Nephrol Dial Transplant (2020) 35: i48–i55

doi: 10.1093/ndt/gfz252

Sodium-glucose cotransporter 2 inhibition: which patient with

chronic kidney disease should be treated in the future?
REVIEW

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Brendon L. Neuen, Meg J. Jardine and Vlado Perkovic
George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia

Correspondence to: Vlado Perkovic; E-mail: [email protected]; Twitter handles: @brendonneuen,

@jardine_meg, @vladoperkovic

ABSTRACT over a decade later, almost 20 large-scale cardiovascular or kid-

The advent of sodium-glucose cotransporter 2 (SGLT2) ney outcome trials have been completed, resulting in an explo-
inhibitors represents a major advance for people with type 2 di- sion of evidence that has transformed diabetes care. Of the
abetes (T2DM) and chronic kidney disease (CKD). The results newer classes of glucose-lowering agents, sodium-glucose
of the Canagliflozin and Renal Events in Diabetes with cotransporter 2 (SGLT2) inhibitors have been shown to consis-
Established Nephropathy Clinical Evaluation (CREDENCE) tently reduce the risk of clinically important, patient-level car-
trial have clearly demonstrated that canagliflozin prevents kid- diovascular outcomes, including atherosclerotic cardiovascular
ney failure and cardiovascular events. The results from three events and hospitalization for heart failure (HF) [2]. The advent
other large-scale randomized trials, collectively enrolling of SGLT2 inhibitors thus represents a major advance for indi-
>30 000 participants, have provided further evidence that the viduals with type 2 diabetes mellitus (T2DM) and those who
effects of SGLT2 inhibition on major kidney outcomes in people care for them.
with T2DM may be present across the class, although this will The emergence of evidence for the SGLT2 inhibitor class has
only be known for certain when Dapagliflozin and Renal been watched with great anticipation in the nephrology com-
Outcomes and Cardiovascular Mortality in Patients with CKD munity. It has been almost two decades since the benefits of re-
(DAPA-CKD) (NCT03036150) and The Study of Heart and nin–angiotensin system (RAS) blockade were confirmed in
Kidney Protection with Empagliflozin (EMPA-KIDNEY) Irbesartan Diabetic Nephropathy Trial (IDNT) [3] and
(NCT03594110) are reported over coming years. Importantly, Reduction of Endpoints in Non-Insulin-Dependent Diabetes
the benefits of SGLT2 inhibition have been achieved in addition Mellitus with Angiotensin 2 Antagonist Losartan (RENAAL)
to the current standard of care. This review summarizes evi- [4]; however, despite this, growth in the global burden of dia-
dence for SGLT2 inhibition in people with T2DM and CKD, betic kidney disease (DKD) has continued unabated [5, 6]. The
evaluates key patient characteristics and concomitant drug use capacity of SGLT2 inhibitors to reduce albuminuria created
that may influence the use of these drugs in people with CKD, hope for a clinically meaningful kidney benefit. This optimism
discusses current guideline recommendations and explores how was further reinforced by secondary analyses of the SGLT2 car-
these drugs may be used in people with CKD in the future, in- diovascular outcome trials, which demonstrated that these
cluding in combination with other treatments. drugs consistently reduced the risk of serum creatinine-based
kidney outcomes [7–10]. However, most participants in these
Keywords: chronic kidney disease, clinical outcomes, SGLT2 trials were at low risk of end-stage kidney disease (ESKD) and
inhibitors, type 2 diabetes thus the effect of SGLT2 inhibitors on the most important
patient-level kidney outcome—namely the need for dialysis or
transplantation—was uncertain.
INTRODUCTION The Canagliflozin and Renal Events in Diabetes with
Since 2008, the US Food and Drug Administration (FDA) and Established Nephropathy Clinical Evaluation (CREDENCE)
other regulators have mandated that all new glucose-lowering trial was designed to specifically address this evidence gap [11].
agents undergo long-term cardiovascular outcome trials to The trial demonstrated that an SGLT2 inhibitor, canagliflozin,
demonstrate safety, primarily in response to concerns that substantially reduced the progression of DKD (doubling of
drugs (notably rosiglitazone) that were effective in improving serum creatinine, ESKD or cardiovascular or kidney-related
glycaemic control could increase cardiovascular risk [1]. Just death) in participants with T2DM and severely increased
C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial
re-use, please contact [email protected] i48
albuminuria who were already receiving RAS blockade. Indeed, down to an eGFR of 30 mL/min/1.73 m2. The effect of canagli-
CREDENCE demonstrated, for the first time ever, that a single flozin on cardiovascular death, non-fatal myocardial infarction
intervention reduced the need for dialysis, transplantation or non-fatal stroke [HR 0.80 (95% CI 0.67–0.95)] was also not
or death due to kidney disease in its own right. A 2019 meta- modified by baseline kidney function. While largely powered by
analysis [12] synthesizing the accumulated trial evidence pro- the effects of canagliflozin observed in the CREDENCE trial, a
vided further strong support for the role of SGLT2 inhibition recent meta-analysis [12] of the four major trials showed that
for kidney protection in people with T2DM and that the SGLT2 inhibition reduces the risk of progression of kidney dis-
combination of RAS blockade and SGLT2 inhibition should be ease across all levels of kidney function studied to date, includ-
routinely offered to patients with T2DM who have, or are ing 30% proportional risk reduction in people with an eGFR
at high risk of, progressive kidney disease, with the strongest of 30–45 mL/min/1.73 m2, in whom the glucose-lowering effect
evidence for canagliflozin. is almost completely abrogated.
In the face of these clear and substantial benefits for cardio- The disconnect between glucose lowering and effects on kid-

