CLINICAL FOCUS: DIABETESREVIEW

SGLT2 inhibitors in patients with type 2 diabetes and renal disease: overview ofcurrent evidenceJaime A Davidson

The University of Texas Southwestern Medical Center, Touchstone Diabetes Center, Dallas, TX, USA

ABSTRACTChronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and isassociated with poor clinical outcomes, including an increased risk of all-cause and cardiovascularmortality, as well as adverse economic and social effects. Slowing the development and progression ofCKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2)inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering thatinclude cardiovascular benefits and potential renoprotective effects. Although the glucose-loweringefficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m2.Clinical evidence has indicated that these agents can reduce the risk of development or worsening ofalbuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressurelowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory pro-cesses, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressure-lowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute toreduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies inthese patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding tothe growing evidence of the potential renoprotective effects of these agents in patients with T2DM.Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinicalrole of SGLT2 inhibitors in slowing the development and progression of renal impairment in individualswith T2DM.

ARTICLE HISTORYReceived 14 February 2019Accepted 26 March 2019

KEYWORDSAlbuminuria; canagliflozin;chronic kidney disease;chronic renal insufficiency;dapagliflozin; empagliflozin;ertugliflozin; renalinsufficiency; SGLT2inhibitor; type 2 diabetesmellitus

1. Introduction

Individuals with type 2 diabetes (T2DM) frequently have con-current chronic kidney disease (CKD), characterized by persis-tent albuminuria, decline in glomerular filtration rate (GFR),rising blood pressure, and increased cardiovascular (CV) risk[1,2]. In the United States, the crude prevalence of CKD (stages1–4) among adults (aged ≥20 years) with diagnosed diabeteswas 36.5% (95% confidence interval [CI], 32.2–40.8) during2011–2012 [3]. The presence of CKD in patients with T2DM isof particular clinical importance as it is associated with anincreased risk of both all-cause and CV mortality [4].Moreover, increases in mortality and poor clinical outcomeshave been observed in patients with early indications of CKDprogression, such as reductions in estimated glomerular filtra-tion rate (eGFR) that are below usual thresholds (less thana doubling of serum creatinine concentration) [5], and also inpatients with asymptomatic microalbuminuria [6,7]. The occur-rence of clinical complications, including CKD and the need forrenal dialysis, is expected to rise among older patients withT2DM as the prevalence of T2DM continues to rise in theUnited States and globally [8,9].

In addition to clinical consequences, CKD has economicand social effects, including increased use of health careresources and the associated costs to individual patients andhealth care providers [10,11], and a reduction in health-relatedquality of life (HRQOL) in line with the severity of the renalimpairment [12].

Despite the availability of treatments, patients with early-stage diabetic kidney disease may be undertreated and are atrisk of progression to more advanced stages of renal impair-ment [13]. There remains a need for early intervention withtreatments that can prevent or delay the progression of micro-or macroalbuminuria in patients with T2DM.

2. SGLT2 inhibitors in the management of T2DM

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widelyused antidiabetes drugs that improve glycemic control, reducebody weight, and lower hypertension, with no associatedincrease in pulse rate, in patients with T2DM [14–20]. FourSGLT2 inhibitors are currently approved in the United Statesfor use in the improvement of glycemic control in adults withT2DM (dapagliflozin [21], canagliflozin [22], empagliflozin [23],

CONTACT Jaime A Davidson Jaime.Davidson@UTSouthwestern.edu Touchstone Diabetes Center, The University of Texas, Southwestern Medical Center,5323 Harry Hines Blvd. K5.246, Dallas, TX 75390-9082, USA

supplemental data for this article can be accessed here.

POSTGRADUATE MEDICINEhttps://doi.org/10.1080/00325481.2019.1601404

© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

and ertugliflozin [24]). In addition to the glucose-loweringeffects of SGLT2 inhibitors, empagliflozin is also indicated forthe reduction of risk of CV death in patients with T2DM andestablished CV disease (CVD) [23], and similar label expansionhas been recently approved for canagliflozin, which is indi-cated to reduce the risk of major adverse CV events (MACE) inadults with T2DM and established CVD [25]. Furthermore,evidence suggests that SGLT2 inhibitors might confer reno-protective effects, leading to reduction in the rate of progres-sion of diabetic kidney disease [26].

