Cardiorenal Med , DOI: 10.

1159/000524906
Received: December 20, 2021
Accepted: April 22, 2022
Published online: July 14, 2022

Roles for SGLT2 Inhibitors in Cardiorenal Disease

Green JB, McCullough PA

ISSN: 1664-3828 (Print), eISSN: 1664-5502 (Online)

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Cardiorenal Medicine

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Review Article
Roles for SGLT2 Inhibitors in Cardiorenal Disease

Jennifer B. Green MDa and Peter A. McCullough, MD, MPHb

a
Duke Clinical Research Institute, Duke University School of Medicine, Durham, N.C., USA;
b
Cardiorenal Society of America, Phoenix, AZ

Correspondence: Jennifer B. Green

Department of Medicine, Division of Endocrinology
Duke Clinical Research Institute
P.O. Box 17969
Durham, North Carolina 27715
919-668-8900
Jennifer.green@duke.edu
Number of Tables: 3 (5 Supplementary)
Number of Figures: 1
Abstract: 242 words
Key Words: Type 2 diabetes · Sodium-glucose cotransporter 2 inhibitor · Chronic kidney disease ·
Cardiovascular disease · Heart failure

2
Abstract
Introduction: Cardiovascular disease (CVD) and chronic kidney disease (CKD) share common risk
factors, including type 2 diabetes mellitus (T2DM). In cardiovascular outcome studies of patients
with T2DM, sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy was associated with risk
reductions in cardiorenal endpoints. This article aims to provide a comprehensive overview of the
efficacy of SGLT2i therapy in patients at risk of cardiorenal disease. Methods: A literature review of
large outcome studies of patients who had CKD or heart failure with reduced ejection fraction
(HFrEF, defined as having a left ventricular ejection fraction [LVEF] <40%) or heart failure with
preserved ejection fraction (LVEF ≥50%) was undertaken to evaluate the associations between
SGLT2i use and cardiorenal events. Results: In the cardiorenal outcome studies, patients with CKD
who received canagliflozin or dapagliflozin had a lowered risk of a sustained decline in kidney
function, end-stage kidney disease, or death from renal or cardiovascular (CV) causes than patients
who received placebo. In outcome studies that enrolled patients with HFrEF, dapagliflozin,
empagliflozin, and sotagliflozin lowered the risk of the composite endpoint of CV death and
hospitalization for heart failure (HHF) versus placebo, an effect driven largely by a reduced risk of
HHF. SGLT2i therapy was associated with risk reductions in the CV death/HHF composite and stand-
alone HHF endpoints in patients with CKD. Conversely, patients with HFrEF attained renal benefit
from SGLT2i use. Conclusion: The efficacy of SGLT2i was observed across a diverse range of patient
subgroups. SGLT2i therapy has been found to substantially mitigate cardiorenal morbidity in patients
with CKD or HFrEF, regardless of the presence of T2DM, and severity of CKD or HF.

3
Introduction
Chronic kidney disease (CKD) and cardiovascular (CV) disease (CVD) share risk factors for their
development and progression, frequently occur together, and are associated with poorer outcomes
when present in the same patient [1-3]. CV risk and mortality increase as estimated glomerular
filtration rate (eGFR) decreases below 60 mL/min/1.73 m2, independently of other risk factors,
including diabetes mellitus [4-6]. Heart failure, CV events resulting from atherosclerotic CVD
(ASCVD), myocardial dysfunction, valvular disease, and arrhythmias are, in sum, the most frequent
cause of death in patients with CKD [7]. Hyperalbuminuria, a marker of kidney damage, is associated
with an increased risk of overall and CV-related mortality independently of eGFR and diabetes
mellitus [4].
Common overlapping factors predisposing to both CKD and CVD include age, obesity, smoking,
hypertension, dyslipidemia, and diabetes mellitus. Type 2 diabetes mellitus (T2DM) is an
independent risk factor for CKD, end-stage kidney disease (ESKD), ASCVD, and heart failure (HF), and
worsens their prognosis [8-21]. Epidemiologic data suggest that strict glycemic control in patients
with T2DM may reduce the incidence of ASCVD events and kidney failure [22-24], but intensive
glucose-lowering strategies have not been found to provide these benefits, and instead may
increase the risk of severe hypoglycemia and mortality [25-27]. There is also a paucity of data
showing that optimal glucose control mitigates advanced kidney complications [26,28-31]. These
findings have led to the implementation of treatment strategies beyond glucose control and
blockade of the renin–angiotensin–aldosterone system (RAAS) for the management of CKD and CVD
to reduce morbidity and mortality associated with T2DM [32-36].
Sodium-glucose cotransporter (SGLT)2 inhibitors reduce hyperglycemia in patients with T2DM by
decreasing the reabsorption of glucose in the kidneys, thereby increasing urinary glucose excretion
[26,37-39]. Four SGLT2 inhibitors (SGLT2is) (empagliflozin [Jardiance®], canagliflozin [Invokana®],
dapagliflozin [Farxiga®], and ertugliflozin [Steglatro®]) are approved by the United States Food and
Drug Administration (FDA). All agents satisfied regulatory guidance mandating that new drugs for
the treatment of patients with T2DM must not increase the risk for major adverse cardiac events
(MACE), defined as the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke; in
fact empagliflozin and canagliflozin appear to decrease the risk of MACE (Table S1) [40].
A similar but not yet FDA-approved drug is sotagliflozin (Zynquista®, which inhibits SGLT2 and
gastrointestinal SGLT1. Clinical development of sotagliflozin was hampered by funding issues
resulting in early closure of trials [41,42], necessitating changes in the CV outcome trial (CVOT)
owing to a lack of events. However, tentative data from the trial revealed no significant effect on
MACE risk with sotagliflozin treatment in patients with T2DM and CKD [41].
Unexpectedly, statistically significant risk reductions in other key cardiorenal endpoints were
detected with canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in their respective CVOTs in
patients with T2DM at high risk for MACE [43-46]. All SGLT2is studied in these trials reduced the risk
of HHF [43-46], and three of the four agents (empagliflozin, canagliflozin, and dapagliflozin) were
associated with slowing progression of kidney disease and reducing the incidence of clinically
relevant kidney events [47-49]. The kidney protection conferred by empagliflozin, canagliflozin, and
dapagliflozin in these patient populations with T2DM appeared independent of their effects on
glycosylated hemoglobin (HbA1c) lowering [45,49,50]. These findings provided strong impetus to
examine the efficacy of SGLT2i therapy in patients at risk of cardiorenal events, regardless of T2DM
status, in subsequent cardiorenal trials. The mechanisms behind these observed CV and renal
benefits of SGLT2is are not fully known, although several have been proposed that could all
potentially contribute or even act synergistically (Fig. 1).
This review provides an account of the evidence for the current and evolving role of SGLT2is in the
treatment of patients with or at risk of CKD and/or HF.
Methods
Medline (via PubMed) was searched for articles to October 2020 (inclusive) indexed as randomized
clinical trials, associated secondary analyses, and meta-analyses containing the following terms:

4
empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, and sotagliflozin. Only data pertaining to
large outcome studies were included.

5
CVOTs in Patients with T2DM at High CV Risk

MACE Outcomes
Four seminal SGLT2i CVOTs have been conducted in T2DM patient populations at high CV risk; all
four were large randomized, double-blind, placebo-controlled clinical trials that compared SGLTi
with placebo when added to standard of care [43-46]. In two of the four CVOTs, empagliflozin (in
EMPA-REG OUTCOME) and canagliflozin (in CANVAS) reduced MACE risk [43,44]. In the dual
composite endpoint DECLARE-TIMI 58 trial, dapagliflozin met the prespecified criterion for
noninferiority with respect to MACE, but was also associated with a significantly lower rate of CV
death or hospitalization for HF (HHF) than placebo [45]. In VERTIS CV, ertugliflozin demonstrated
noninferiority to placebo with respect to MACE risk [46]. More recently, data from the SCORED trial
has indicated noninferiority of sotagliflozin to placebo with respect to MACE outcomes risk in
patients with T2DM and CKD [41].

HF Outcomes
A salient finding in all of the studies was that the benefit provided by SGLT2is with respect to the
composite endpoints was driven by a reduction in HHF and kidney composite events as opposed to
ischemia-related vascular events [43-46]. Table 1 shows that a 17–34% risk reduction in the CV
death/HHF composite endpoint was observed among patients with T2DM and high CV risk (largely
defined as ASCVD) receiving SGLT2i in EMPA-REG OUTCOME, DECLARE-TIMI 58, and CANVAS (no
such risk reduction was detected in VERTIS CV) [43-46]. This benefit was driven by a statistically
significant 27–35% risk reduction in HHF in all four trials (Table 1) [43-46]. Interpretation and
application of these findings were limited by the under-representation of patients with pre-existing
HF in these CVOTs (10–24%) and the lack of HF characterization (e.g. LVEF, atrial size or strain) at
baseline. Nevertheless, analyses of specific patient subsets showed consistent reductions in the risk
of HHF in favor of SGLT2is versus placebo across demographic and clinical subgroups (Table S2).

Kidney Outcomes
SGLT2is improved both surrogate and clinically important kidney outcomes (Table 1) [46-48]. In
EMPA-REG OUTCOME, prespecified analysis of treatment differences in eGFR slopes across all study
periods (i.e. during treatment initiation, chronic maintenance of treatment, and post-treatment)
indicated that empagliflozin contributed to long-term preservation of kidney function in the overall
intention-to-treat population [53]. Post hoc analyses of EMPA-REG OUTCOME detected similar
benefits across patient subgroups at higher CKD risk as defined by baseline eGFR, urine albumin to
creatinine ratio (UACR), race, blood pressure, age, and HbA1c levels [53]. Subgroup analysis of
EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS CV revealed consistent effects of
SGLT2is on incident or worsening nephropathy regardless of patient demographics, clinical
characteristics (including presence of HF or CKD at baseline), background glucose-lowering therapy,
or HbA1c lowering (Table S3) [45,49,50,54].

Cardiorenal Outcome Trials in Patients with CKD

The results of the earliest CVOTs indicating that SGLT2is improve kidney outcomes in patients with
T2DM led to initiation of multiple large cardiorenal outcome studies enrolling patients with CKD
(CREDENCE, DAPA-CKD, SCORED and EMPA-KIDNEY) [41,55-58]. As these cardiorenal outcome trials
included patients with substantially greater baseline renal risk than those who participated in the
CVOTs, comparatively high rates of CV and kidney outcomes have been observed in the completed
trials (Table 2) [41,55,57].

CREDENCE

6
CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical
Evaluation) showed that administration of canagliflozin 100 mg/day provided cardiorenal protection
in patients with T2DM and comorbid CKD [55,56]. Half of the patients had established CVD, and all
patients had an eGFR of 30 to <90 mL/min/1.73 m2 (mean, 56 mL/min/1.73 m2), albuminuria (UACR,
>300 to 5,000 mg/g) and were treated with RAAS blockade [55]. When CREDENCE was terminated
early due to fulfillment of prespecified efficacy criteria, 4,401 patients had undergone
randomization, with a median follow-up of 2.6 years [55]. The risk of the primary composite
outcome (ESKD, a doubling of serum creatinine level, or death from kidney or CV causes) was 30%
lower in the canagliflozin group than in the placebo group (Table 2) [55]. The individual risks of ESKD,
a doubling of the creatinine level, and CV death were all lower in the canagliflozin group [55], as was
the risk of HHF, a prespecified secondary endpoint [55].
Subgroup analysis of CREDENCE demonstrated that the relative benefits conferred by canagliflozin
for kidney and CV outcomes were consistent across baseline eGFR subgroups, although the benefits
for kidney outcomes were greatest in subgroups with lower eGFR and greater albuminuria (Table S4)
[55,59]. The risk of the primary composite kidney outcome, kidney component endpoints, and HHF
were also consistently reduced in patients with and without pre-existing CVD [60].
Over the course of CREDENCE, the decline in eGFR was slower and the reduction in UACR greater (by
31%) in the canagliflozin group than in the placebo group [55]. Notably, this took the form of an
initial drop in the eGFR in the SGLT2i-treated group, followed by a stabilization of kidney function
decline. Only modest between-group differences in blood glucose level, weight, and blood pressure
were detected.