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vascular and kidney outcomes, a number of other important ney and cardiovascular outcomes is a characteristic feature of
questions remain. Who might benefit most from treatment? SGLT2 inhibition. This is further supported by head-to-head
How should this evidence be applied in routine practice to max- data showing that canagliflozin slows the loss of kidney func-
imize benefits and ensure potential harms are minimized? Are tion compared with glimepiride [19] and that kidney benefits
there other patient groups, aside from those with T2DM, who are independent of HbA1c before and during therapy, and by
may benefit from SGLT2 inhibitors? Finally, how should these the degree of HbA1c lowering [20].
agents be used in combination with other currently available Because the risk of ESKD and cardiovascular mortality
and future treatments? increases substantially as eGFR declines [21, 22], the absolute
Some of these issues, including SGLT2 inhibition in people effects of treatment with SGLT2 inhibition are likely to be at
with type 1 diabetes and in people with non-DKD, have been least as large, if not greater, in patients with an eGFR <60 mL/
examined in this special issue of NDT. In this analysis we ex- min/1.73 m2 compared with those with preserved kidney func-
plore how select patient characteristics and how concomitant tion. In the CREDENCE trial, the estimated number of primary
drug use might influence the use of SGLT2 inhibitors in people events prevented per 1000 patients treated over 2.6 years is sub-
with T2DM and chronic kidney disease (CKD), discuss current stantially greater in participants with a starting eGFR <60 mL/
guidelines recommendations and explore future research min/1.73 m2 (Figure 1).
priorities in this area. The accumulated trial evidence provides strong evidence
that SGLT2 inhibition should be prioritized in people with
T2DM and CKD, including those with a starting eGFR of 30–
SGLT2 inhibition across different levels of estimated 45 mL/min/1.73 m2. Importantly, in the CREDENCE trial, par-
glomerular filtration rate (eGFR) ticipants whose eGFR fell to <30 mL/min/1.73 m2 continued
The completed trials included participants with varying lev- on randomized treatment until dialysis or transplantation. As a
els of baseline eGFR and albuminuria. In the three cardiovascu- result, the FDA now permits the continued use of canagliflozin
lar outcome trials, the proportion of participants with baseline with an eGFR <30 mL/min/1.73 m2 until dialysis or transplan-
eGFR <60 mL/min/1.73 m2 ranged from 7.4 to 25.9% [8, 13, tation in people already initiated on therapy [23].
14]. In contrast, 60% of participants in CREDENCE had a
baseline eGFR <60 mL/min/1.73 m2. Most participants in the
cardiovascular outcome trials had levels of albuminuria within Impact of albuminuria
the normal range at baseline [9, 15, 16], whereas those in the SGLT2 inhibition ameliorates albuminuria by approximately
CREDENCE trial were required to have a urinary albumin:crea- a third in patients with moderate or severely increased albumin-
tinine ratio of at least 300 mg/g at enrolment. While protection uria, with lesser effects in those with normal albuminuria
against kidney failure with SGLT2 inhibitors other than canagli- [15, 24]. If these drugs protect the kidney solely by lowering
flozin remains to be demonstrated in the ongoing kidney out- albuminuria as hypothesized, then people with higher levels of
come trials, the accumulated trial evidence has allowed for a albuminuria should benefit more. However, a meta-analysis of
robust assessment of the effects of SGLT2 inhibition in patients the major SGLT2 inhibitor trials, which included CREDENCE,
with T2DM across varying levels of eGFR and albuminuria. demonstrated that the proportional kidney benefits are
The glucose-lowering effect of SGLT2 inhibitors is directly consistent irrespective of baseline albuminuria [12]. Secondary
proportional to glomerular filtration, and thus glycaemic effi- analyses of the cardiovascular outcome trials also suggest that
cacy decreases substantially as kidney function declines [17]. cardiovascular benefits might be similar across different levels
Because regulatory approvals for these drugs have been primar- of albuminuria [15, 16].
ily based on their ability to reduce glycated haemoglobin The consistent evidence of kidney protection across the
(HbA1c), SGLT2 inhibitors have largely not been approved for spectrum of albuminuria has important implications because
use in people with an eGFR <45 mL/min1.73 m2 [18]. the clinical phenotype and presentation of DKD have changed
However, in the CREDENCE trial, the effect of canagliflozin on in recent decades [25]. Normoalbuminuric DKD is increasingly
doubling of serum creatinine, ESKD or death due to kidney dis- common; it is estimated that 40% of people with T2DM de-
ease {hazard ratio [HR] 0.66 [95% confidence interval (CI) velop reduced kidney function without having albuminuria
0.53–0.81]} was consistent across all levels of kidney function documented [26, 27]. While the risk of ESKD for these