SGLT2 inhibitors have a unique mechanism of action that isindependent of insulin or insulin sensitivity, and results frominhibition of SGLT2 in the proximal tubule of the kidney [27].The mechanism of action of SGLT2 inhibitors has been describedin detail previously and is summarized here [28,29]. SGLT2 isa transport protein responsible for the reabsorption of approxi-mately 90% of filtered glucose, the remainder being absorbed byanother transporter protein, sodium-glucose co-transporter 1(SGLT1). Inhibition of SGLT2 results in a reduction in renal capa-city for glucose reabsorption by approximately 50%. Preclinicalresearch suggests that glycosuria may not be the only mechan-ism of glucose-lowering of SGLT2 inhibitors: at least one agentappears to also suppress hepatic glucagon signaling by down-regulation of hepatic glucagon receptors [30]. Overall, the glu-cose-lowering effect of SGLT2 inhibition results from glycosuria[28] and is associated with improvements in glycemic controland reductions in glycated hemoglobin (HbA1c) levels [31].SGLT2 inhibition also produces a modest natriuretic effect thatmay contribute to blood pressure lowering; however, theseeffects are relatively small and transient due to stimulation ofhomeostatic mechanisms [29]. The blood pressure-loweringeffect of SGLT2 inhibitors is likely affected by several other effectsof SGLT2 inhibition, including weight loss and diuresis [32].

2.1. Role of SGLT2 inhibitors in patients with T2DM andrenal impairment

SGLT2 inhibitors are largely metabolized by the liver viaglucuronidation to inactive metabolites, with renal elimina-tion of the unchanged drug [33–36]. There is some variabilityin the percentage of drug cleared via the liver and kidneybetween individual SGLT2 inhibitors [33], a feature that influ-ences the tolerability of individual agents in the presence ofliver or kidney insufficiency. Overall, the pharmacokineticparameters of these agents are slightly altered in the pres-ence of CKD, although no dose adjustment is required in thecase of mild CKD (defined as eGFR 60–89 mL/min/1.73 m2,using the CKD classification system of the Kidney DiseaseOutcomes Quality Initiative [KDOQI] and Kidney Disease:Improving Global Outcomes [KDIGO] [37]) [33]. For moderateCKD (defined as eGFR 30–59 mL/min/1.73 m2) [37], currentprescribing information for these agents states that they maybe unsuitable or only used at a reduced daily dose [21–24,33]. The use of SGLT2 inhibitors is contraindicated inpatients with severe CKD (eGFR 15–29 mL/min/1.73 m2) [37]including patients with severe renal impairment, end-stagekidney disease (ESRD), or who require dialysis [21–23].Assessment of renal function is advised before initiatingtherapy with SGLT2 inhibitors, and these agents should not

be initiated if the eGFR is below a certain threshold (specifi-cally, empagliflozin or canagliflozin should not be initiated orshould be discontinued if the eGFR is <45 mL/min/1.73 m2;no empagliflozin dose adjustment is needed if the eGFR is≥45 mL/min/1.73 m2; canagliflozin should be limited to100 mg/day if the eGFR is between 45 and <60 mL/min/1.73 m2; and dapagliflozin and ertugliflozin should not beinitiated or should be discontinued if the eGFR is <60 mL/min/1.73 m2) [21–24]. As the eGFR levels for which SGLT2inhibitors are indicated/contraindicated can differ betweenindividual agents, the choice of agent must be carefullyconsidered for patients with renal impairment. Since theglucose-lowering effect of SGLT2 inhibitors is dependent onglomerular filtration, urinary glucose excretion declines withincreasing severity of renal impairment (as indicated bya reduction in eGFR) [33]. Nonetheless, in patients withmild CKD, glucose-lowering efficacy and safety of SGLT2inhibitors are similar to these effects in patients with normalkidney function. However, in patients with moderate CKD, theefficacy of SGLT2 inhibitors is reduced and there is a greaterrisk of adverse effects in general, versus patients with normalrenal function [33,38].