DAPA-CKD
The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial
assessed the long-term efficacy and safety of dapagliflozin in patients with CKD, with or without
T2DM [57,58]. More than one-third of the patients (37%) had established CVD, 89% had an eGFR <60
mL/min/1.73 m2, all had albuminuria (UACR, 200−5,000 mg/g), and 97% were treated with RAAS
blockade. DAPA-CKD was stopped early as it met prespecified efficacy criteria. At that time, 4,304
patients had undergone randomization, with a median follow-up of 2.4 years. The risk of a sustained
decline in eGFR of ≥50%, ESKD, or death from kidney or CV causes was 39% lower with dapagliflozin
than with placebo (Table 2) [57]. The risks of a doubling of the creatinine level, ESKD, and CV death
were all lower in the dapagliflozin group than the placebo group [57]. The risk reduction in HHF was
not reported as a stand-alone endpoint; however, risk of death from CV causes or HHF was 29%
lower in the dapagliflozin group [57]. The benefit of dapagliflozin over placebo for the composite
primary endpoint was observed across prespecified subgroups, including presence/absence of
T2DM, presence/absence of ASCVD, baseline eGFR, baseline albuminuria, systolic blood pressure
(SBP), and age (Table S4) [57,61,62]. As in CREDENCE [55], there was an initial drop in the eGFR in
the SGLT2i-treated group, followed by a stabilization of kidney function decline [57].

SCORED
Eligibility criteria in CREDENCE and DAPA-CKD required the presence of significant albuminuria in
addition to reduced eGFR [55,57]. However, the SCORED (Effect of Sotagliflozin on Cardiovascular
and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at
Cardiovascular Risk) trial was designed to test the impact of sotagliflozin versus placebo on the risk
of CV events in patients with T2DM and CKD with or without albuminuria. Of the 10,584 patients
enrolled in SCORED, 89% had CVD, all patients had an eGFR <60 mL/min/1.73 m2, 65% had a UACR
≥30 mg/g, and 19.9% had an LVEF ≤40% within the past year or HHF during the previous 2 years [41].
The median LVEF was 60% (interquartile range, 51−65). The median duration of exposure to
sotagliflozin and placebo was 14.2 and 14.3 months, respectively. Clinical development of
sotagliflozin was hampered by funding issues resulting in early closure of trials [41,42]. This
complication necessitated changes in the CVOT from a time to first event analysis to a total events

7
analysis because of a lack of events. The resulting data indicated that the risk of CV death, HHF, or an
urgent visit for HF was 26% lower in the sotagliflozin group relative to the placebo group (Table 2).
The risk reduction for the primary composite endpoint was driven by a 33% reduction in the risk for
HHF or an urgent visit for HF. There were no statistically significant between-group differences
regarding deaths from CV causes and kidney endpoints. Although the median eGFR in SCORED was
low (44.5 mL/min/1.73 m2), kidney injury did not differ significantly between the sotagliflozin and
placebo groups [41].

EMPA-KIDNEY
The EMPA-KIDNEY trial (NCT03594110) will examine the efficacy of empagliflozin in preventing
worsening kidney disease or CV death in an as yet unstudied patient population with CKD with or
without albuminuria. Eligibility criteria require patients to have an eGFR of 20–45 mL/min/1.73 m2 or
and eGFR 45–90 mL/min/1.73 m2 with a UACR ≥200 mg/g. Patients should also be receiving RAAS
blockade as clinically appropriate, except in cases where it is not tolerated. Further, of the 6,609
patients enrolled in the study, the aim was to include at least one-third of patients without T2DM,
and at least one-third of patients with T2DM. The composite primary endpoint is the time to first
occurrence of a sustained decline of 40% or more in eGFR, ESKD, or death from kidney or CV causes.
Secondary endpoints will include time to CV death or HHF; all-cause mortality; all-cause
hospitalizations; occurrence of kidney disease progression; CV death; and CV death or ESKD. This
randomized, double-blind, phase 3 trial was expected to complete in 2022 [63], but was terminated
early on the recommendation of the independent data monitoring committee owing to a clear
positive effect. Findings are due to be reported in 2022.

Outcome Trials in Patients with HF

The majority of patients in the initial, MACE-focused CVOTs of SGLT2is did not have HF at baseline,
thus the reduced risk of HHF was driven largely by reductions in incident HF [43-45,55,59].
Reductions in HHF risk were identified early after randomization and appeared unrelated to the
glycemic effects of the medications. Two large studies (DAPA-HF and EMPEROR-Reduced) tested the
hypothesis that when added to standard of care, dapagliflozin and empagliflozin improve outcomes
in patients with stable HF with reduced ejection fraction (HFrEF) in patients with or without diabetes
[64-66], and a third, EMPEROR-Preserved, assessed empagliflozin in patients with HF and a
preserved ejection fraction (HFpEF) with or without diabetes [67]. A fourth study (SOLOIST-WHF)
assessed the effects of sotagliflozin initiated soon after an episode of decompensated HF in patients
with T2DM [42]. The DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and SOLOIST-WHF
populations are thus distinct from those in previous trials of SGLT2is.

DAPA-HF
The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial randomized
4,744 patients with New York Heart Association (NYHA) class II–IV HF, an LVEF ≤40%, and elevated
NT-proBNP levels to receive dapagliflozin 10 mg/day or placebo in addition to recommended HF
therapy (Table 3) [64,65]. In addition, all patients were required to receive standard HF device
therapy (implantable cardioverter-defibrillator, cardiac resynchronization therapy, or both) and
standard drug therapy (angiotensin-converting enzyme inhibitor/angiotensin receptor
blocker/angiotensin receptor–neprilysin inhibitors + β-blocker unless contraindicated or resulting in
unacceptable side effects). MRA (mineralocorticoid receptor antagonism) use was encouraged. Over
a median follow-up of 18 months, the risk of the primary composite outcome (worsening HF [i.e.
hospitalization or an urgent visit requiring intravenous therapy for HF] or CV death) was significantly
reduced with dapagliflozin treatment, with a greater risk reduction detected for HHF than for CV
death (Table 3) [65]. Dapagliflozin-dependent effects on the primary outcome were independent of
T2DM status, kidney function, and other baseline clinical variables (Table S5). However, patients in

8
NYHA functional class III/IV may have benefited less than those in class II. Subgroup analyses did not
suggest that dapagliflozin-related benefits varied by use of sacubitril/valsartan, though only 11% of
patients were treated with these agents at baseline [68]. Although no treatment difference was
detected regarding incidence of the prespecified kidney composite outcome (Table 3) [65],
dapagliflozin did slow the rate of decline in eGFR in patients with and without diabetes [69]. In a
further prespecified analysis, dapagliflozin reduced the risk of outpatient worsening of HF requiring
intensification of oral HF therapy by 26% [70].