SGLT2 inhibition in CKD i49

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FIGURE 1: Estimated number of primary events (doubling of serum creatinine, ESKD or cardiovascular or kidney-related death) prevented
per 1000 patients treated over 2.6 years in the CREDENCE trial by baseline eGFR. aAbsolute risk reductions estimated as the number of events
prevented per 1000 patients treated over 2.6 years.

FIGURE 2: Estimated number of primary events (doubling of serum creatinine, ESKD or cardiovascular or kidney-related death) prevented
per 1000 patients treated over 2.6 years in the CREDENCE trial by baseline UACR. Absolute risk reductions estimated as the number of events
prevented per 1000 patients treated over 2.6 years. UACR: urinary albumin:creatinine ratio.

individuals is low, progressive loss of kidney function can still promising therapeutic option for this patient population.
occur [28], with a heterogeneous range of structural changes on Furthermore, T2DM with normal albuminuria is much more
kidney biopsy [25], suggesting that there are probably a number common than classically progressive DKD, therefore SGLT2 in-
of different mechanisms of disease progression aside from clas- hibition may be an important strategy for kidney (and cardio-
sically progressive albuminuria. SGLT2 inhibition clearly vascular) risk reduction at a population level. At the same time,
reduces cardiovascular events and may reduce kidney events because patients with substantially increased albuminuria are at
even in people with normal albuminuria and thus represents a much higher risk of ESKD, treatment with SGLT2 inhibitors in

i50 B.L. Neuen et al.

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FIGURE 3: Effect of canagliflozin on eGFR over time by baseline UACR in the Canagliflozin Cardiovascular Asssessment Study (CANVAS)
Program. P-interaction <0.0001 for differences between UACR subgroups. UACR: urinary albumin:creatinine ratio. Reproduced from Neuen
et al. [15].

these individuals should be prioritized because the absolute addition to RAS blockade, as the use of RAS blockade was man-
benefits are greater (Figures 2 and 3; note the scale in Figure 2 is dated for entry into the trial. In comparison, there is less data
twice as wide as in Figure 1) [15]. on whether SGLT2 inhibitor monotherapy is effective at slow-
ing the progression of kidney disease, although subgroup data
Stratification of risk based on atherosclerotic from the cardiovascular outcome trials appear promising. A
cardiovascular disease meta-analysis of these trials found that kidney protection was
The presence or absence of atherosclerotic cardiovascular consistent regardless of baseline use of RAS blockade, a finding
disease has typically been used to stratify absolute cardio- limited somewhat by the fact all but 20% of participants were
vascular risk and identify which patients should be treated with receiving RAS blockade [12]. Nevertheless, these data provide
cardioprotective therapies (i.e. primary versus secondary pre- some justification for the use of SGLT2 inhibitors without back-
vention). While this may be a useful approach for the preven- ground RAS blockade in certain patients, for example, those
tion of atherosclerotic vascular events in patients without with normoalbuminuric DKD, for whom there is somewhat
CKD, this distinction is probably of limited use in patients less data on kidney protection at lower levels of albuminuria
with CKD. A 2018 meta-analysis of the cardiovascular out- [30], or those experiencing hyperkalaemia, which occurs more
come trials showed that benefits for HF and kidney disease frequently as kidney function declines [31]. Reassuringly, no in-
progression are consistent irrespective of a history of athero- creased risk of acute kidney injury, volume depletion or hyper-
sclerotic cardiovascular disease [2]. Because individuals with kalaemia were observed in the CREDENCE trial, suggesting
T2DM and CKD are at very high risk of both outcomes, that the combined use of SGLT2 inhibition and RAS blockade
treatment with SGLT2 inhibitors should be offered should be well tolerated from a haemodynamic perspective, if
regardless, as suggested in the most recent clinical practice used appropriately.
guidelines (discussed below). In CREDENCE, consistent
protection against cardiovascular and kidney outcomes was Concomitant diuretics: safe and effective?
observed for primary and secondary prevention cohorts [29], The efficacy and safety of SGLT2 inhibitors in combination
further emphasizing that stratifying absolute risk based on with diuretics are of particular clinical relevance because the use
the history of atherosclerotic cardiovascular disease alone of diuretics becomes increasingly common as kidney function
is short-sighted, particularly in patients with T2DM and declines and because hypertension and HF are highly prevalent
severely increased albuminuria, for whom the absolute risk in patients with DKD [32, 33]. Concerns have been expressed
of adverse outcomes is particularly high. about the potential for volume depletion with broad untargeted
use of SGLT2 inhibitors, particularly, when used in conjunction
SGLT2 inhibition with and without RAS blockade with loop diuretics [34]. To minimize this risk, SGLT2 inhibi-
The CREDENCE trial provided strong evidence that kidney tors should not be initiated in people with unstable volume
and cardiovascular protection with canagliflozin is achieved in status or those with hypovolaemia. Furthermore, loop diuretic

