Received: 13 December 2019 Revised: 22 January 2020 Accepted: 30 January 2020

DOI: 10.1111/dom.13987

REVIEW ARTICLE

Dedicated kidney disease-focused outcome trials with

sodium-glucose cotransporter-2 inhibitors: Lessons from
CREDENCE and expectations from DAPA-HF, DAPA-CKD,
and EMPA-KIDNEY

Jinnie J. Rhee ScD, MS1,2 | Meg J. Jardine MBBS, PhD3,4 |

Glenn M. Chertow MD, MPH1,2,5 | Kenneth W. Mahaffey MD2,6,7

1
Division of Nephrology, Department of
Medicine, Stanford University School of Abstract
Medicine, Stanford, California In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and
2
Stanford Diabetes Research Center, Stanford
safety of glucose-lowering agents have been completed. Amongst newer agents
University School of Medicine, Stanford,
California available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose
3
The George Institute for Global Health, cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary
UNSW, Sydney, New South Wales, Australia
4
clinical practice due to observed benefits on cardiovascular and kidney outcomes
Department of Renal Medicine, Concord
Repatriation General Hospital, Sydney, among patients with T2DM, as reported in large randomized controlled trials (RCT).
Australia
These findings are reflected in the updated clinical guidelines of several major profes-
5
Department of Epidemiology and Population
Health, Stanford University School of
sional societies. Herein, we briefly review the mechanism of action of SGLT2 inhibi-
Medicine, Stanford, California tors and their pleiotropic effects, summarize key findings and limitations of initial
6
Division of Cardiovascular Medicine, Stanford CVOTs, then discuss three major kidney disease-focused outcome trials, including
University School of Medicine, Stanford,
California the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical
7
Stanford Center for Clinical Research, Evaluation (CREDENCE) trial as well as two ongoing RCTs: Dapagliflozin and Preven-
Stanford University School of Medicine,
tion of Adverse Outcomes in Heart Failure-chronic kidney disease and EMPA-
Stanford, California
KIDNEY.
Correspondence
Jinnie J. Rhee, ScD, Division of Nephrology,
KEYWORDS
Department of Medicine, Stanford University
School of Medicine, 1070 Arastradero Road, chronic kidney disease, clinical trials, diabetes, kidney outcomes, SGLT2 inhibitors
Suite 3C3109, Palo Alto, CA 94304.
Email: [email protected]

Funding information
Medical Research Future Fund Next
Generation Clinical Researchers Program
Career Development Fellowship; National
Institute of Diabetes and Digestive and Kidney
Diseases, Grant/Award Numbers: K01
DK110221, K24 DK085446

Peer Review
The peer review history for this article is
available at https://publons.com/publon/10.
1111/dom.13987.

46 © 2020 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/dom Diabetes Obes Metab. 2020;22(Suppl. 1):46–54.
RHEE ET AL. 47

1 | I N T RO DU CT I O N inhibitors is independent of insulin resistance and islet β-cell failure,