EMPEROR-Reduced
EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a
Reduced Ejection Fraction) compared empagliflozin 10 mg/day versus placebo in a patient
population (N = 3,730) with class II to IV chronic HF and an LVEF of ≤40% (Table 3) [66]. EMPEROR-
Reduced patients had more severe HF than those in the DAPA-HF trial (mean LVEF of 27% vs. 31%,
median NT-proBNP level 1,907 versus 1,437 pg/mL, respectively) [65,66]. Similar to DAPA-HF [65],
48% of patients had an eGFR <60 mL/min/1.73 m2, and 50% did not have T2DM [66]. Over 16
months’ median follow-up, there was a 25% lower risk of CV death or HHF in the empagliflozin group
than in the placebo group, regardless of T2DM status [66], driven by a 31% reduced risk of HHF [66].
The effect of empagliflozin on the primary outcome was consistent across subgroups, including
patients with and without T2DM and by category of baseline kidney function (Table S5). As in DAPA-
HF [65], patients in NYHA functional class III or IV had a lesser benefit than those in class II [66].
Approximately 20% of each treatment group in EMPEROR-Reduced were receiving
sacubitril/valsartan at baseline, and empagliflozin reduced the risk of CV death or HHF versus
placebo irrespective of sacubitril/valsartan use [66]. Additionally, the annual rate of decline in eGFR
was reduced in the empagliflozin group compared with placebo (–0.55 vs. –2.28 mL/min/1.73
m2/year, p < 0.001), and was accompanied by a lower risk of serious kidney outcomes [66]. The
slower rate of kidney function decline with empagliflozin occurred in patients with and without CKD,
and across a broad range of kidney function [71].

EMPEROR-Preserved
EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a
Preserved Ejection Fraction) compared empagliflozin 10 mg/day versus placebo in a patient
population (N = 5,988) with class II to IV chronic HF and an LVEF >40% (Table 3) [67]. Similar to
DAPA-HF and EMPEROR-Reduced, ~50% of patients had an eGFR <60 mL/min/1.73 m2, and 51% did
not have diabetes. Over 26 months’ median follow-up, there was a 21% lower risk of CV death or
HHF in the empagliflozin group than in the placebo group, regardless of diabetes status [67],
primarily driven by a 29% reduced risk of HHF. The effect of empagliflozin on the primary outcome
was consistent across subgroups, including by category of LVEF (<40 to <50%, ≥50 to <60%, and
≥60%) and by presence or absence of CKD. As in EMPEROR-Reduced, the rate of decline in eGFR was
slower in the empagliflozin group than in the placebo group (–1.25 vs –2.62 mL/min/1.73 m2/year,
respectively; p < 0.001).

SOLOIST-WHF
While findings from DAPA-HF and EMPEROR-Reduced showed the beneficial effects of SGLT2is in
patients with ambulatory, stable HFrEF [65,66], the SOLOIST-WHF (Effect of Sotagliflozin on
Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial
demonstrated the benefit of prompt initiation of SGLT1/2is prior to or shortly after discharge in
patients with T2DM who were hospitalized for worsening HF (including HFrEF and HF with preserved
ejection fraction [HFpEF], defined as having an LVEF ≥50% in this analysis) and treated with
intravenous diuretic therapy [42]. Patients were included on the basis of symptoms and signs of HF,
rather than by inclusion criteria based on EF or HF stage. Exclusion criteria included end-stage HF or
recent acute coronary syndrome. Importantly, all patients by the time of randomization no longer

9
required oxygen therapy, had an SBP of ≥100 mm Hg, did not need intravenous inotropic or
vasodilator therapy (excluding nitrates), and had transitioned from intravenous to oral diuretic
therapy [42]. The first dose of sotagliflozin or placebo was administered before discharge in 49% of
patients and a median of 2 days after discharge in 51%. Over a median follow-up period of 9.0
months, the risk of CV death or hospitalizations and urgent visits for HF based on total events
(primary composite endpoint) was 33% lower in the sotagliflozin group than the placebo group, with
a greater risk reduction detected for hospitalizations and urgent visits for HF than for CV death [42].
Sotagliflozin-related benefits were consistent across multiple prespecified subgroups, including
those stratified by timing of the first dose and LVEF (Table S5) [42]. The slower rate of kidney
function decline in the sotagliflozin group occurred in patients with and without CKD, and across a
broad range of kidney function. The between-group difference in the change in the eGFR during the
truncated follow-up period were −0.16 mL/min/1.73 m2 (95% CI, −1.30 to 0.98) in favor of the
placebo group [42].
Results from the ongoing DELIVER and ERADICATE-HF trials will determine the efficacy of
dapagliflozin and ertugliflozin, respectively, in reducing CV events in patients with HFpEF.

