Introduction: Cardiovascular (CV) disease and chronic kidney disease (CKD) share common risk factors, including type 2 diabetes mellitus (T2DM). In CV 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 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.

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 (HF), CV events resulting from atherosclerotic CVD (ASCVD), myocardial dysfunction, valvular disease, and arrhythmias are, in sum, the most frequent causes 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 HF, and it 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 US 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 (online suppl. Table S1; see www.karger.com/doi/10.1159/000524906 for all online suppl. material) [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 hospitalization for HF (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.

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. [51] and Scheen and Delanaye [52]. CV, cardiovascular; SGLT2, sodium-glucose cotransporter 2.

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. [51] and Scheen and Delanaye [52]. CV, cardiovascular; SGLT2, sodium-glucose cotransporter 2.

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

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 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 have 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 preexisting 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 (online suppl. Table S2).

Table 1.

HF, CV, and kidney outcomes in trials of SGLT2i in patients with T2DM and high CV riska

HF, CV, and kidney outcomes in trials of SGLT2i in patients with T2DM and high CV riska
HF, CV, and kidney outcomes in trials of SGLT2i in patients with T2DM and high CV riska

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 posttreatment) 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 (online suppl. 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; online suppl. video) [41, 55, 57].

Table 2.

HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in CKDa

HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in CKDa
HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in CKDa

CREDENCE

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) and 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 (online suppl. 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 preexisting 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 (online suppl. 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 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 (online suppl. Table S5). However, patients in 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 the 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].

Table 3.

HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in HFa

HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in HFa
HF, CV, and kidney outcomes in trials of SGLT2i or SGLT1/2i in HFa

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 vs. 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 (online suppl. 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 was 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 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 (online suppl. 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 was −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]; and 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].

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 USA to reduce the risk of MACE in adults with T2DM and established ASCVD, and empagliflozin is indicated in the USA 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 CKD who are at risk of disease progression based on the findings from DAPA-CKD [57, 93].

Clinical practice guidelines for the 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 is 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 of CV death and HHF regardless of preexisting ASCVD [55, 57]. Note 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 the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America were updated in Q1 2022 to include SGLT2 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 the 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 the 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.

SGLT2i therapy has been shown to provide a 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 a 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 the category of CKD at baseline. The risk of CV death or HHF and HHF alone was 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 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 the timely utilization of these valuable medicines.

Writing and editorial support for the 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) and Lilly USA, LLC. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

This was a review of the published literature; no ethical approval was required.

The authors received no direct compensation related to the development of this manuscript.

Writing and editorial support for development of this manuscript was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Lilly USA, LLC.

Jennifer B. Green and Peter A. McCullough were involved in data interpretation and in the conception, drafting, critical revision, and approval of the manuscript.

All data presented has been published previously as cited, and no new data was generated for this manuscript.