making these agents modestly effective glucose-lowering drugs in
Chronic kidney disease (CKD), a common microvascular complication patients with T2DM and without severe impairment of kidney
of type 2 diabetes mellitus (T2DM), occurs in approximately 40% of function.12
1
patients with T2DM, and is associated with morbidity and mortality Results from inverse variance random-effects meta-analysis
as well as with increased health care expenditures.2 T2DM is the lead- showed that in patients with T2DM, preserved kidney function, and
ing cause of end-stage kidney disease (ESKD) worldwide. Diabetic kid- baseline haemoglobin A1c (HbA1c) 6.9% to 9.2%, the weighted mean
ney disease (DKD) accounts for most of the excess risk of difference in change in HbA1c from baseline, when comparing SGLT2
cardiovascular (CV) and all-cause mortality in patients with T2DM.3,4 inhibitors to placebo, was −0.79% when used as monotherapy and
The number of deaths attributable to DKD increased by 94% between −0.61% when used as combination therapy.24 In patients with normal
1990 and 2012.5 Kidney failure due to T2DM remains a major yet or near normal kidney function, efficacy increases at higher baseline
often under-recognized global public health problem.6 glycaemic levels due to filtered glucose load that increases in parallel
For the last 18 years, inhibitors of the renin-angiotensin- with hyperglycaemia.12 In patients with impaired kidney function, the
aldosterone system (ie, angiotensin-converting enzyme (ACE) inhibi- filtered glucose load is lower and therefore, glucose-lowering efficacy
tors or angiotensin receptor blockers (ARBs) have been the only ther- may decline.12 As a result, these agents were initially approved on the
7-11
apies demonstrated to attenuate the progression of DKD. grounds of their glycaemia-lowering efficacy for use as glucose-
However, the risk and burden of DKD still remain high for these lowering drugs for persons with T2DM and normal or near normal kid-
patients, and the complexity of managing multiple medical regimens ney function.
for the management of DKD and its associated comorbidities and In addition to their glucose-lowering effects, SGLT2 inhibitors
complications, is a growing challenge in clinical practice. have demonstrated non-glycaemic pleiotropic effects. SGLT2 inhibi-
tors induce weight loss of 2 to 3 kg likely due to acute osmotic diure-
sis and associated caloric losses resulting from blockade of the SGLT2
1.1 | Emergence of sodium-glucose cotransporter- receptor.25,26 Possibly due in part to the natriuretic effects of SGLT2
2 inhibitors and mechanisms and pleiotropic effects inhibitors27 and resultant intravascular volume contraction and effects
on intrarenal haemodynamics, these agents have also been shown to
A relatively new class of glucose-lowering medications known as reduce systolic blood pressure and diastolic blood pressure by an
sodium-glucose cotransporter-2 (SGLT2) inhibitors has garnered much average of 5 and 2 mm Hg, respectively, and lead to 30% to 50%
attention over recent years. Currently, four oral agents—canagliflozin, reductions in albuminuria in patients with microalbuminuria or
dapagliflozin, empagliflozin, and ertugliflozin—are approved for the macroalbuminuria.21,28 Preclinical and clinical studies have demon-
treatment of T2DM by the US Food and Drug Administration (FDA) strated that SGLT2 inhibitors may have beneficial renal hemodynamic
as monotherapy or in combination with other glucose-lowering medi- effects by reducing hyperfiltration and intraglomerular pressure via
cations.12 While ertugliflozin is indicated for glycaemic control as an disruption of the tubuloglomerular feedback loop.29 SGLT2 inhibitors
adjunct to diet and exercise, large randomized controlled trials (RCTs) reduce sodium reabsorption in the proximal tubule, which in turn
have demonstrated the superiority of empagliflozin and canagliflozin leads to afferent arteriole vasoconstriction through the
compared with placebo and non-inferiority of dapagliflozin compare tubuloglomerular feedback loop, reducing hyperfiltration. Recent data
with placebo on a composite endpoint of nonfatal myocardial infarc- suggest that SGLT2 inhibitors also have anti-inflammatory and antiox-
tion (MI), nonfatal stroke, or CV death. All three drugs were superior idant properties to reduce oxidative damage. These agents may play a
to placebo in reducing hospitalization for heart failure. Additionally, role in reducing CV and renal complications observed in clinical trials
the FDA recently approved a renal indication for canagliflozin to by protecting tissues against oxidative damage via amelioration of
reduce the incidence and progression of CKD.13-19 In addition to free-radical generation or cellular antioxidative capacity.30 in vitro
enhancing glycaemic control in T2DM, SGLT2 inhibitors provide the data from a study done in human proximal tubular cells also suggest
additional clinical benefits of reducing body weight, blood pressure, that SGLT2 inhibitors have anti-inflammatory and anti-fibrotic effects,
20
and albuminuria. rendering renoprotection by limiting glucose-induced damage of the
The primary mechanism by which SGLT2 inhibitors lower blood proximal tubule through reduction of inflammatory and fibrotic
glucose concentrations is via blocking the paired reuptake of sodium markers induced by hyperglycaemia.31 The beneficial effects of
and glucose in the proximal tubule and promoting glycosuria.21 SGLT- SGLT2 inhibitors on blood pressure, and albuminuria are largely inde-
2 inhibitors promote approximately 50% of filtered glucose to be pendent of estimated glomerular filtration rate (eGFR),32 and the
excreted, which is equivalent to about 50 to 80 g/day in a normal or pleiotropic effects of these drugs beyond glycosuria may account for
modest hyperglycaemic state and up to >100 g/day in a diabetic or the promising role of these drugs in reducing CV morbidity and mor-
hyperfiltration state.22 Some of the glucose is still reabsorbed despite tality as well as providing nephroprotective effects, including reducing
treatment with SGLT2 inhibitors due to overexpression or activity of the incidence and complications of heart failure and slowing the
sodium-glucose cotransporter 1 in the distal segment of the proximal progression of DKD, as observed in recently completed
tubule as a result of SGLT2 inhibition.23 The mode of action of SGLT2 RCTs.13,15,16,18,33,34
48 RHEE ET AL.