SGLT2 inhibition in CKD i51

dose should be adjusted appropriately (SGLT2 inhibitors are with T2DM at high or very high risk of cardiovascular disease,
loop diuretic sparing). Subgroup analyses from the cardiovascu- irrespective of whether they are treatment naı̈ve or already on
lar outcome trials suggest that the effects of SGLT2 inhibition metformin.
on kidney and cardiovascular outcomes are mostly consistent Given the consistent evidence that SGLT2 inhibition can
in patients receiving and not receiving diuretics, and data from reduce the risk of hospitalization for HF and kidney disease
the EMPA-REG OUTCOME trial (NCT01131676) showed progression, the ADA–EASD consensus report also recom-
that diuretic use did not alter the risk of kidney or volume-re- mends the use of SGLT2 inhibitors in people with T2DM and
lated adverse events [7, 9, 35, 36]. However, the overall risk of HF or CKD (irrespective of a history of atherosclerotic cardio-
adverse kidney outcomes in these trials was low, and corre- vascular disease). Based on the results of the CREDENCE trial,
sponding data in a high-risk population, such as CREDENCE, the updated 2019 ADA Standards of Care specifically endorse
will provide further important information. the use of SGLT2 inhibitors for the prevention of kidney failure,
cardiovascular events or both in patients with an eGFR

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Metformin and the question of first-line treatment >30 mL/min/1.73 m2, particularly in those with severely in-
creased albuminuria (Grade A recommendation) [47].
In almost all clinical practice guidelines, metformin remains
the preferred first-line pharmacotherapy for T2DM, in large
part due to its low cost, tolerability and safety. However, Implementation of evidence into clinical practice
evidence for cardiovascular and kidney benefits with new There is strong evidence from completed trials that patients
glucose-lowering agents has led to some debate about metfor- with T2DM and CKD are among those who are likely to benefit
min’s place as first-line treatment for all patients [37], especially most from SGLT2 inhibition, with larger absolute risk reduc-
since its effects on cardiovascular outcomes are not clear [38], tions for those with reduced kidney function and higher levels
with little direct evidence for kidney outcomes. Most recently, of albuminuria (Figures 1 and 2). The strongest evidence for
joint guidelines from the European Society of Cardiology (ESC) kidney protection is with canagliflozin, and while data from car-
and European Association for the Study of Diabetes (EASD) diovascular outcome trials of other SGLT2 inhibitors are prom-
suggest SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) ising, a class effect on patient-level kidney outcomes (i.e.
agonists should be used in patients with T2DM who have or are dialysis or transplantation) remains to be demonstrated in on-
at high risk of cardiovascular disease, whether they are treat- going kidney outcome trials. Nevertheless, there is currently
ment naı̈ve or already receiving metformin [39]. In the EMPA- limited evidence that key patient characteristics or use of con-
REG OUTCOME trial, compared with participants receiving comitant drugs modifies the efficacy or safety of SGLT2 inhibi-
metformin, the effects on cardiovascular death and on hospital- tion (Table 1), supporting that these drugs should be routinely
ization for HF were at least as large in participants not on met- offered to most patients with T2DM and CKD.
formin [36, 40], but otherwise there are currently scant data on Collaborative efforts from the nephrology community and
the effects of SGLT2 inhibitors with and without metformin. other stakeholders are now required to ensure that findings
Absolute benefits, possible adverse effects, reimbursement from randomized trials are translated into routine clinical prac-
and out-of-pocket costs would all be important to consider if tice. In this respect, initiatives such as the Diabetic Kidney
SGLT2 inhibitors are to be used as first-line oral therapy. Disease Collaborative (DKD-C) are welcome. The DKD-C was
recently launched by the American Society of Nephrology to in-
Latest guideline recommendations on the use of SGLT2 crease coordination between primary care, nephrologists and
inhibitors other specialties to deliver optimal care to people with diabetes
and CKD. Current data suggest that a substantial proportion of
Several major clinical practice guidelines have been updated
patients with CKD who would benefit from treatment with
in the past 18 months to reflect the evolving evidence for cardio-
RAS blockade still do not receive it [48]. As such, implementa-
vascular and kidney protection from SGLT2 trials. Major
tion research should be a priority to speed the incorporation
updates include a joint consensus report from the American
of SGLT2 inhibitors and other proven therapies into clinical
Diabetes Association (ADA) and the EASD, and the ADA
practice for the benefit of patients.
Standards of Care [41, 42]. These have been accompanied by a
number of statements from other organizations including the
American College of Cardiology, ESC, American Association Looking to the future
of Clinical Endocrinologists, Diabetes Canada and European With the growing number of therapeutic options for people
Renal Association-European Dialysis and Transplant with T2DM, there is a need to better understand the optimal
Association [39, 43–46]. combination of treatments. There is strong evidence that GLP-
Most noticeably, guidelines now recommended the selection 1 receptor agonists also reduce the risk of a range of cardiovas-
of agents based on end-organ protection and patient co- cular events [49]. The types of events prevented with GLP-1 re-
morbidities. Most guidelines recommend either SGLT2 inhibi- ceptor agonists, and time frames over which benefits accrue,
tors or GLP-1 receptor agonists as second-line treatment (after highlight that the mechanism of cardioprotection with these
metformin) in people with T2DM and a history of atheroscle- agents is likely to be distinct from SGLT2 inhibitors and medi-
rotic cardiovascular disease (i.e. for the secondary prevention of ated mainly through anti-atherothrombotic effects. In contrast,
cardiovascular events). The ESC–EASD guidelines recommend SGLT2 inhibitors have greater benefits on HF and kidney
either an SGLT2 inhibitor or GLP-1 receptor agonist in people outcomes, underscoring their unique haemodynamic effects.