1.
Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).
Kidney Int
. 2011;80(6):572–86.
2.
McCullough PA. Why is chronic kidney disease the “spoiler” for cardiovascular outcomes?
J Am Coll Cardiol
. 2003;41(5):725–8.
3.
Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
Circulation
. 2003;108(17):2154–69.
4.
Chronic Kidney Disease Prognosis Consortium; Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
Lancet
. 2010;375(9731):2073–81.
5.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
N Engl J Med
. 2004;351(13):1296–305.
6.
Kottgen A, Russell SD, Loehr LR, Crainiceanu CM, Rosamond WD, Chang PP, et al. Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study.
J Am Soc Nephrol
. 2007;18(4):1307–15.
7.
Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJL, Mann JF, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
Lancet
. 2013;382(9889):339–52.
8.
Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes.
Eur J Heart Fail
. 2017;19(1):43–53.
9.
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives.
Lancet
. 2013;382(9888):260–72.
10.
Kastarinen M, Juutilainen A, Kastarinen H, Salomaa V, Karhapaa P, Tuomilehto J, et al. Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25, 821 men and women in eastern Finland.
J Intern Med
. 2010;267(6):612–20.
11.
Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB, Kannel WB, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study.
Circulation
. 2002;106(24):3068–72.
12.
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction.
N Engl J Med
. 2006;355(3):251–9.
13.
Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review.
J Am Coll Cardiol
. 2018;72(15):1845–55.
14.
Writing Group Members; Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association.
Circulation
. 2016;133(4):e38–360.
15.
Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.
Circulation
. 1999;100(10):1134–46.
16.
Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes.
J Am Soc Nephrol
. 2013;24:302–8.
17.
de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States.
JAMA
. 2011;305(24):2532–9.
18.
Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up.
Arch Intern Med
. 2004;164(13):1422–6.
19.
Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study.
JAMA
. 1979;241(19):2035–8.
20.
Koskinen P, Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.
Diabetes Care
. 1992;15(7):820–5.
21.
Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
Diabetes Care
. 1993;16(2):434–44.
22.
Gerstein HC, Pogue J, Mann JFE, Lonn E, Dagenais GR, McQueen M, et al. The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: a prospective epidemiological analysis.
Diabetologia
. 2005;48(9):1749–55.
23.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.
Ann Intern Med
. 2004;141(6):421–31.
24.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
BMJ
. 2000;321(7258):405–12.
25.
Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med
. 1993;329(14):977–86.
26.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet
. 1998;352:837–53.
27.
Gerstein H, Miller ME, Byington RP. The action to control cardiovascular risk in diabetes study group: effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med
2008;358:2545−59.
28.
Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes.
Arch Intern Med
. 2012;172(10):761–9.
29.
ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
N Engl J Med
. 2008;358(24):2560–72.
30.
Perkovic V, Heerspink HL, Chalmers J, Woodward M, Jun M, Li Q, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes.
Kidney Int
. 2013;83(3):517–23.
31.
Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.
N Engl J Med
. 2014;371(15):1392–406.
32.
Molitch ME, Adler AI, Flyvbjerg A, Nelson RG, So WY, Wanner C, et al. Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes.
Kidney Int
. 2015;87(1):20–30.
33.
Roscioni SS, Heerspink HJL, de Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy.
Nat Rev Nephrol
. 2014;10(2):77–87.
34.
Mannucci E, Monami M. Cardiovascular safety of incretin-based therapies in type 2 diabetes: systematic review of integrated analyses and randomized controlled trials.
Adv Ther
. 2017;34:1–40.
35.
Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials.
Acta Diabetol
. 2017;54(1):19–36.
36.
Li J, Albajrami O, Zhuo M, Hawley CE, Paik JM. Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
Clin J Am Soc Nephrol
. 2020;15(11):1678–88.
37.
Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes.
Diabetes Obes Metab
. 2013;15(7):613–21.
38.
List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.
Diabetes Care
. 2009;32(4):650–7.
39.
Devineni D, Curtin CR, Polidori D, Gutierrez MJ, Murphy J, Rusch S, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus.
J Clin Pharmacol
. 2013;53(6):601–10.
40.
McGuire DK, Marx N, Johansen OE, Inzucchi SE, Rosenstock J, George JT. FDA guidance on antihyperglyacemic therapies for type 2 diabetes: one decade later.
Diabetes Obes Metab
. 2019;21(5):1073–8.
41.
Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease.
N Engl J Med
. 2021;384(2):129–39.
42.
Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure.