T A B L E 1 Summary of key findings from earlier large CVOTs that were event-driven, double-blind, and placebo-controlled in which
participants received guideline-directed care

EMPA-REG OUTCOME CANVAS-PROGRAM

DECLARE-TIMI 58 (dapagliflozin)
(empagliflozin) (canagliflozin)
Patients (N) 7020 10 142 17 160
Tested drug (intervention) Empagliflozin Canagliflozin Dapagliflozin
Median duration of follow-up 3.1 y CANVAS-PROGRAM, 126.1 wk 4.2 y
CV inclusion criteria >18 y with established CVD ≥30 y with history of symptomatic ≥40 y with multiple risk factors for
atherosclerotic CVD or ≥50 y atherosclerotic CVD (≥55 (M) or
with ≥2 CV risk factors ≥60 (F) y with CVD risk factors)
or established atherosclerotic
CVD
Minimum eGFR inclusion eGFR ≥30 mL/min/1.73 m2 eGFR ≥30 mL/min/1.73 m2 Estimated creatinine clearance
criteria (mL/min/1.73 m2) ≥60 mL/min
HbA1c inclusion criteria (%) 7-10 7-10.5 6.5-12
Background antidiabetic ADD-naïve All ADDs All ADDs except pioglitazone
medications All ADDs
Combination
% History of CVD 99.0 65.6 40.6
2
Mean eGFR (mL/min/1.73 m ) 74.2 (GFR MDRD) 76.5 (GFR MDRD) 85.3 (GFR CKD-EPI)
% on ACE inhibitor/ARB 81% 80% 81%
% UACR by category <30: 60% <30: 70% <30: 69%
30-300: 29% 30-300: 22% 30-300: 24%
>300: 11% >300: 8% >300: 7%
Primary outcomes (HR [95% CI]) Composite: CV death, nonfatal MI, Composite: CV death, nonfatal MI, Composite: CV death, nonfatal MI,
nonfatal stroke nonfatal stroke nonfatal stroke
0.86 (0.74-0.99) 0.86 (0.75-0.97) 0.93 (0.84-1.03)
Secondary outcomes (HR [95% HF hospitalization or CV death Hospitalization for HF HF hospitalization of CV death
CI]) 0.66 (0.55-0.79) 0.67 (0.52-0.87) 0.83 (0.73-0.95)
Hospitalization for HF CV death Hospitalization for HF
0.65 (0.50-0.85) 0.87 (0.72-1.06) 0.73 (0.61-0.88)
CV death All-cause mortality CV death
0.62 (0.49-0.77) 0.87 (0.74-1.01) 0.98 (0.82-1.17)
All-cause mortality All-cause mortality
0.68 (0.57-0.82) 0.93 (0.82-1.04)
Secondary kidney outcomes Incident or worsening nephropathy Progression of albuminuria ≥40% decrease in eGFR to <60,
(HR [95% CI]) 0.61 (0.53-0.70) 0.73 (0.67-0.79) ESKD, or kidney-related death
0.53 (0.43-0.66)
Doubling of serum creatinine 40% reduction in eGFR, kidney ESKD
accompanied by eGFR ≤45, replacement therapy, or 0.31 (0.13-0.79)
initiation of kidney kidney-related death
replacement therapy, or 0.60 (0.47-0.77)
kidney-related death
0.54 (0.40-0.75)
Initiation of kidney replacement ESKD or kidney-related death
therapy 0.41 (0.20-0.92)
0.45 (0.21-0.97)

Abbreviations: ACE inhibitor, angiotensin-converting enzyme inhibitor; ADDs, antidiabetic medications; ARB, angiotensin II receptor blocker; CKD-EPI,
Chronic Kidney Disease Epidemiology Collaboration; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular
outcome trials; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HbA1c, haemoglobin A1c; HF, heart failure; HR, hazard ratio;
MDRD, Modification of Diet in Renal Disease; MI, myocardial infarction; UACR, urinary albumin-to-creatinine ratio.