Safety of SGLT2is and SGLT1/2is

In all but one of the outcome trials [42-45,55,57,59,65,66], SGLT2is either reduced the overall
incidence of adverse events (AEs) and serious AEs or were not associated with an excess of AEs
versus placebo. However, in SCORED, use of the SGLT1/2i sotagliflozin was associated with more
serious AEs than placebo, along with the unique side effect of a greater incidence of diarrhea [41].
SGLT2is are associated with increased risk of genital mycotic infections consistent with their
promotion of glucosuria, as well as euglycemic ketoacidosis and volume depletion [72]. Thus,
patients with a history of or predisposition for these AEs require close monitoring if a decision is
made to prescribe an SGLT2i. Acute kidney injury was of lower or similar incidence in the SGLT2i
arms compared with the placebo arms of the T2DM CVOTs [43-45,59], cardiorenal outcome trials in
patients with CKD [55,57], and in the DAPA-HF outcome trial [65]. The incidence of acute kidney
injury was similar in the sotagliflozin arms and placebo arms of SCORED and SOLOIST-WHF [41,42].
There were no clear trends regarding risk of fracture, urinary tract infections, or Fournier’s gangrene
(i.e. necrotizing fasciitis of the perineum) in trials with patients with T2DM or CKD [72]. Canagliflozin
was associated with increased risks for fractures and amputations in CANVAS [44] but not in
CREDENCE [55], and amputations were performed in a greater proportion of patients receiving
ertugliflozin than placebo in VERTIS CV (2.0% vs. 1.6%) [59]. This imbalance was not seen with
empagliflozin in EMPA-REG OUTCOME or with dapagliflozin in DECLARE-TIMI 58 [43,45].
Safety profiles across cardiorenal risk categories have been studied in CVOTs and cardiorenal
outcomes studies including: TIMI Risk Score for HF in Diabetes [73]; diabetic kidney disease
phenotype [49,74]; CKD stage and UACR level [59,69,71,75,76]; coronary artery bypass graft surgery
(yes/no) [77]; presence/absence of ASCVD or HF in patients with T2DM [78-81]; presence/absence of
ASCVD in patients with CKD [60,62]; presence/absence of T2DM in patients with CKD or HF
[61,82,83]. Additional analyses have looked at SBP in patients with HF [70], chronic obstructive
pulmonary disease [84], and diuretic or sacubitril/valsartan use in patients with HF [68,85]. Overall,
observed safety profiles of SGLT2is were consistent across key cardiorenal subgroups, and no
differences were found in EMPA-REG OUTCOME, DECLARE, or CANVAS with respect to age (i.e. <65
vs. ≥65 years) [86,87], gender [88], race [89], and body mass index [90].

10
Discussion
The landmark findings seen with SGLT2is in large and well conducted randomized, placebo-
controlled clinical trials have produced compelling results and changes to clinical practice guidelines
for treating CKD and HF in patients with and without T2DM. More updates are anticipated soon as
evidence from ongoing CKD and HF studies come to light. Although expectations are high that SGLT2i
will improve outcomes in the practice setting at rates comparable to those seen in clinical trials, it is
important to note that to date, the adoption of SGLT2i prescribing in patients with T2DM and high
risk of CVD and CKD has been slow [91,92]. Promulgating the importance of newer T2DM, CKD, and
HF clinical practice guidelines will provide the impetus for clinicians to meet the challenge of
providing the most effective care for their highest-risk patients.
Initially, the US FDA granted regulatory approval for empagliflozin, canagliflozin, dapagliflozin, and
ertugliflozin as adjuncts to diet and exercise to improve glycemic control in adults with T2DM [93-
96]. Based on CVOT data [43,44], canagliflozin is now indicated in the US to reduce the risk of MACE
in adults with T2DM and established ASCVD, and empagliflozin is indicated in the US to reduce the
risk of CV death in patients with T2DM and established CVD [94,95]. Subsequent to the CREDENCE
trial, canagliflozin received approval to reduce the risks for doubling of serum creatinine level, ESKD,
HHF, and CV death in adults with T2DM and CKD with macroalbuminuria and eGFR ≥30 mL/min/1.73
m2 [55,94]. Dapagliflozin and empagliflozin have been approved to reduce the risks for CV death and
HHF in adults with HFrEF (NYHA Class II−IV) based on DAPA-HF and EMPEROR-Reduced [93,95], and
empagliflozin approval was extended to include patients with HF regardless of LVEF (i.e. including
patients with HFpEF) based on EMPEROR-preserved in February 2022 [95]. Dapagliflozin has also
been granted approval to reduce the risk of kidney function decline, kidney failure, CV death and
HHF in adults with chronic kidney disease who are at risk of disease progression based on the
findings from DAPA-CKD [57,93].
Clinical practice guidelines for use of SGLT2is in the management of CKD and HF have evolved
dramatically in response to this new information. Although most of the guidelines focus on
management of T2DM due to the sheer amount of data generated in this patient population, T2DM
is only one (albeit important) risk factor for cardiorenal disease and SGLT2i use should be considered
independent of the need for glucose lowering.
The 2021 American Diabetes Association guidelines recommend SGLT2i therapy in T2DM patients
with indicators of high risk or established ASCVD, CKD, or HF [97]. Integration of SGLT2i therapy into
the care of these patients is recommended as part of the glucose-lowering and/or CV risk reduction
regimen independent of HbA1c and in consideration of patient-specific factors [97]. Specifically,
SGLT2i therapy (or glucagon-like peptide 1 receptor agonist [GLP-1RA] therapy) is recommended for
T2DM patients with high-risk or established ASCVD whereas SGLT2i therapy (and not GLP-1RA
therapy) is recommended for those with HFrEF [97]. For T2DM patients with CKD and albuminuria,
SGLT2i therapy is preferred over GLP-1RA therapy, but either SGLT2i or GLP-1RA therapy is suitable
for T2DM patients with CKD in the absence of albuminuria [97]. KDIGO guidelines currently
recommend combination pharmacotherapy with metformin and an SGLT2i as first-line therapy in
patients with T2DM to mitigate CKD [98].
Although most patients in the T2DM CVOT were receiving metformin at baseline, subgroup analysis
of EMPA-REG OUTCOME and DECLARE-TIMI 58, respectively, showed that the cardiorenal benefits of
empagliflozin and dapagliflozin versus placebo were consistent regardless of background metformin
use [99,100]. There was no need for metformin therapy or, for that matter, T2DM to be present in
DAPA-CKD, DAPA-HF, or EMPEROR-Reduced for patients to derive a benefit from SGLT2i therapy
[57,65,66].
The next iteration of KDIGO guidelines for CKD evaluation and management are expected to include
evidence from CREDENCE, DAPA-CKD, SCORED, and EMPA-KIDNEY. Methodologic differences aside,
data from CREDENCE and DAPA-CKD showed that SGLT2i can mitigate CKD progression [55,57].
Furthermore, the kidney benefits of SGLT2is in CREDENCE and DAPA-CKD were accompanied by CV
benefits, namely, a reduced risk for CV death and HHF regardless of pre-existing ASCVD [55,57]. Note