i52 B.L. Neuen et al.

Table 1. Key patient characteristics and concomitant drug use influencing the decision to use SGLT2 inhibitors

Key patient characteristics/ Overall conclusion Level of evidence Limitations and other considerations
concomitant drug use
eGFR Kidney protection achieved across all Meta-analysis of subgroup data No randomized evidence in people with starting
levels of starting eGFR >30 mL/min/ from the major SGLT2 trials eGFR <30 mL/min/1.73 m2
1.73 m2 Effects in participants with eGFR <60 mL/min/
1.7 3m2 driven predominantly by one trial
(CREDENCE)
Albuminuria Kidney protection consistent across Meta-analysis of subgroup data Fewer kidney events in participants with normal
different levels of albuminuria from the major SGLT2 trials or moderately increased albuminuria
Most participants with normal or moderately in-
creased albuminuria had normal kidney

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function
ASCVD Consistent protection against progression Meta-analysis of CVOTs and Risk stratification based on ASCVD alone
of kidney disease and HF irrespective pre-specified secondary analy- likely to be of limited value in people with
of prior ASCVD sis of CREDENCE CKD who are already at elevated risk of
cardiovascular events
RAS blockade Effect on kidney outcomes probably Meta-analysis of subgroup data Few participants not receiving RAS blockade at
similar in participants receiving and from major SGLT2 trials baseline in the CVOTs and therefore few
not receiving RAS blockade events
Trials were not designed to assess effects
on outcomes without RAS blockade
Diuretics Benefits probably unaltered by Subgroup data from CVOTs Participants in the CVOTs were generally at
concomitant diuretics and safe if (efficacy) and EMPA-REG low risk of kidney-related adverse events
used appropriately OUTCOME (safety)
Metformin Possibly similar irrespective of metfor- Subgroup data from the Limited randomized evidence
min use (cardiovascular outcomes) EMPA-REG OUTCOME trial No published data for kidney outcomes
GLP-1 receptor agonists Potential for additive protection by Theoretical benefits No randomized evidence for patient-level
different mechanisms cardiovascular or kidney outcomes
ASCVD, atherosclerotic cardiovascular disease; CVOT, cardiovascular outcome trial.

