485–490 reduces renal growth and albuminuria in proportion to hyperglycemia and prevents 75. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014; arterial stiffness and heart rate variability in subjects with uncomplicated type 306:F194–F204 1 diabetes mellitus. Cardiovasc Diabetol 2014;13:28 57. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyper- 76. Cardoso CR, Ferreira MT, Leite NC, Salles GF. Prognostic impact of aortic filtration in experimental diabetes mellitus: potential role of tubular reabsorption. J stiffness in high-risk type 2 diabetic patients: the Rio deJaneiro Type 2 Diabetes Am Soc Nephrol 1999;10:2569–2576 Cohort Study. Diabetes Care 2013;36:3772–3778 diabetes.diabetesjournals.org Alicic and Associates 257

77. Pollock CA, Lawrence JR, Field MJ. Tubular sodium handling and tubulo- 86. INVOKANA (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ, glomerular feedback in experimental diabetes mellitus. Am J Physiol 1991;260: Janssen Pharmaceuticals, Inc., 2018 F946–F952 87. AstraZeneca. A study to evaluate the effect of dapagliflozin on renal outcomes 78. Vestri S, Okamoto MM, de Freitas HS, et al. Changes in sodium or glucose and cardiovascular mortality in patients with chronic kidney disease (Dapa-CKD). filtration rate modulate expression of glucose transporters in renal proximal tubular In: ClinicalTrials.gov [Internet]. Bethesda, MD, National Library of Medicine, 2018. cells of rat. J Membr Biol 2001;182:105–112 Available from https://clinicaltrials.gov/ct2/show/NCT03036150. NLM Identifier: 79. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium- NCT03036150. Accessed 15 October 2018 glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: 88. Sanofi. A phase 3 study to evaluate the safety of sotagliflozin in patients with – proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025 1029 type 1 diabetes who have inadequate glycemic control with insulin therapy alone 80. Girardi AC, Di Sole F. Deciphering the mechanisms of the Na+/H+ ex- (inTandem3). In: ClinicalTrials.gov [Internet]. Bethesda, MD, National Library of changer-3 regulation in organ dysfunction. Am J Physiol Cell Physiol 2012;302: Medicine, 2017. Available from https://clinicaltrials.gov/ct2/show/NCT02531035. C1569–C1587 NLM Identifier: NCT02531035. Accessed 15 October 2018 81. Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic G. Functional 89. Sanofi.Efficacy, safety, and tolerability study of sotagliflozin as adjunct role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter therapy in adult patients with type 1 diabetes mellitus who have inadequate isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal glycemic control with insulin therapy (inTandem2). In: ClinicalTrials.gov [Internet]. proximal tubule. J Am Soc Nephrol 2014;25:2028–2039 Bethesda, MD, National Library of Medicine, 2017. Available from https://clinicaltrials 82. American Diabetes Association. Standards of Medical Care in Diabetes— .gov/ct2/show/NCT02421510. NLM Identifier: NCT02421510. Accessed 15 2018 abridged for primary care providers. Clin Diabetes 2018;36:14–37 83. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the October 2018 fl American Association of Clinical Endocrinologists and American College of En- 90. Merck Sharp & Dohme Corp. Cardiovascular outcomes following ertugli ozin docrinology on the comprehensive type 2 diabetes management algorithm - treatment in type 2 diabetes mellitus. participants with vascular disease, the 2018 executive summary. Endocr Pract 2018;24:91–120 VERTIS CV Study (MK-8835-004). In: ClinicalTrials.gov [Internet]. Bethesda, MD, 84. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in National Library of Medicine, 2018. Available from https://clinicaltrials.gov/ct2/ type 2 diabetes, 2018. A consensus report by the American Diabetes Association show/NCT01986881. NLM Indentifier: NCT01986881. Accessed 15 October 2018 (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes 91. Boehringer Ingelheim. EMPA-KIDNEY (The study of heart and kidney pro- Care 2018;41:2669–2701 tection with empagliflozin). In: ClinicalTrials.gov [Internet]. Bethesda, MD, National 85. JARDIANCE (empagliflozin) tablets, for oral use [package insert], Ingelheim, Library of Medicine, 2018. Available from https://www.clinicaltrials.gov/ct2/show/ Germany, Boehringer Ingelheim International GmbH, 2018 NCT03594110. NLM Identifier: NCT03594110. Accessed 15 October 2018