11
that the CV death and HHF risk reduction observed for the SGLT1/2i sotagliflozin versus placebo in
SCORED occurred without reduction in kidney events but this lack of association may be confounded
by early cessation of the trial [41]. The CREDENCE and DAPA-CKD outcomes are consistent with CKD
as a known risk factor for HF independent of ASCVD [1]. Conversely, an abnormal GFR is
commonplace in patients with HF [101]. In the EMPEROR-Reduced [66] and DAPA-HF [65] trials of
patients with stable HFrEF, SGLT2i decreased the rate of eGFR decline over time and reduced the risk
of ESKD, in addition to HF benefits. Meta-analysis of EMPEROR-Reduced and DAPA-HF revealed that
SGLT2i therapy reduced the risk of major kidney outcomes in patients with HFrEF by 38% (HR 0.62,
95% CI 0.43−0.90) [102].
Of the cardiology guideline committees, joint guidelines issued by American College of Cardiology,
American Heart Association, and the Heart Failure Society of America were updated in Q1 2022 to
include SGLT-2 as a fourth class of medication for the treatment of HFrEF, regardless of the
presence or absence of T2DM [103]. Similarly, the Canadian Cardiovascular Society and the Canadian
Heart Failure Society have recommended use of SGLT2is in patients with mild or moderate HF who
have an LVEF ≤40% [104]. For patients with T2DM, CKD, and stable HFrEF, the current window of
therapeutic opportunity with SGLT2i is only open for as long as GFR remains above levels tested in
the completed trials. In the CVOTs of patients with T2DM, CREDENCE and DAPA-HF, an eGFR >30
mL/min/1.73 m2 was a prerequisite for entry [43-45,59]. SGLT2i withdrawal was not required if eGFR
decreased to <30 mL/min/1.73 m2 in CREDENCE, and the SCORED and DAPA-CKD protocols enrolled
T2DM patients with an eGFR >25 mL/min/1.73 m2 [41,55]. EMPEROR-Reduced enrolled patients with
an eGFR as low as 20 mL/min/1.73 m2 without compromising efficacy or safety [71]. Although early
use of SGLT2i therapy may provide the greatest benefit by theoretically preventing deterioration of
kidney function into moderate disease (when CV risk and mortality increase) [4-6], this hypothesis
has not been tested in clinical trials thus far.
SGLT2i therapy should not be reserved only for those with worse NYHA functional class, as those
with less severe symptoms may benefit most [65,66,102]. At present there is a lack of consensus
regarding when SGLT2i therapy should be started following hospital admission with acute coronary
syndrome or HFrEF. Initiation of SGLT2i therapy at the time of HF admission cannot be
recommended until this approach is more fully evaluated in clinical trials. Rather, an SGLT2i should
be considered once the admitted patient has been stabilized, similar to the approach described in
the SOLOIST-WHF protocol [42]. In DAPA-HF and EMPEROR-Reduced, the benefit of SGLT2i therapy
was observed regardless of use of sacubitril/valsartan [66,68]. This means that patients with HFrEF
on standard of care with an angiotensin receptor–neprilysin inhibitor may obtain independent
benefit from the addition of SGLT2i therapy.
By definition, patient populations in randomized clinical trials are defined by the trial
inclusion and exclusion criteria, and may not be representative of the broad range of patients seen
in real-world settings. For example, patients may be receiving concomitant medications or
comorbidities that would have excluded them from participation in a trial. For this reason, while
there is a large body of evidence for the efficacy and safety of SGLT2i therapy from clinical trials, real
world data will be needed to accurately assess their potential benefits in routine clinical practice.

Conclusions
SGLT2i therapy has been shown to provide statistically significant risk reduction across composite
cardiorenal endpoints. In the cardiorenal outcome studies, patients with CKD who received
canagliflozin or dapagliflozin had a lower risk of a doubling of serum creatinine (canagliflozin) or
sustained decline in eGFR of ≥50% (dapagliflozin), ESKD, or death from renal or CV causes than
patients who received placebo. These benefits were observed regardless of the presence of T2DM
and category of CKD at baseline. The risk of CV death or HHF and HHF alone were also reduced with
canagliflozin, dapagliflozin, or sotagliflozin therapy in patients with CKD. In the outcome studies that
enrolled patients with HFrEF, dapagliflozin, empagliflozin, and sotagliflozin lowered the risk of the
composite endpoint of CV death and HHF versus placebo, an effect driven largely by a reduced risk

12
of HHF. In the dapagliflozin and empagliflozin studies, kidney outcomes were improved in the SGLT2i
arms versus the placebo arms, and kidney and CV benefits have also been demonstrated with
empagliflozin in patients with HFpEF. That large populations with CKD or HF obtain both renal and
CV benefits during treatment with SGLT2i therapy is entirely consistent with the interplay of shared
risk factors for CV and renal disease.
The benefits of SGLT2i therapy were preserved across multiple patient subgroups defined according
to known cardiorenal risk factors. Clinical guidelines for the management of T2DM, CKD, and HFrEF
now recommend SGLT2i therapy as a cornerstone of care. The public health challenge now is to
improve timely utilization of these valuable medicines.

Acknowledgments
Writing and editorial support for development of this manuscript was provided by Malcolm Darkes
and Andy Shepherd of Elevate Scientific Solutions, which was contracted and funded by Boehringer
Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for
medical and scientific accuracy as well as intellectual property considerations.

Statement of Ethics
This was a review of the published literature; no ethical approval was required.
Conflict of Interest Statement
The authors received no direct compensation related to the development of this manuscript.
Funding sources
Writing and editorial support for development of this manuscript was contracted and funded by
Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI).
Authorship
Both authors confirm that they meet International Committee of Medical Journal Editors (ICMJE)
authorship criteria and that no one who would qualify for authorship has been excluded.
Author contributions
Jennifer B. Green and Peter McCullough were involved in data interpretation and in the conception,
drafting, critical revision and approval of the manuscript.
Data Availability
All data presented has been published previously as cited, and no new data was generated for this
manuscript.