In terms of glucose-lowering efficacy, there are conflictingdata on the degree of CKD for which SGLT2 inhibition continuesto offer clinically relevant reductions in HbA1c. A long-term(104 weeks), phase 2/3, randomized, placebo-controlled trialassessed the efficacy and safety of dapagliflozin in patientswith T2DM and moderate renal impairment and showed thatglycemic control was not improved versus placebo [39].However, post hoc analysis by baseline CKD stage revealeda modest reduction in HbA1c (placebo-corrected mean reduc-tion from baseline between –0.33% and –0.37% at Week 24)with dapagliflozin 5 mg and 10 mg among patients with stage3A CKD (eGFR ≥45 and <60 mL/min/1.73 m2), whereas nochange in HbA1c was observed in patients with stage 3B CKD(eGFR ≥30 and <45 mL/min/1.73 m2). Similarly, in a 52-week,phase 3, randomized, placebo-controlled study in which cana-gliflozin was administered to patients with T2DM and stage 3CKD (eGFR ≥30 and <50 mL/min/1.73 m2), both 100 mg and300 mg doses of canagliflozin produced reductions in HbA1cversus placebo (–0.19%, –0.33%, and 0.07%, respectively); pla-cebo-subtracted differences in HbA1c (95% CI) were –0.27%(–0.53, 0.001%) and –0.41% (–0.68, –0.14), respectively [40].Similar findings were observed in an assessment of empagli-flozin as an add-on treatment in patients with T2DM and CKD ina 52-week, phase 3, randomized, placebo-controlled trial [41]. Inthis trial, the addition of empagliflozin to existing treatmentproduced reductions in HbA1c in patients with stage 2 and 3CKD, although no improvements were observed among thosewith stage 4 CKD [41]. In patients with stage 2 CKD (eGFR ≥60to <90 mL/min/1.73 m2), adjusted mean treatment differencesversus placebo in changes from baseline in HbA1c at Week 24were –0.52% (95% CI, –0.72, –0.32) for empagliflozin 10 mgand –0.68% (95% CI, –0.88, –0.49) for empagliflozin 25 mg(both p < 0.0001). These HbA1c changes were sustained atWeek 52. In patients with stage 3 CKD (eGFR ≥30 to <60 mL/min/1.73 m2), the adjusted mean treatment difference versusplacebo in HbA1c change from baseline at Week 24 was –0.42%(95% CI, –0.56, –0.28) with empagliflozin 25 mg (p < 0.0001) and

2 J. A. DAVIDSON

was sustained at Week 52. For ertugliflozin, a 52-week study ofpatients with stage 3 CKD (eGFR ≥30 to <60 mL/min/1.73 m2)showed that the addition of this drug to standard T2DM ther-apy was associated with reductions in HbA1c (although thecomparison to the placebo group was not statistically signifi-cant, possibly due to an unusually large placebo responselinked to surreptitious metformin use) and treatment was gen-erally well tolerated [42].

Because SGLT2 inhibitors can cause contraction of bloodvolume, physicians are advised to consider factors that mightincrease the risk of acute kidney injury, including hypovole-mia, chronic renal insufficiency, chronic heart failure, andconcomitant medications (e.g. diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor block-ers, nonsteroidal anti-inflammatory drugs) [21–24]. The USFood and Drug Administration (FDA) has previously raisedconcerns that long-term treatment with SGLT2 inhibitionmight lead to deterioration in renal function secondary todiuresis, with the development of volume depletion andmodest reductions in eGFR [43–45]. However, current evi-dence suggests that small changes in eGFR after long-termtreatment (52 weeks) are reversed within 3 weeks of treat-ment discontinuation, indicating that the initial changes inrenal function in response to SGLT2 inhibitor therapy area result of hemodynamic changes induced by treatment[41,46].