N Engl J Med
. 2021;384(2):117–28.
43.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
N Engl J Med
. 2015;373(22):2117–28.
44.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes.
N Engl J Med
. 2017;377(7):644–57.
45.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
N Engl J Med
. 2019;380(4):347–57.
46.
Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
N Engl J Med
. 2020;383(15):1425–35.
47.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes.
N Engl J Med
. 2016;375(4):323–34.
48.
Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
Lancet Diabetes Endocrinol
. 2019;7(8):606–17.
49.
Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
Lancet Diabetes Endocrinol
. 2018;6(9):691–704.
50.
Cooper ME, Inzucchi SE, Zinman B, Hantel S, von Eynatten M, Wanner C, et al. Glucose control and the effect of empagliflozin on kidney outcomes in type 2 diabetes: an analysis from the EMPA-REG OUTCOME trial.
Am J Kidney Dis
. 2019;74(5):713–5.
51.
Gronda E, Lopaschuk GD, Arduini A, Santoro A, Benincasa G, Palazzuoli A, et al. Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis.
Can J Physiol Pharmacol
. 2022;100(2):93–106.
52.
Scheen AJ, Delanaye P. Understanding the protective effects of SGLT2 inhibitors in type 2 diabetes patients with chronic kidney disease.
Expert Rev Endocrinol Metab
. 2022;17(1):35–46.
53.
Wanner C, Heerspink HJL, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, et al. Empagliflozin and kidney function decline in patients with type 2 diabetes: a slope analysis from the EMPA-REG OUTCOME trial.
J Am Soc Nephrol
. 2018;29(11):2755–69.
54.
Bohm M, Fitchett D, Ofstad AP, Brueckmann M, Kaspers S, George JT, et al. Heart failure and renal outcomes according to baseline and achieved blood pressure in patients with type 2 diabetes: results from EMPA-REG OUTCOME.
J Hypertens
. 2020;38(9):1829–40.
55.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
N Engl J Med
. 2019;380(24):2295–306.
56.
Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics.
Am J Nephrol
. 2017;46(6):462–72.
57.
Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease.
N Engl J Med
. 2020;383(15):1436–46.
58.
Heerspink HJL, Stefansson BV, Chertow GM, Correa-Rotter R, Greene T, Hou FF, et al. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.
Nephrol Dial Transplant
. 2020;35(2):274–82.
59.
Jardine MJ, Zhou Z, Mahaffey KW, Oshima M, Agarwal R, Bakris G, et al. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial.
J Am Soc Nephrol
. 2020;31(5):1128–39.
60.
Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
Circulation
. 2019;140(9):739–50.
61.
Wheeler DC, Stefansson BV, Jongs N, Chertow GM, Greene T, Hou FF, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial.
Lancet Diabetes Endocrinol
. 2021;9(1):22–31.
62.
McMurray JJV, Wheeler DC, Stefansson BV, Jongs N, Postmus D, Correa-Rotter R, et al. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease.
Circulation
. 2021;143(5):438–48.
63.
Herrington WG, Preiss D, Haynes R, von Eynatten M, Staplin N, Hauske SJ, et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.
Clin Kidney J
. 2018;11(6):749–61.
64.
McMurray JJV, DeMets DL, Inzucchi SE, Kober L, Kosiborod MN, Langkilde AM, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF).
Eur J Heart Fail
. 2019;21(5):665–75.
65.
McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction.
N Engl J Med
. 2019;381(21):1995–2008.
66.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure.
N Engl J Med
. 2020;383(15):1413–24.
67.
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction.
N Engl J Med
. 2021;385(16):1451–61.
68.
Solomon SD, Jhund PS, Claggett BL, Dewan P, Kober L, Kosiborod MN, et al. Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: The DAPA-HF trial.
JACC Heart Fail
. 2020;8(10):811–8.
69.
Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Bohm M, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF.
Circulation
. 2021;143(4):298–309.
70.
Serenelli M, Bohm M, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Eur Heart J
. 2020;41(36):3402–18.
71.
Zannad F, Ferreira JP, Pocock SJ, Zeller C, Anker SD, Butler J, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced.
Circulation
. 2021;143(4):310–21.
72.
Tuttle KR, Brosius FC3rd, Cavender MA, Fioretto P, Fowler KJ, Heerspink HJL, et al. SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
Am J Kidney Dis
. 2021;77(1):94–109.
73.
Verma S, Sharma A, Zinman B, Ofstad AP, Fitchett D, Brueckmann M, et al. Empagliflozin reduces the risk of mortality and hospitalization for heart failure across Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes categories: post hoc analysis of the EMPA-REG OUTCOME trial.
Diabetes Obes Metab
. 2020;22(7):1141–50.
74.
Wanner C, Inzucchi SE, Zinman B, Koitka-Weber A, Mattheus M, George JT, et al. Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: insights from the EMPA-REG OUTCOME trial.
Diabetes Obes Metab
. 2020;22(12):2335–47.
75.
Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function.
Circulation
. 2018;138(15):1537–50.