Additionally, GLP-1 receptor agonists are permitted for use CKD and EMPA-KIDNEY are also enrolling participants with-
down to an eGFR of 15 mL/min/1.73 m2 in some regions, out T2DM, and thus are expected to provide important evi-
presenting an important treatment option for patients with dence on the effects of SGLT2 inhibition on kidney outcomes in
advanced CKD. The contrasting mechanisms and benefits of people without diabetes [53, 54]. These trials also include par-
these two classes of drugs raise the possibility that combination ticipants with a starting eGFR as low as 20 mL/min/1.73 m2 and
therapy with GLP-1 receptor agonists and SGLT2 inhibitors thus may potentially provide some important information in
could provide additive cardiovascular and kidney benefits. people with advanced CKD.
Short-term trials of semaglutide and dulaglutide suggest that
combination treatment reduces HbA1c and body weight to a
greater extent than SGLT2 inhibition alone, without additional CONCLUSION
safety concerns [50, 51]. However, randomized evidence on SGLT2 inhibitors are undoubtedly a practice-changing develop-
patient-level cardiovascular and kidney outcomes is currently ment for patients with T2DM and CKD. Evidence from com-
lacking and a trial designed to test these agents in combination pleted trials strongly supports the role of SGLT2 inhibition to
would be very valuable. In lieu of such trials, the uptake of prevent kidney and cardiovascular events in patients with
SGLT2 inhibitors in routine clinical practice will mean that fu- T2DM, and those with lower levels of eGFR and higher levels of
ture randomized studies, including of GLP-1 receptor agonists, albuminuria are among those who stand to gain the greatest ab-
may well include substantial numbers of participants receiving solute benefits.
SGLT2 inhibitor therapy, and thus provide indirect evidence on
the effects of these drug classes used in combination.
Most recently, the results of the first dedicated HF outcome ACKNOWLEDGEMENTS
trial of an SGLT2 inhibitor, DAPA-HF (dapagliflozin; This work was not specifically funded. B.L.N. is supported
NCT03036124), were presented at the 2019 ESC Congress. by an Australian National Health and Medical Research
DAPA-HF is notable because it is the first SGLT2 inhibitor trial Council Postgraduate Scholarship; the John Chalmers PhD
enrolling participants with and without T2DM. In this trial, the Scholarship from the George Institute for Global Health; a
effect on the primary outcome of urgent HF visit, hospitaliza- University Postgraduate Award from the University of New
tion for HF or cardiovascular death [HR 0.74 (95% CI 0.65– South Wales Sydney; the Graduate Research Fund at Lincoln
0.85)] was similar in participants with and without T2DM [52], College, University of Oxford; and an Oxford Australia
further strengthening the hypothesis that these drugs may also Clarendon Scholarship from the University of Oxford. M.J.J. is
benefit individuals with non-diabetic CKD. Likewise, DAPA- supported by a Medical Research Future Fund Next-Generation

SGLT2 inhibition in CKD i53

Clinical Researchers Programme Career Development 13. Neuen BL, Ohkuma T, Neal B et al. Cardiovascular and renal outcomes
Fellowship; V.P. reports receiving research support from the with canagliflozin according to baseline kidney function: data from the
CANVAS Program. Circulation 2018; 138: 1537–1550
Australian National Health and Medical Research Council 14. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardiovascular
(Senior Research Fellowship and Programme Grant). outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347–357
15. Neuen BL, Ohkuma T, Neal B et al. Effect of canagliflozin on renal and
cardiovascular outcomes across different levels of albuminuria: data from
CONFLICT OF INTEREST STATEMENT the CANVAS Program. J Am Soc Nephrol 2019; 30: 2229–2242
He has received travel support from Janssen. Serves on steer- 16. Wanner C, Lachin JM, Inzucchi SE et al. Empagliflozin and clinical
outcomes in patients with type 2 diabetes mellitus, established cardiovascu-
ing committees for Janssen and CSL; is responsible for re- lar disease, and chronic kidney disease. Circulation 2018; 137: 119–129
search projects that have received unrestricted funding from 17. Heerspink HJ, Perkins BA, Fitchett DH et al. Sodium glucose cotransporter
Gambro, Baxter, CSL, Amgen, Eli Lilly and Merck; has served 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney
on advisory boards sponsored by Akebia, Baxter and effects, potential mechanisms, and clinical applications. Circulation 2016;

Downloaded from https://academic.oup.com/ndt/article-abstract/35/Supplement_1/i48/5718401 by guest on 07 February 2020