13
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91 Arnold SV, de Lemos JA, Rosenson RS, Ballantyne CM, Liu Y, Mues KE, et al: Use of guideline-
recommended risk reduction strategies among patients with diabetes and atherosclerotic
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92 Arnold SV, Inzucchi SE, Tang F, McGuire DK, Mehta SN, Maddox TM, et al: Real-world use
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99 Cahn A, Wiviott SD, Mosenzon O, Murphy SA, Goodrich EL, Yanuv I, et al: Cardiorenal
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TIMI 58. Diabetes Obes Metab 2020
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Figure legends:
Fig. 1. Potential mechanisms behind the CV and kidney benefits of SGLT2 inhibitors.
Further details on the potential mechanisms by which SGLT2 inhibitors may contribute to cardiorenal protection are
reviewed in detail by Gronda et al. and Scheen et al. [51,52].
CV = cardiovascular; SGLT2 = sodium-glucose cotransporter 2

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21
Table 1. Heart failure (HF), CV, and kidney outcomes in trials of SGLT2i in patients with T2DM and high CV risk a
HF outcomes Kidney outcomes HR (95% CI)
Doubling of serum
Number (%) creatinine level,
Number and type of
Active reference of HF Rate per 1,000 patient- HR (95% CI), initiation of kidney
Trial patients ESKD
patients years, SGLT2i vs. placebo p-valueb replacement therapy,
or death from renal
disease
EMPA-REG OUTCOME Empagliflozin N = 7,020 n = 706 (10) CV death/HHF: 5.7 vs. 8.5 0.66 (0.55–0.79) 0.45 0.54
[43,47] 10 or 25 mg once • Prior CVD: 99% HHF: 9.4 vs. 14.5 p < 0.001 (0.21–0.97) (0.40–0.75)
daily • eGFRb <60: 0.65 (0.50–0.85),p < 0.04 p < 0.001
26% p = 0.002
• Mean eGFR: 74
DECLARE-TIMI 58 [45] Dapagliflozin N = 17,160 n = 1,724 (10) CV death/HHF: 12.2 vs. 0.83 (0.73–0.95) Not reported 0.76
10 mg once daily • Prior CVD: 41% 14.7c p = 0.005 (0.67–0.87)d
• d
eGFR <60: 7% HHF: 6.2 vs. 8.5 0.73 (0.61–0.88), p-value not stated
• Mean eGFR: 85 p-value not stated
CANVAS program Canagliflozin N = 10,142 n = 1,461 (14) CV death/HHF: 16.3 vs. 0.78 (0.67–0.91) 0.77 0.53
(CANVAS and 100 or 300 mg • Prior CVD: 66% 20.8 0.67 (0.52–0.87), (0.30–1.97) (0.33–0.84)
CANVAS-R) [44,49] once daily • eGFRb <60: HHF: 5.5 vs. 8.7 p-values not stated p-value not p-value not stated
16% stated
• Mean eGFR: 77
VERTIS CV [46] Ertugliflozin N = 8,246 n = 1,958 (24) CV death/HHF: 23 vs. 27 0.88 (0.75–1.03) Not reported 0.81
5 or 15 mg once • Prior CVD: 76% HHF: 7 vs. 11 p = 0.11 (0.63–1.04)
daily • b
eGFR <60: 0.70 (0.54–0.90), p-value not stated
22% p-value not stated
• Mean eGFR: 76
CANVAS = CANagliflozin Cardio-Vascular Assessment Study (CANVAS); CANVAS-R = CANVAS-Renal; CI = confidence interval; CV = cardiovascular; DECLARE-TIMI 58 =
Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58; eGFR = estimated glomerular filtration rate in mL/min/1.73 m2; EMPA-REG OUTCOME =
Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose; ESKD = end-stage kidney disease; HHF = hospitalization for HF; HR
= hazard ratio; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2DM = type 2 diabetes mellitus; VERTIS CV = Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular
Outcomes Trial.
a Direct comparison between these trials are not possible because of variations in study methodology and patient selection.
b Versus placebo.
c Coprimary composite endpoint.
d Prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in eGFR to <60 mL/min/1.73 m2, ESKD, or death from renal or CV causes.

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Table 2. Heart failure (HF), CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in CKDa
Incidence or rates per 1,000 patient-years, SGLT2i vs. placebo, (HR, 95% CI, p-value)
Active Number and type of Primary Components of primary composite outcome HF outcomes
Trial, analysis treatment patients composite Kidney
ESKD CV death
outcome death
CREDENCE Canagliflozin N = 4,401 43 vs. 61 Doubling of 20 vs. 29 0.3 vs. 0.9 19 vs. 24 CV death/HHF: 32 vs.
[56,59] 100 mg once • Prior CVD: 50% (0.70, 0.59–0.82, serum creatinine (0.68, 0.54–0.86, (0.78, 0.61–1.00, 45
daily • eGFRb < 60: 60% p = 0.00001)c 21 vs. 34 p = 0.002) p = 0.05) (0.69, 0.57–0.83) P <
• Mean eGFR: 56 (0.60, 0.48–0.76, 0.001
• T2DM: 100% p < 0.001) HHF: 15.7 vs. 25.3
(0.61, 0.47, 0.80, p <
0.001)
DAPA-CKD Dapagliflozin N = 4,304 46 vs. 75 Decline in eGFR 25 vs. 38 0.0 vs. 1.0 14 vs. 17 CV death/HHF: 22 vs.
[57,58] 10 mg once • Prior CVD: 37% (0.61, 0.51–0.72, ≥50% (0.64, 0.50–0.82) (0.81, 0.58–1.12) 30 (0.71, 0.55–0.92, p
daily • eGFRb < 60: 89% p < 0.001)d 26 vs. 48 = 0.009)
• Mean eGFR: 43 (0.53, 0.42–0.67)e
• T2DM: 68%
SCORED [41] Sotagliflozin N = 10,584 56 vs. 75g 22 vs. 24 CV death/HHF: 64 vs.
200 mg once • Prior CVD: 89% (0.74, 0.63–0.88, (0.90, 0.73–1.12, 83 (0.76, 0.65–0.89, p-
dailyf • eGFR < 60: 100% p < 0.001)h p = 0.35) value not stated)
• Median eGFR: 45 HHF: 35 vs. 51
• T2DM: 100% (0.67, 0.55–0.82, p <
0.001)i
CKD = chronic kidney disease; CREDENCE = Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CI = confidence interval; CV =
cardiovascular; CVD = CV disease; DAPA-CKD = Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; eGFR = estimated glomerular filtration rate in
mL/min/1.73 m2; ESKD = end-stage kidney disease; HHF = hospitalization for heart failure; HR = hazard ratio; SCORED = Effect of Sotagliflozin on Cardiovascular and Renal Events in
Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2DM = type 2 diabetes mellitus.
a Direct comparison between these trials are not possible because of variations in study methodology and patient selection.
b As calculated by the Chronic Kidney Disease Epidemiology Collaboration equation.
c Composite of ESKD (dialysis, transplantation, or a sustained eGFR of <15 mL/min/1.73 m2), a doubling of the serum creatinine level, or death from kidney or CV causes.
d Composite of a sustained decline in the eGFR of ≥50%, ESKD, or death from kidney or CV causes.
e Reported as a decline in eGFR of ≥50%.
f Increased to 400 mg once daily if unacceptable adverse effects did not occur.