Overall, the safety of SGLT2 inhibitors does not appear todiffer substantially according to the stage of CKD [33]. Forexample, in a study of empagliflozin in patients with CKD,adverse events (AEs) were reported over 52 weeks [41].Among patients with stage 2 CKD, AEs were reported in 80%taking empagliflozin 25 mg versus 87% in the placebo group.Corresponding frequencies in patients with stage 3 CKD were83% for both groups, and were 92% and 84% for empagli-flozin 25 mg and placebo groups, respectively, in patients withstage 4 CKD. The incidence of severe and serious AEs wassimilar in patients treated with empagliflozin and in thosereceiving placebo.

3. Evidence for potential renal benefits of SGLT2inhibitors

SGLT2 inhibition is associated with pleiotropic effects, includ-ing reductions in blood glucose concentrations, urinary glu-cose excretion, natriuresis, and decreases in blood pressureand body weight [14–18,47]. These changes might conferprotective effects on the kidney by reducing CV and renalrisk factors in individuals with T2DM (Figure 1) [29].Furthermore, there is evidence that SGLT2 inhibitors canreduce the risk of development or worsening of albuminuria,a marker of glomerular damage, in patients with T2DM. Ina long-term study of patients with T2DM and moderate renalimpairment, participants were more likely to regress to a lowercategory of albumin excretion when receiving dapagliflozinversus placebo over 104 weeks [39]. In this study, urinaryalbumin to creatinine ratio (UACR) was divided into threeprespecified categories: 0 to <30 mg/g (normoalbuminuria),30 to <300 mg/g (microalbuminuria), or ≥300 mg/g (macro-albuminuria). For patients who received dapagliflozin (5 mg

and 10 mg groups, n = 168 in total), 38 patients shifted frombaseline to a lower category at Week 104 compared with 18patients who shifted to a higher category. For the placebogroup (n = 84), a similar number of patients shifted to a lowercategory (n = 9) of UACR as to a higher category (n = 12).Similarly, a study of patients with T2DM and CKD showed thatthe addition of empagliflozin to standard care was associatedwith a reduction in albuminuria over 52 weeks [41]. At the endof treatment, comparison of treatment groups in patients withstage 3 CKD showed that more patients who received empa-gliflozin 25 mg improved from macroalbuminuria at baselineto microalbuminuria, or from microalbuminuria to no albumi-nuria, compared with placebo (32.6% [n = 14] with empagli-flozin 25 mg vs. 8.6% [n = 3] with placebo, and 27.5% [n = 14]with empagliflozin 25 mg vs. 21.4% [n = 15] with placebo,respectively). The administration of canagliflozin in patientswith T2DM and CKD has also been associated with a slowingof the progression of kidney disease versus placebo [48]. Ina study of 42 Japanese patients with T2DM, reductions inalbuminuria and in markers of tubulointerstitial damage (urin-ary liver-type fatty acid binding protein, N-acetyl-β-D-glucosaminidase, and β2-microglobulin) were observedover 52 weeks among patients who received canagliflozin100 mg added to usual care compared with the controlgroup [48].

A mechanistic trial that evaluated the renal hemodynamiceffects of SGLT2 inhibition in type 1 diabetes mellitus [49]showed that empagliflozin administration was associatedwith a reduction in renal hyperfiltration, a potential risk factorfor renal disease progression in T2DM [50], probably by affect-ing tubular-glomerular feedback mechanisms. The findings ofthis trial indicate that SGLT2 inhibition may produce renopro-tective effects due to a reduction in intraglomerular pressure

Figure 1. Summary of potential renal benefits of SGLT2 inhibition in patientswith T2DM [29] eGFR, estimated glomerular filtration rate, HbA1c, glycatedhemoglobin.