Boehringer Ingelheim; and has spoken at scientific meetings 134: 752–772
18. Toyama T, Neuen BL, Jun M et al. Effect of SGLT2 inhibitors on cardiovas-
sponsored by Janssen, Amgen and Roche, with any consul- cular, renal and safety outcomes in patients with type 2 diabetes mellitus
tancy, honoraria or travel support paid to her institution. and chronic kidney disease: a systematic review and meta-analysis. Diabetes
Serving on steering committees for AbbVie, Boehringer Obes Metab 2019; 21: 1237–1250
Ingelheim, Gilead, GlaxoSmithKline, Janssen, Novo Nordisk 19. Heerspink HJ, Desai M, Jardine M et al. Canagliflozin slows progression of
and Pfizer; serving on advisory boards and/or speaking at sci- renal function decline independently of glycemic effects. J Am Soc Nephrol
2017; 28: 368–375
entific meetings for AbbVie, Astellas, AstraZeneca, Bayer, 20. Cooper ME, Inzucchi SE, Zinman B et al. Glucose control and the effect of
Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, empagliflozin on kidney outcomes in type 2 diabetes: an analysis from the
Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, EMPA-REG OUTCOME trial. Am J Kidney Dis 2019; 74: 713
Novo Nordisk, Pfizer, Pharmalink, Relypsa, Roche, Sanofi, 21. Gansevoort RT, Matsushita K, van der Velde M et al. Lower estimated GFR
Servier and Vitae; and receiving personal fees for consulting and higher albuminuria are associated with adverse kidney outcomes. A col-
laborative meta-analysis of general and high-risk population cohorts.
and scientific presentations related to canagliflozin from Kidney Int 2011; 80: 93–104
Mitsubishi Tanabe and Mundipharma. 22. Matsushita K, Coresh J, Sang Y et al. Estimated glomerular filtration rate
and albuminuria for prediction of cardiovascular outcomes: a collaborative
meta-analysis of individual participant data. Lancet Diabetes Endocrinol
REFERENCES
2015; 3: 514–525
1. Cefalu WT, Kaul S, Gerstein HC et al. Cardiovascular outcomes trials in 23. Highlights of prescribing information. Invokana (canagliflozin) tablets.
type 2 diabetes: where do we go from here? Reflections from a diabetes care http://www.janssenlabels.com/package-insert/product-monograph/prescrib
editors’ expert forum. Diabetes Care 2018; 41: 14–31 ing-information/INVOKANA-pi.pdf (15 November 2019, date last
2. Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and sec- accessed)
ondary prevention of cardiovascular and renal outcomes in type 2 diabetes: 24. Cherney DZ, Zinman B, Inzucchi SE et al. Effects of empagliflozin on the
a systematic review and meta-analysis of cardiovascular outcome trials. urinary albumin-to-creatinine ratio in patients with type 2 diabetes and
Lancet 2019; 393: 31–39 established cardiovascular disease: an exploratory analysis from the EMPA-
3. Parving HH, Lehnert H, Bröchner-Mortensen J et al. The effect of irbesartan REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes
on the development of diabetic nephropathy in patients with type 2 diabetes. Endocrinol 2017; 5: 610–621
N Engl J Med 2001; 345: 870–878 25. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, prog-
4. Brenner BM, Cooper ME, De Zeeuw D et al. Effects of losartan on renal and ress, and possibilities. Clin J Am Soc Nephrol 2017; 12: 2032–2045
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. 26. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S et al. Nonalbuminuric re-
N Engl J Med 2001; 345: 861–869 nal insufficiency in type 2 diabetes. Diabetes Care 2004; 27: 195–200
5. Neuen BL, Chadban SJ, Demaio AR et al. Chronic kidney disease and the 27. Retnakaran R, Cull CA, Thorne KI et al. Risk factors for renal dysfunction
global NCDs agenda. BMJ Glob Health 2017; 2: e000380 in type 2 diabetes: UK Prospective Diabetes Study 74. Diabetes 2006; 55:
6. Xie Y, Bowe B, Mokdad AH et al. Analysis of the Global Burden of 1832–1839
Disease study highlights the global, regional, and national trends of chronic 28. Vistisen D, Andersen GS, Hulman A et al. Progressive decline in estimated
kidney disease epidemiology from 1990 to 2016. Kidney Int 2018; 94: glomerular filtration rate in patients with diabetes after moderate loss in
567–581 kidney function—even without albuminuria. Diabetes Care 2019; 42:
7. Perkovic V, de Zeeuw D, Mahaffey KW et al. Canagliflozin and renal out- 1886–1894
comes in type 2 diabetes: results from the CANVAS Program randomised 29. Mahaffey K, Jardine M, Bompoint S et al. Canagliflozin and cardiovascular
clinical trials. Lancet Diabetes Endocrinol 2018; 6: 691–704 and renal outcomes in type 2 diabetes and chronic kidney disease in pri-
8. Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and progression of mary and secondary cardiovascular prevention groups: results from the ran-
kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–334 domized CREDENCE trial. Circulation 2019; 140: 739
9. Mosenzon O, Wiviott SD, Cahn A et al. Effects of dapagliflozin on develop- 30. Ruilope LM, Solini A. RAS blockade for every diabetic patient: pro and con.
ment and progression of kidney disease in patients with type 2 diabetes: an Diabetes Care 2011; 34(Suppl 2): S320–S324
analysis from the DECLARE–TIMI 58 randomised trial. Lancet Diabetes 31. Lazich I, Bakris GL. Prediction and management of hyperkalemia across
Endocrinol 2019; 7: 606–617 the spectrum of chronic kidney disease. Semin Nephrol 2014; 34:
10. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular 333–339
and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–657 32. House AA, Wanner C, Sarnak MJ et al. Heart failure in chronic kidney
11. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal outcomes in disease: conclusions from a Kidney Disease: Improving Global
type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–2306 Outcomes (KDIGO) Controversies Conference. Kidney Int 2019; 95:
12. Neuen BL, Young T, Heerspink HJ et al. SGLT2 inhibitors for the preven- 1304–1317
tion of kidney failure in patients with type 2 diabetes: a systematic review 33. Horowitz B, Miskulin D, Zager P. Epidemiology of hypertension in CKD.
and meta-analysis. Lancet Diabetes Endocrinol 2019; 7: 845–854 Adv Chronic Kidney Dis 2015; 22: 88–95

i54 B.L. Neuen et al.