76.
Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Effect of canagliflozin on renal and cardiovascular outcomes across different levels of albuminuria: data from the CANVAS program.
J Am Soc Nephrol
. 2019;30(11):2229–42.
77.
Verma S, Mazer CD, Fitchett D, Inzucchi SE, Pfarr E, George JT, et al. Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial.
Diabetologia
. 2018;61(8):1712–23.
78.
Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: Results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study).
Circulation
. 2018;137(4):323–34.
79.
Butler J, Zannad F, Fitchett D, Zinman B, Koitka-Weber A, von Eynatten M, et al. Empagliflozin improves kidney outcomes in patients with or without heart failure.
Circ Heart Fail
. 2019;12(6):e005875.
80.
Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
Circulation
. 2019;139(22):2528–36.
81.
Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program.
Circulation
. 2018;138(5):458–68.
82.
Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-reduced trial.
Circulation
. 2021;143(4):337–49.
83.
Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlavek J, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.
JAMA
. 2020;323(14):1353–68.
84.
Dewan P, Docherty KF, Bengtsson O, de Boer RA, Desai AS, Drozdz J, et al. Effects of dapagliflozin in heart failure with reduced ejection fraction, and chronic obstructive pulmonary disease: an analysis of DAPA-HF.
Eur J Heart Fail
. 2021;23(4):632–43.
85.
Jackson AM, Dewan P, Anand IS, Belohlavek J, Bengtsson O, de Boer RA, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF.
Circulation
. 2020;142(11):1040–54.
86.
Monteiro P, Bergenstal RM, Toural E, Inzucchi SE, Zinman B, Hantel S, et al. Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME® trial.
Age Ageing
. 2019;48(6):859–66.
87.
Cahn A, Mosenzon O, Wiviott SD, Rozenberg A, Yanuv I, Goodrich EL, et al. Efficacy and safety of dapagliflozin in the elderly: analysis from the DECLARE-TIMI 58 study.
Diabetes Care
. 2020;43(2):468–75.
88.
Zinman B, Inzucchi SE, Wanner C, Hehnke U, George JT, Johansen OE, et al. Empagliflozin in women with type 2 diabetes and cardiovascular disease: an analysis of EMPA-REG OUTCOME®.
Diabetologia
. 2018;61(7):1522–7.
89.
Kadowaki T, Nangaku M, Hantel S, Okamura T, von Eynatten M, Wanner C, et al. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: results from the EMPA-REG OUTCOME® trial.
J Diabetes Investig
. 2019;10(3):760–70.
90.
Ohkuma T, Van Gaal L, Shaw W, Mahaffey KW, de Zeeuw D, Matthews DR, et al. Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program.
Diabetes Obes Metab
. 2020;22(4):530–9.
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 cardiovascular disease.
Circulation
. 2019;140(7):618–20.
92.
Arnold SV, Inzucchi SE, Tang F, McGuire DK, Mehta SN, Maddox TM, et al. Real-world use and modeled impact of glucose-lowering therapies evaluated in recent cardiovascular outcomes trials: an NCDR® Research to Practice project.
Eur J Prev Cardiol
. 2017;24(15):1637–45.
93.
AstraZeneca Pharmaceuticals LP.
FARXIGA® (dapagliflozin) tablets for oral use. Prescribing information
. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021.
94.
Janssen Pharmaceuticals Inc.
INVOKANA® (canagliflozin) tablets for oral use. Prescribing information
. Titusville, NJ: Janssen Pharmaceuticals Inc; 2020.
95.
Boehringer Ingelheim International GmbH.
JARDIANCE® (empagliflozin) tablets for oral use. Prescribing information
. Ingelheim, Germany: Boehringer Ingelheim International GmbH; 2022.
96.
Merck Sharp & Dohme Corp.
STEGLATRO® (ertugliflozin) tablets for oral use. Prescribing information
. Kenilworth, NJ: Merck Sharp & Dohme Corp; 2020.
97.
American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2021.
Diabetes Care
. 2021;44(Suppl 1):S111–24.
98.
de Boer IH, Caramori ML, Chan JCN, Heerspink HJL, Hurst C, Khunti K, et al. Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
Kidney Int
. 2020;98(4):839–48.
99.
Cahn A, Wiviott SD, Mosenzon O, Murphy SA, Goodrich EL, Yanuv I, et al. Cardiorenal outcomes with dapagliflozin by baseline glucose-lowering agents: post hoc analyses from DECLARE-TIMI 58.
Diabetes Obes Metab
. 2021;23(1):29–38.
100.
Inzucchi SE, Fitchett D, Jurisic-Erzen D, Woo V, Hantel S, Janista C, et al. Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?
Diabetes Obes Metab
. 2020;22(4):631–9.
101.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012: clinical practice guideline for the evaluation and management of chronic kidney disease.
Kidney Int Suppl
. 2013;3:1–150.
102.
Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-reduced and DAPA-HF trials.
Lancet
. 2020;396(10254):819–29.
103.
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary – a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines.
J Am Coll Cardiol
. 2022;79(17):1757–80.
104.
O’Meara E, McDonald M, Chan M, Ducharme A, Ezekowitz JA, Giannetti N, et al. CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis.
Can J Cardiol
. 2020;36(2):159–69.

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