g The SCORED trial was terminated early owing to funding issues and revised from a time to event analysis to a total events analysis owing to allow for the reduced number of events

captured
h Composite of the total number of deaths from CV causes, HHF, and urgent visits for HF.
i Component of the primary composite endpoint.

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Table 3. Heart failure (HF), CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in HFa
Incidence or rates per 1,000 patient-years, SGLT2i vs. placebo, (HR, 95% CI, p-value)
Trial, Worsening kidney
Components of primary composite outcome
analysis, Number and type of Primary function
Active patients composite HHF or an urgent HHF Urgent HF visit CV death
reference outcome HF visit

DAPA-HF [64, N = 4,744 with HFrEF 116 vs. 156 71 vs. 101 69 vs. 98 3 vs. 7 65 vs. 79 8 vs. 12
65] • NYHA class II: (0.74, 0.65−0.85, (0.70, 0.59−0.83) (0.70, 0.59−0.83) (0.43, 0.20−0.90) (0.82, 0.69−0.98) (0.71, 0.44−1.16)c
b
68% p < 0.001) p-value not stated p-value not stated p-value not stated p-value not stated p-value not stated
Dapagliflozin • NYHA class III:
10 mg once 32%
daily • NYHA class IV:
1%
• Mean LVEF: 31%
• eGFR <60: 41%
• Mean eGFR: 66
• T2DM: 42%d
EMPEROR- N = 3,730 with HFrEF 158 vs. 210 107 vs. 155 76 vs. 81 16 vs. 31
Reduced [66] • NYHA class II: (0.75, 0.65−0.86, (0.69, 0.59−0.81) (0.92, 0.75−1.12) (0.50, 0.32−0.77)f
e
75% p < 0.001) p-value not stated p-value not stated p-value not stated
Empagliflozin • NYHA class III:
10 mg once 24%
daily • NYHA class IV:
<1%
• Mean LVEF: 27%
• eGFR <60: 48%
• Mean eGFR: 62
• T2DM: 50%
EMPEROR- N = 5,988 with HFpEF 69 vs. 87 43 vs. 60 34 vs. 38 21 vs. 22
Preserved • NYHA class II: (0.79, 0.69–0.90, (0.71, 0.60–0.83) (0.91, 0.76–1.09) 0.95 (0.73, 1.24)c
[67] 82% p < 0.001) p-value not stated p-value not stated p-value not stated
• NYHA class III:
Empagliflozin 18%
10 mg once • NYHA class IV:
daily <1%
• Mean LVEF: 54%
• eGFR <60: 50%
• Mean eGFR: 61
• T2DM: 49%
SOLOIST- N = 1,222 with recent 510 vs. 763h 404 vs. 639 106 vs. 125
WHF [42] HHF (0.67, 0.52−0.85, (0.64, 0.49−0.83, (0.84, 0.58−1.22)
• Median LVEF: p < 0.001)i p < 0.001) p = 0.36j
Sotagliflozin 35%
200 mg once • eGFR <60: 41%
dailyg • Median eGFR: 50
• T2DM: 100%
a Direct comparison between these trials are not possible because of variations in study methodology and patient selection.
b Composite of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or CV death.
c Worsening kidney function is a composite outcome of a reduction of 50% or more in the eGFR sustained for ≥28 days, ESKD, or death from kidney causes. ESKD was defined as an eGFR
<15 mL/min/1.73m2 that was sustained for ≥28 days, long-term dialysis treatment (sustained for ≥28 days), or kidney transplantation.
d An additional 3% received a diagnosis of T2DM.
e Composite composite of CV death or hospitalization for worsening HF.
f The composite kidney outcome includes chronic dialysis or kidney transplantation or a sustained reduction of ≥40% eGFR or a sustained estimated GFR of <15 mL/min/1.73m2 in patients
with a baseline eGFR of ≥30 mL/min/1.73m2 or a sustained eGFR of <10 mL/min/1.73m2 in those with a baseline eGFR of < 30 mL/min/1.73m 2.

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g Increased to 400 mg once daily if unacceptable adverse effects did not occur.
h The SOLOIST-WHF trial was terminated early owing to funding issues and revised from a time to event analysis to a total events analysis owing to allow for the reduced number of events
captured
i Composite of CV death and hospitalizations and urgent visits for HF (first and subsequent events).
j Heirarchical analysis was stopped after the first endpoint that did not meet significance.
CI = confidence interval; CV = cardiovascular; CVD = CV disease; DAPA-HF = Dapagliflozin And Prevention of Adverse outcomes in Heart Failure; eGFR = estimated glomerular filtration rate
in mL/min/1.73m2; EMPEROR-Reduced = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; HHF = hospitalization for heart failure; HR =
hazard ratio; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SGLT2i = sodium-glucose cotransporter 2 inhibitor; SOLOIST-WHF = Sotagliflozin on
Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; T2DM = type 2 diabetes mellitus.

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