POSTGRADUATE MEDICINE 3

[49]. Although clinical data supporting the benefits of SGLT2inhibitors on renal outcomes are currently limited [2], severalongoing trials are expected to provide further evidence of theeffects of these agents on renal function. Furthermore, severalCV outcomes trials (CVOTs) have included renal endpoints andthese provide some insights into the longer-term effects ofglucose-lowering therapies on renal outcomes, as describedbelow.

3.1. Clinical evidence from CVOTs with SGLT2 inhibitorsthat included renal endpoints

Two large randomized CVOTs have evaluated the long-termCV safety of empagliflozin (EMPA-REG OUTCOME trial[EMPAgliflozin Removal of Excess Glucose: CardiovascularOUTCOME Event Trial in Type 2 Diabetes Mellitus Patients])[51,52] and canagliflozin (the CANVAS [CanagliflozinCardiovascular Assessment Study] Program) [53,54]. Thesestudies were primarily designed to evaluate CV outcomesbut secondary outcomes also indicated that SGLT2 inhibi-tors could offer clinically relevant renal benefits to patientswith T2DM. A further ongoing CVOT is evaluating ertugli-flozin in 8238 patients with established atherosclerotic CVD(ASCVD), and includes a secondary composite outcome ofrenal death, dialysis/transplant, or doubling of serum crea-tinine from baseline [55]; the trial is expected to completein September 2019. In the EMPA-REG OUTCOME trial, a totalof 7020 patients with T2DM and at high CV risk wererandomized to receive empagliflozin (10 mg or 25 mgonce daily) or placebo in addition to standard care, witha median observation time of 3.1 years [51]. Empagliflozinwas associated with a reduction in the primary compositeendpoint of 3-point MACE (defined as death from CVcauses, nonfatal myocardial infarction [MI], or nonfatalstroke) versus placebo (10.5% vs. 12.1%, respectively; hazardratio [HR], 0.86; 95.02% CI, 0.74–0.99; p < 0.001 for non-inferiority; p = 0.04 for superiority). In the empagliflozingroup the rate of CV death was significantly reduced versusplacebo (3.7% vs. 5.9%, respectively; 38% relative risk reduc-tion). Empagliflozin was also associated with significantreductions in hospitalization for heart failure (2.7% and4.1%, respectively; 35% relative risk reduction) and deathfrom any cause (5.7% and 8.3%, respectively; 32% relativerisk reduction) compared with placebo. On the basis ofthese findings, the FDA approved a label change for empa-gliflozin to include a new indication for the reduction of CVmortality in patients with T2DM and established CVD [56].The addition of empagliflozin to standard care also wasassociated with slower progression of kidney disease andlower rates of clinically relevant renal events versus placebo[52]. Incident or worsening nephropathy was observed in525 of 4124 patients (12.7%) receiving empagliflozin versus388 of 2061 (18.8%) in the placebo group (HR for empagli-flozin group, 0.61; 95% CI, 0.53–0.70; p < 0.001). There wasalso a significant relative risk reduction of 44% in the occur-rence of doubling of serum creatinine levels (70 of 4645patients [1.5%] in the empagliflozin group vs. 60 of 2323[2.6%] for placebo). Renal-replacement therapy was initiated

in 13 of 4687 patients (0.3%) in the empagliflozin groupversus in 14 of 2333 (0.6%) in the placebo group, a relativerisk reduction of 55% for the empagliflozin group. AlthoughEMPA-REG OUTCOME [51] was not a dedicated renal out-comes trial and renal outcomes were not adjudicated dur-ing the study, subsequent analysis has shown similar resultsusing retrospectively confirmed events [57]. In a post hocanalysis of data from the EMPA-REG OUTCOME trial, patientswith T2DM and a history of coronary artery bypass graftsurgery who were treated with empagliflozin also demon-strated reductions in incident or worsening nephropathy, inaddition to reductions in CV mortality, all-cause mortality,and hospitalizations for heart failure, compared with pla-cebo [58]. Similar effects on renal function and CV eventswere observed in a subanalysis of EMPA-REG OUTCOME datain another high-risk group of patients with T2DM and per-ipheral artery disease [59]. In a recent slope analysis fromthe EMPA-REG OUTCOME trial, the decline in eGFR that isobserved shortly after initiation of treatment with empagli-flozin was shown to be reduced with chronic maintenancetreatment, and increased to pretreatment levels after cessa-tion of the drug [60]. This pattern was consistent acrosspatients with a range of eGFR values in the trial, includingsubgroups at increased risk of CKD progression, and isindicative of the renal hemodynamic effect of empagliflozin.It is possible that the hemodynamic effect of empagliflozinassociated with the reduction of intraglomerular pressuremay contribute to the long-term preservation of kidneyfunction [61].