34. Cherney DZ, Udell JA. Use of sodium glucose cotransporter 2 inhibitors in of Endocrinology on the comprehensive type 2 diabetes management
the hands of cardiologists: with great power comes great responsibility. algorithm–2018 executive summary. Endocr Pract 2018; 24: 91–120
Circulation 2016; 134: 1915–1917 45. Lipscombe L, Booth G, Butalia S et al. Pharmacologic glycemic management
35. Mayer GJ, Wanner C, Weir MR et al. Analysis from the EMPA-REG of type 2 diabetes in adults. Can J Diabetes 2018; 42(Suppl 1): S88–S103
R
OUTCOMEV trial indicates empagliflozin may assist in preventing the pro- 46. Sarafidis P, Ferro CJ, Morales E et al. SGLT-2 inhibitors and GLP-1 receptor
gression of chronic kidney disease in patients with type 2 diabetes irrespec- agonists for nephroprotection and cardioprotection in patients with
tive of medications that alter intrarenal hemodynamics. Kidney Int 2019; 96: diabetes mellitus and chronic kidney disease. A consensus statement by the
489–504 EURECA-m and the DIABESITY working groups of the ERA-EDTA.
36. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular out- Nephrol Dial Transplant 2019; 34: 208–230
comes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128 47. American Diabetes Association. 11. Microvascular complications and foot
37. Khunti K, Seidu S, Davies MJ. Should sodium glucose co-transporter 2 care: standards of medical care in diabetes—2019. Diabetes Care 2019;
inhibitors be considered as first line oral therapy for people with type 2 dia- 42(Suppl 1): S124–S138
betes? Diabetes Obes Metab 2018; 21: 207–209 48. Murphy DP, Drawz PE, Foley RN. Trends in angiotensin-converting en-
38. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular dis- zyme inhibitor and angiotensin II receptor blocker use among those with

Downloaded from https://academic.oup.com/ndt/article-abstract/35/Supplement_1/i48/5718401 by guest on 07 February 2020

ease: a meta-analysis of randomised trials among people with type 2 diabe- impaired kidney function in the United States. J Am Soc Nephrol 2019; 30:
tes. Diabetologia 2017; 60: 1620–1629 1314–1321
39. Cosentino F, Grant PJ, Aboyans V et al. 2019 ESC guidelines on diabetes, 49. Kristensen SL, Rørth R, Jhund PS et al. Cardiovascular, mortality, and kid-
pre-diabetes, and cardiovascular diseases developed in collaboration with the ney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes:
EASDThe task force for diabetes, pre-diabetes, and cardiovascular diseases of a systematic review and meta-analysis of cardiovascular outcome trials.
the European Society of Cardiology (ESC) and the European Association for Lancet Diabetes Endocrinol 2019; 7: 776–785
the Study of Diabetes (EASD). Eur Heart J 2013; 34: 3035–3087 50. Zinman B, Bhosekar V, Busch R et al. Semaglutide once weekly as add-on
40. Fitchett D, Zinman B, Wanner C et al. Heart failure outcomes with empagli- to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised,
flozin in patients with type 2 diabetes at high cardiovascular risk: results of placebo-controlled trial. Lancet Diabetes Endocrinol 2019; 7: 356–367
R
the EMPA-REG OUTCOMEV trial. Eur Heart J 2016; 37: 1526–1534 51. Ludvik B, Frı́as JP, Tinahones FJ et al. Dulaglutide as add-on therapy to
41. Davies MJ, D’Alessio DA, Fradkin J et al. Management of hyperglycaemia SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes
in type 2 diabetes, 2018. A consensus report by the American Diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled
Association (ADA) and the European Association for the Study of Diabetes trial. Lancet Diabetes Endocrinol 2018; 6: 370–381
(EASD). Diabetologia 2018; 61: 2461–2498 52. McMurray JJ, Solomon SD, Inzucchi SE et al. Dapagliflozin in patients with
42. American Diabetes Association. 9. Pharmacologic approaches to glycemic heart failure and reduced ejection fraction. N Engl J Med 2019; 381:
treatment: standards of medical care in diabetes—2019. Diabetes Care 2019; 1995–2008
42(Suppl 1): S90–S102 53. Herrington WG, Preiss D, Haynes R et al. The potential for improving
43. Das SR, Everett BM, Birtcher KK et al. 2018 ACC expert consensus decision cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in
pathway on novel therapies for cardiovascular risk reduction in patients people with chronic kidney disease: a rationale for the EMPA-KIDNEY
with type 2 diabetes and atherosclerotic cardiovascular disease: a report of study. Clin Kidney J 2018; 11: 749–761
the American College of Cardiology Task Force on Expert Consensus 54. Pecoits-Filho R, Perkovic V. Are SGLT2 inhibitors ready for prime time for
Decision Pathways. J Am Coll Cardiol 2018; 72: 3200–3223 CKD? Clin J Am Soc Nephrol 2018; 13: 318–320
44. Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the
American Association of Clinical Endocrinologists and American College Received: 20.9.2019; Editorial decision: 29.10.2019

SGLT2 inhibition in CKD i55