1.2 | Initial CVOTs: key findings and limitations safety according to the 2008 Guidance for Industry.20 These trials
assessed the effects of SGLT2 inhibitors on MACE (defined as non-
Earlier large-scale randomized CV outcome trials (CVOTs) were pri- fatal MI, nonfatal stroke, or CV death) as the primary outcome in
marily designed to meet regulatory requirements for ensuring CV patients who had or were at high risk of atherosclerotic CV
RHEE ET AL. 49

disease.13-15 A summary of the design and key findings from these

studies are summarized in Table 1. The Empagliflozin Cardiovascular
Outcome Event Trial in T2DM Patients (EMPA-REG-OUTCOME) trial
was the first trial to report CV benefits of the SGLT2 inhibitor
empagliflozin, followed by the Canagliflozin Cardiovascular Assess-
ment Study (CANVAS) Program, both of which showed significant
reductions in MACE; the Dapagliflozin Effect on Cardiovascular
Events-Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58)
trials showed non-inferiority for the same endpoint. All three pro-
grams showed reductions in heart failure events and albuminuria, and
meaningful declines in kidney function (assessed by eGFR) were infre-
quent in SGLT2 inhibitor- and placebo-treated groups.13-15,17,19 These
results suggest that SGLT-2 inhibitors can be used in secondary pre-
F I G U R E 1 Heat map indicating the urine albumin-to-creatinine
vention to prevent major CV events and heart failure in patients with
ratio (UACR) and estimated glomerular filtration rate (eGFR) range for
T2DM with either a previous CV event or risk factors for CV disease. enrolment in the earlier cardiovascular outcome trials (CVOTs;
Other CVOTs included relatively few patients with CKD at baseline, indicated in circles) and CREDENCE according to the National Kidney
and very few participants developed kidney failure requiring dialysis Foundation Classification of Chronic Kidney Disease. This figure was
or kidney transplantation, or died from kidney disease.20 Moreover, adapted from the collaborative work by the CKD Prognosis
Consortium1
these studies were not primarily designed to assess the effects of
SGLT2 inhibitors on sustained kidney disease-related endpoints, but
rather evaluated secondary kidney outcome measures without any
prespecified or adjudicated kidney disease-related endpoints.35 42 months after randomization, there was a 60% reduction in the rate
of eGFR decline with canagliflozin.16 The trial showed modest differ-
ences in HbA1c, body weight, blood pressure, and UACR, suggesting
1.3 | CREDENCE: Kidney-related outcomes in that the mechanism responsible for the observed benefit on kidney-
patients with CKD related outcomes was at least in part independent of glycaemic con-
trol, and could possibly be a result of a reduction in intraglomerular
The Canagliflozin and Renal Events in Diabetes and Established pressure, above and beyond what is induced by ACE inhibitors or
Nephropathy Clinical Evaluation (CREDENCE) trial was the first of the ARBs.27,37,38 With respect to secondary CV outcomes, canagliflozin
SGLT2 inhibitor RCTs with a primary cardiorenal composite endpoint, reduced the relative risk of: CV death or hospitalization for heart fail-
conducted in a population with substantial albuminuria and/or ure by 31% (HR, 0.69, 95% confidence interval, 0.57-0.83); CV death,
impaired kidney function. CREDENCE was a double-blind, placebo MI, or stroke by 20% (HR 0.80, 95% 0.67-0.95); and hospitalization
controlled RCT which began enrolling participants in 2014. CRE- for heart failure by 39% (HR 0.61, 95% CI 0.47-0.80).16 These findings
DENCE differed from previous SGLT2 inhibitor trials in that it show that canagliflozin, when used in conjunction with ACE inhibitors
restricted enrolment to participants with T2DM and albuminuric CKD, and ARBs in adult patients with T2DM and albuminuric CKD (stages
with a baseline eGFR of 30 to <90 mL/min/1.73 m2 and urine 2, 3a, and 3b), results in a clinically meaningful incremental benefit on
albumin-to-creatinine ratio (UACR) of 300 to <5000 mg/g renal and CV events. CREDENCE allowed participants to continue
(Figure 1).36 As inclusion criteria, all participants had background canagliflozin until initiation of dialysis or kidney transplantation and
standard-of-care therapy with an ACE inhibitor or ARB, and approxi- demonstrated that canagliflozin can be safely initiated in patients with
mately 50% of participants had a history of CV disease. The primary eGFR as low as 30 mL/min/1.73 m2, yielding kidney benefits to
outcome was a composite of ESKD (defined as the provision of dialy- patients at high risk.16
sis, kidney transplantation, or a sustained eGFR below 15 mL/ Overall, CREDENCE showed that canagliflozin could be safely
2
min/1.73 m ), doubling of serum creatinine, or death from kidney or administered to a population with DKD. Despite an initial drop in
CV causes. The study was stopped early for efficacy after an interim eGFR, there were few renal adverse events reported in the can-
analysis and the recommendation from the independent Data Moni- agliflozin group, and canagliflozin did not increase the risk acute kid-
toring Committee. The trial showed a 30% lower relative risk of the ney injury (AKI).14 In CREDENCE, the risks of amputation or fracture
primary composite outcome in patients randomized to canagliflozin were not increased in canagliflozin-treated patients in contrast to pre-
(hazard ratio (HR), 0.70, 95% confidence interval (95% CI), vious trials; whether these findings related to differences in the
0.59-0.82).16 The primary kidney disease-related composite endpoint enrolled populations and/or protocols, or were due to chance, is
of ESKD, doubling of serum creatinine, or renal death was reduced by unknown.14,16 A heightened risk of hyperkalemia was not observed in
34% (HR, 0.66, 95% CI, 0.53-0.81). There was an initial acute reduc- CREDENCE, and with respect to other adverse events of interest, the
tion in eGFR that was observed with canagliflozin treatment due to risks of male genital mycotic infections and female genital mycotic
what was thought to represent hemodynamic effects. However, infections were higher in patients treated with canagliflozin, but there
50 RHEE ET AL.