In the CANVAS Program, 10,142 patients with T2DM andhigh CV risk (approximately two-thirds of whom hada history of CVD) were randomized to canagliflozin or pla-cebo in two trials (CANVAS and CANVAS Renal Endpoints[CANVAS-R] trials) and followed for a median of 2.4 years[53]. Canagliflozin therapy was associated with a reductionin the occurrence of the primary composite outcome (deathfrom CV causes, nonfatal MI, or nonfatal stroke) versusplacebo (26.9 vs. 31.5 participants per 1000 patient-years,respectively; HR, 0.86; 95% CI, 0.75–0.97; p < 0.001 fornoninferiority; p = 0.02 for superiority) [53]. The resultsalso showed a reduction in the progression of albuminuria(89.4 vs. 128.7 participants with an event per 1000 patient-years; HR, 0.73; 95% CI, 0.67–0.79), regression of albuminuria(293.4 vs. 187.5 participants with regression per 1000patient-years; HR, 1.70; 95% CI, 1.51–1.91), and in the com-posite outcome of a sustained 40% reduction in eGFR, needfor renal-replacement therapy, or death from renal causes inpatients with T2DM and high CV risk with canagliflozinversus placebo (5.5 vs. 9.0 participants with the outcomeper 1000 patient-years, respectively; HR, 0.60; 95% CI,0.47–0.77) [53]. However, these renal outcomes were notconsidered statistically significant on the basis of the study’sprespecified hypothesis-testing sequence. These potentialbenefits of canagliflozin therapy were slightly offset by anincreased risk of amputation, and possible increased bonefracture risk [53], although further data are required on thesafety of canagliflozin [62]. A recent prespecified exploratoryanalysis of data from the CANVAS Program showed that

4 J. A. DAVIDSON

canagliflozin was associated with renoprotective effects ver-sus placebo, as indicated by a reduced occurrence of albu-minuria and a reduced likelihood of developing micro- ormacroalbuminuria, in addition to stabilization of renal func-tion (attenuated decline in eGFR over time) [54]. The com-posite outcome of sustained doubling of serum creatinine,ESRD, and death from renal causes was also observed lessfrequently among patients receiving canagliflozin versusplacebo (1.5 vs. 2.8 per 1000 patient-years, respectively;HR, 0.53; 95% CI, 0.33–0.84). In addition, post hoc analysesof data from the CANVAS Program have shown that thebeneficial effects of canagliflozin on CV and renal outcomeswere not influenced by baseline renal function in peoplewith T2DM and a history or high risk of CVD down to eGFRlevels of 30 mL/min/1.73 m2 [63]. This finding has led to thesuggestion that the use of canagliflozin might be appropri-ate for patients with eGFR levels that are below the cur-rently recommended level in view of the potential CV andrenal benefits of therapy [63].