were no increased risks of urinary tract infections, malignancies, or between CREDENCE and these ongoing studies (Table 2).
acute pancreatitis.16 There was a higher relative risk of diabetic Dapagliflozin and prevention of adverse outcomes in CKD (DAPA-
ketoacidosis (DKA) (HR, 10.80; 95% CI, 1.39-83.65) in patients ran- CKD, NCT03036150) is a multinational, multicenter, randomized,
domized to canagliflozin, although the incidence of DKA was low (the double-blind, parallel-group, placebo-controlled trial testing the
number of DKA events was 11 in the canagliflozin group and 1 in the hypothesis that treatment with dapagliflozin is superior to placebo in
placebo group).16 These findings suggest that while DKA following reducing the risk of kidney disease-related and CV events in patients
treatment with SGLT2 inhibitors is rare, it remains a serious complica- with CKD, with or without concomitant T2DM, who are on back-
tion that warrants focused patient and provider education. ground therapy with ACE inhibitors or ARBs.39 The trial has enrolled
4094 patients at 370 sites in 21 countries with eGFR 25 to <75 mL/
min/1.73 m2 and UACR 200 to <5000 mg albumin/g creatinine, with
1.4 | Dapagliflozin and Prevention of Adverse the vast majority receiving a maximum tolerated dose of ACE inhibitor
Outcomes in Heart Failure: Additional experience in or ARB.39 Like CREDENCE, the primary composite endpoint is a kid-
patients with stage 3 CKD ney disease-related composite: decline in eGFR of 50% or more,
ESKD (defined as the provision of dialysis for more than 28 days or
Another trial noteworthy to the medical community is the Dapagliflozin kidney transplantation), or renal death (ie, cases wherein there is
and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. insufficient kidney function to be dialysis independent, but the patient
DAPA-HF was a phase 3, placebo-controlled trial that prospectively eval- and/or his or her family elects to pursue conservative care), or CV
uated the efficacy and safety of dapagliflozin in 4744 patients with death.39 The composite endpoint of hospitalization for heart failure or
New York Heart Association classes II, III, or IV heart failure and ejection CV death, and all-cause mortality are key secondary outcomes. The
fraction of 40% or less.34 The study included patients with and without trial was powered to conclude after the occurrence of 681 primary
T2DM as well as those baseline eGFR as low as 30 mL/min/1.73 m2. kidney-disease related composite endpoints. Safety endpoints include:
Approximately 45% of enrolled patients had diabetes, 37% had prediabe- (a) serious adverse events; (b) discontinuation of dapagliflozin due to
tes, and 18% were normoglycaemic with baseline HbA1c <5.7% at visit adverse events; (c) changes in any clinical chemistry or haematology
1 and 2 of the study.34 Background therapy for heart failure with reduced parameters: and (d) prespecified adverse events of interest, including
ejection fraction (HFrEF) was superb, with the large majority of patients volume depletion, adverse renal events including AKI, major hyp-
treated with either an ACE inhibitor and ARB, and more than two-thirds oglycaemic events, fractures, DKA, and adverse events leading to
with a mineralocorticoid receptor antagonist. The DAPA-HF trial showed amputations and risk for lower limb amputations.39 Since SGLT2
that dapagliflozin reduced the risk of worsening heart failure, defined as inhibitors promote afferent arteriolar vasoconstriction, clinicians have
hospitalization or an urgent visit resulting in intravenous therapy for heart been concerned about the incidence of AKI with provision of these
failure or CV death, by 26% (HR 0.74, 95% CI, 0.65-0.85).34 Findings in agents; however, patients randomized to canagliflozin and
patients with diabetes did not differ from those in patients without diabe- dapagliflozin, respectively, in CREDENCE and DAPA-HF experienced
tes, and primary and key secondary outcomes were markedly improved fewer AKI events than patients randomized to placebo.16,34 The
in the CKD subgroup. DAPA-CKD trial was designed to include no more than 10% of partici-
By virtue of the inclusion criteria in the CREDENCE and DAPA- pants with eGFR in excess of 60 mL/min/1.73 m2 and at least 30%
HF trials, we now have evidence that SGLT2 inhibition appears safe without T2DM, so that the study sample will include a broader spec-
and efficacious in patients with moderate (stage 3) CKD. There is evi- trum of patients with CKD and generally patients with more advanced
dence that canagliflozin not only reduces CV events in patients with CKD compared with CREDENCE (wherein the eGFR inclusion crite-
T2DM and DKD, but also slows DKD progression. The DAPA-HF trial rion was 30 to <90 mL/min/1.73 m2).
showed that in patients with HFrEF, with or without CKD and/or Similarly, the Study of Heart and Kidney Protection With
T2DM, dapagliflozin reduce heart failure events. These newer trials Empagliflozin (EMPA-KIDNEY, NCT03594110) is investigating the
showed that canagliflozin and dapagliflozin can be used safely in effects of empagliflozin (10 mg/day) on kidney disease progression or
patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m2). It has yet CV death, compared with placebo, in patients with eGFR 20 to
to be determined whether kidney disease-related benefits observed in <45 mL/min/1.73 m2 or eGFR 45 to <90 mL/min/1.73 m2 with UACR
the CREDENCE trial would also be observed in patients with eGFR ≥200 mg/g or protein to creatinine ratio ≥200 mg/g receiving back-
<30 mL/min/1.73 m2 and/or UACR <300 mg/g, or in patients with ground renoprotective therapy with ACE inhibitors or ARBs.40 In con-
non-diabetic CKD. trast to CREDENCE and DAPA-CKD, the EMPA-KIDNEY trial extends
inclusion criteria to patients with type 1 diabetes mellitus and patients
with eGFR between 20 and < 45 min/min/1.73 m2 who have little or
1.5 | Ongoing trials in CKD: DAPA-CKD and no albuminuria/proteinuria.16 The expected enrolment is 5000. While
EMPA-KIDNEY the primary outcome in EMPA-KIDNEY is also a kidney disease-
related composite including ESKD and renal or CV death, the compo-
Two large-scale RCTs are examining the effects of SGLT2 inhibitors nent related to progressive, non-dialysis-requiring kidney disease is
on kidney disease-related outcomes; there are several key differences more liberal (40% or more decline in eGFR) than what was included in
RHEE ET AL. 51