A post hoc analysis of a long-term study of dapagliflozinin patients with renal impairment showed that dapagliflozinreduced UACR versus placebo over 2 years in patients withT2DM and stage 3 CKD, without increasing the occurrenceof serious renal AEs [64]. Dapagliflozin (5 mg and 10 mg)therapy, compared with placebo, was associated with anincreased likelihood of shifting to a lower UACR category(39.6% and 33.9%, respectively, vs. 15.8% with placebo),with fewer patients progressing to a higher UACR category(4.3% and 14.7%, respectively, vs. 27.3% with placebo).Overall, 18.9% and 17.8% of patients in the dapagliflozin5 mg and 10 mg groups, respectively, improved to normo-albuminuria status versus 7.0% of patients receiving pla-cebo. The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58)trial is the most recent and largest CVOT for the SGLT2inhibitor class (n = 17,160) [65]. In this trial, dapagliflozin10 mg was associated with a lower rate of CV death orhospitalization for heart failure versus placebo (HR, 0.83;95% CI, 0.73–0.95; p = 0.005), primarily due to a 27% reduc-tion in heart failure hospitalizations among patients withT2DM who had or were at risk of ASCVD. Treatment withdapagliflozin was not associated with a reduced rate of3-point MACE (CV death, MI, or ischemic stroke) versusplacebo. Nonetheless, the occurrence of the secondaryrenal composite outcome (≥40% decrease in eGFR to<60 mL/min/1.73 m2, new ESRD, or death from renal or CVcause) was reduced among patients receiving dapagliflozinversus placebo (4.3% and 5.6%, respectively; HR, 0.76; 95%CI, 0.67–0.87), as well as the composite of a sustained ≥40%decrease in eGFR (to eGFR <60 mL/min/1.73 m2), ESRD, ordeath from renal cause (1.5% and 2.8%, respectively; HR,0.53; 95% CI, 0.43–0.66) [65]. Renal outcomes will also beincluded in the DAPA-HF trial (Study to Evaluate the Effectof Dapagliflozin on the Incidence of Worsening Heart Failureor Cardiovascular Death in Patients With Chronic HeartFailure) [66]. This study of patients with chronic heart failurewith reduced ejection fraction will evaluate the effect ofdapagliflozin versus placebo, added to regional standard-of-care therapy, in the prevention of CV death or reduction of

heart failure events. A secondary outcome measure willinclude time to the first occurrence of any of the compo-nents of a renal composite (≥50% sustained decline in eGFR,ESRD, or renal death).

3.2. Suggested mechanisms for potential renal benefitsof SGLT2 inhibitors

The beneficial effects of SGLT2 inhibitors on renal functionare thought to arise from several mechanisms as summar-ized in Figure 2 [29]. These possible mechanisms can bedivided into six areas and are described here. 1) Reductionsin the renal absorption of glucose and sodium in the prox-imal tubules are thought to reduce hyperfiltration byincreasing sodium delivery to the macula densa, whichactivates tubuloglomerular feedback, leading to afferentarteriolar vasoconstriction and a reduction in intraglomeru-lar hyperfiltration [29,49,57,67]. 2) Lowering of blood glu-cose by SGLT2 inhibition results in lowering of potentialglucotoxicity in the kidney and other organs, leading toreduced renal growth, inflammation, and injury [29]. 3)Reductions in blood pressure are preserved in patientswith CKD receiving SGLT2 inhibitor therapy, and it is possi-ble that a decline in sodium and volume overload, as wellas modest decreases in body weight, will lead to a reducedrenal and CV burden [29,51,63,68]. 4) SGLT2 is coexpressedwith the Na+/H+ exchanger 3 (NHE3) membrane protein inthe early proximal tubule, and thus SGLT2 inhibition mightproduce natriuresis, contributing to blood pressure reduc-tion and associated renal benefits [29]. 5) SGLT2 inhibition isassociated with increases in glucagon levels that have a rolein maintaining renal function [69]. The renal effects of rela-tively high doses of glucagon include vasodilation andresultant increases in renal plasma flow, GFR, and electrolyteexcretion. In parallel, insulin levels are reduced with SGLT2inhibition, leading to enhanced lipolysis and hepatic gluco-neogenesis [29]. 6) SGLT2 inhibition is possibly associatedwith a reduced risk of renal injury secondary to ischemiadue to increases in the levels of the transcription factor,hypoxia-inducible factor [29]. Other contributory mechan-isms for potential renal benefits of SGLT2 inhibitors mayinclude reductions in arterial stiffness [70] and vascularresistance [71], decreases in uric acid levels [51], and mod-ulation of the renal-angiotensin-aldosterone system, bothwithin the kidney and systemically (for summary of poten-tial renoprotective mechanisms, see Supplementary Video)[49,72]. Further research is needed to fully elucidate thepotential renal and CV benefits of SGLT2 inhibition andtheir underlying mechanisms.