TABLE 2 Summary of CREDENCE and ongoing kidney outcome trials

CREDENCE DAPA-CKD EMPA-KIDNEY

Patients (N) 4401 Approximately 4000 Approximately 5000

Tested drug (intervention) Canagliflozin Dapagliflozin Empagliflozin
Patient population CKD + T2DM CKD + T2DM CKD + T2DM
CKD without T2DM CKD without T2DM
Participating countries Argentina Argentina Canada
Australia Brazil China
Brazil Canada Germany
Bulgaria China Japan
Canada Denmark Malaysia
Chile Germany United Kingdom
China Hungary United States
Colombia India
Czech Republic Japan
France Mexico
Germany Peru
Guatemala Philippines
Hungary Poland
India Russia
Italy South Korea
Japan Spain
Lithuania Sweden
Malaysia Ukraine
Mexico United Kingdom
New Zealand United States
Philippines Vietnam
Poland
Romania
Russia
Serbia
Slovakia
South Africa
South Korea
Spain
Taiwan
Ukraine
United Arab Emirates
United Kingdom
United States
Inclusion criteria of clinically Yes Yes Yes
appropriate doses of either
ACE inhibitor or ARB unless
such treatment is not
tolerated or not indicated?
Required eGFR eGFR: ≥30-<90 eGFR: ≥25-<75 eGFR: ≥45-<90
(mL/min/1.73 m2) and UACR UACR: >300-≤5000 mg/g UACR: ≥200-≤5000 mg/g UACR: ≥200
(mg/g) range for enrolment OR
eGFR ≥20-<45
Primary endpoint Composite of ESKD, doubling of Composite of ≥50% sustained Kidney disease progression (ESKD,
serum creatinine, renal, or CV decline in eGFR, ESKD, renal, or sustained decline in eGFR to
death CV death <10 mL/min/1.73 m2, renal
death or sustained decline of
≥40% in eGFR) or CV death

Abbreviations: ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; CV,
cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; T2DM, type 2 diabetes mellitus; UACR, urinary
albumin-to-creatinine ratio.
52 RHEE ET AL.

CREDENCE (doubling of serum creatinine corresponding to a 57% multiple comorbid conditions and the need to manage polypharmacy
decline in eGFR) or DAPA-CKD (50% decline in eGFR). Secondary of antihypertensive agents, diuretics, insulin, or other glucose-
outcomes in EMPA-KIDNEY include CV death or hospitalization for lowering medications. Therefore, providers of different specialties
heart failure, all-cause hospitalization, and all-cause mortality.33 should collectively address the gap in provider knowledge regarding
In addition to testing for efficacy and safety of dapagliflozin and SGLT2 inhibitors and their use, so that any provider who sees the
empagliflozin in patients with CKD, both DAPA-CKD and EMPA- patient is able to perform correct dose adjustments, carefully monitor
KIDNEY are notable for inclusion of patients with non-diabetic CKD complications, and educate patients by discussing potential benefits
based on the proposed non-glycaemic, renoprotective effects of these and risks associated with SGLT2 inhibitor use. A team-based approach
drugs, and patients with more advanced kidney disease. It should be among primary care providers, endocrinologists, cardiologists, and
noted that neither DAPA-CKD nor EMPA-KIDNEY is powered to nephrologists would ensure that there is a shared responsibility
detect clinically meaningful effects within the T2DM and non-T2DM among different specialties to optimize glycaemic control and perhaps
subgroups. Conclusions regarding the risks and potential benefits of more importantly, ensure that patients are able to derive CV and kid-
dapagliflozin and empagliflozin will depend on relative effect sizes and ney disease-related benefits. The high cost of SGLT2 inhibitors and
determination of statistical interaction. the frequent requirement for prior authorization, may alter provider
prescribing behaviour and adherence among patients. While clinical
trials have demonstrated CV and renal benefits of these novel agents,
1.6 | Clinical implications and practice guidelines real-world utilization of these drugs will be heavily affected by their
cost and cost-effectiveness.
In 2019, the FDA approved a new indication for canagliflozin to reduce
the risk of ESKD and worsening of kidney function, CV death and hospi-
talization for heart failure in patients with T2DM and CKD. This was the 2 | CONC LU SION
first FDA indication for treatment of DKD since 2001.41 Subsequently,
the American Diabetes Association (ADA) updated its Living Standards of SGLT2 inhibitors, initially developed as glucose-lowering agents, were
Medical Care in Diabetes in June 2019 based on findings from the CRE- subjected to CVOTs to demonstrate CV safety. These agents have
DENCE trial (grade A evidence), recommending the following: “For consistently yielded favourable results vis-à-vis safety and efficacy
patients with type 2 diabetes and diabetic kidney disease, consider use with respect to CV outcomes. CREDENCE was the first kidney
of an SGLT2i in patients with an eGFR ≥30 mL/min/1.73 m and partic-
2
disease-focused trial which demonstrated a sizeable benefit to
ularly in those with >300 mg/g albuminuria to reduce risk of chronic kid- patients with T2DM and albuminuria atop that afforded by the use of
ney disease progression, cardiovascular events, or both.”42 The ADA ACE-inhibitors and ARBs. As a result of CREDENCE, canagliflozin is
further recommends SGLT2 inhibitors as second-line therapy for patients now approved for use in patients with DKD, and to reduce the risk of
with T2DM and CKD who are not meeting glycaemic or weight-loss progressive kidney disease, including the risk of ESKD or renal death.
goals with first-line therapy of metformin and lifestyle interventions.43 Ongoing kidney disease-focused outcomes trials including DAPA-
Similarly, the European Renal Association—European Dialysis and Trans- CKD and EMPA-KIDNEY will further inform care providers regarding
plant Association Consensus Statement and the American College of the use of SGLT2 inhibitors in patients with CKD and without T2DM,
Cardiology/American Heart Association guidelines recommend the use and in patients with more advanced CKD (stage 3b and early stage 4)
of SGLT2 inhibitors as second-line therapy in patients with T2DM and with and without albuminuria.
CKD, defined as eGFR <60 mL/min/1.73 m2 or eGFR >60 mL/
min/1.73 m2 and microalbuminuria or macroalbuminuria, who are not ACKNOWLEDG MENTS
meeting the glycaemic target of HbA1c ≤7% on recommended metfor- This work was supported by the National Institutes of Health grant
min dose or in those who are not meeting the target HbA1c and metfor- numbers 5K01DK110221 (Dr J.J.R.) and K24DK085446 (Dr G.M.C.).
min is not tolerated or contraindicated.44,45 The European Society of M.J.J. is supported by a Medical Research Future Fund Next Genera-
Cardiology, in collaboration with the European Association for the Study tion Clinical Researchers Program Career Development Fellowship.
of Diabetes, now recommends the use of SGLT2 inhibitors to reduce the
progression of DKD in patients with T2DM and albuminuric kidney dis- CONFLIC T OF INT ER E STS
ease, and also for CV benefits in patients with T2DM with prevalent M.J.J. is responsible for research projects that have received
CVD or CV risk factors regardless of whether they are treatment naïve unrestricted funding from Gambro, Baxter, CSL, Amgen, Eli Lilly, and
46
or on background metformin therapy. Merck; has served on advisory boards sponsored by Akebia, Baxter,
In the midst of new clinical trial data and recommendations for and Boehringer Ingelheim; and spoken at scientific meetings spon-
patients with T2DM and CKD, there is substantial need for cross- sored by Janssen, Amgen, and Roche, with any consultancy, honoraria
disciplinary collaboration among professional providers and associated or travel support paid to her institution. G.M.C. serves on the Steering
staff to coordinate patient care. Patients with T2DM and DKD are Committee for DAPA-CKD and served as a national leader for CRE-
treated by multiple specialists including endocrinology, cardiology and DENCE. K.W.M.'s financial disclosures can be viewed at http://med.
nephrology as well as primary care. Many patients present with stanford.edu/profiles/kenneth-mahaffey.
RHEE ET AL. 53

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J.J.R. and G.M.C. contributed to the design of the review, analysis, sion of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):
323-334.
and interpretation of data; J.J.R. drafted the manuscript; J.J.R., M.J.J.,
18. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal
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content; all of the authors gave final approval of the version to be randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6(9):
published and agreed to be accountable for all aspects of the work. 691-704.
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