3.3. Ongoing trials of renal outcomes with SGLT2inhibitors

Although there is growing evidence to suggesta renoprotective role for SGLT2 inhibitors, several ongoingdedicated renal outcomes trials will provide further insightsinto the role of SGLT2 inhibitors on renal function in patientswith T2DM (Table 1).

POSTGRADUATE MEDICINE 5

The CREDENCE trial (Evaluation of the Effects of Canagliflozinon Renal and Cardiovascular Outcomes in Participants WithDiabetic Nephropathy) has been evaluating the efficacy andsafety of adding canagliflozin versus placebo to standard carein patients with CKD and T2DM (n = 4401) [73]. The trial wasstopped early due to achievement of prespecified efficacy criteriaidentified during a planned interim analysis. This decision wasbased on the demonstration of efficacy of canagliflozin in termsof the primary composite endpoint of ESRD (time to dialysis orkidney transplantation), doubling of serum creatinine, and renalor CV death when used in addition to standard care [74]. The fullreport of this trial and the outcomes of other renal outcomestrials of SGLT2 inhibitors are awaited with interest.

A study of dapagliflozin has recently completed (resultsexpected) in which patients with T2DM and CKD were rando-mized to dapagliflozin (with or without saxagliptin) or placebo[75]. For renal endpoints, this study evaluated the percentagechange in UACR between dapagliflozin 10 mg plus saxagliptin2.5 mg and placebo, and between dapagliflozin 10 mg andplacebo, over 24 weeks, in addition to the proportion of patientswho achieve a 30% reduction in UACR over the study period. Ina further trial, the effect of dapagliflozin on the progression ofkidney disease and CV mortality will be evaluated in patientswith CKD, with or without T2DM (DAPA-CKD) [76].

For empagliflozin, two trials are underway to investigatethe safety and efficacy of empagliflozin versus placebo, addedto guideline-directed therapy, in patients with heart failure:two EMPEROR (EMPagliflozin outcomE tRial in Patients WithchrOnic heaRt Failure) trials will include patients with eitherreduced ejection fraction (EMPEROR-Reduced) [77] or withpreserved ejection fraction (EMPEROR-Preserved) [78].Secondary endpoints in both trials will include change ineGFR from baseline, and time to first occurrence of chronicdialysis or renal transplant or sustained reduction of eGFR.Another study, EMPA-KIDNEY, will evaluate patients withestablished CKD, with and without T2DM, to determine theeffect of empagliflozin on time to clinically relevant kidneydisease progression or CV death [79,80]. The findings of thistrial will build on results of the EMPA-REG OUTCOME trial [51],with important new data on the effects of empagliflozin ina broad range of people, with or without T2DM.

4. Translating clinical trial findings into practic

There is now growing evidence to show that SGLT2 inhibitorshave the potential to offer renoprotective effects in patientswith T2DM and CKD. On the basis of the findings of the EMPA-REG OUTCOME study, the latest guidelines from the American

Figure 2. Summary of potential mechanisms by which SGLT2 inhibitors confer renal/CV protection.SGLT2 inhibition may provide its cardioprotective and renal protective effects via several mechanisms: (1) SGLT2 inhibition attenuates primary proximal tubular hyperreabsorption in thekidney in diabetes, increasing/restoring the tubuloglomerular feedback signal at the macula densa ([Na+/Cl−/K+]MD) and hydrostatic pressure in Bowman’s space. This reduces glomerularhyperfiltration, beneficially affecting albumin filtration and tubular transport work and, thus, renal oxygen consumption; (2) by lowering blood glucose levels, SGLT2 inhibitors can reducekidney growth, albuminuria and inflammation; (3) SGLT2 inhibitors have a modest osmotic diuretic, natriuretic and uricosuric effect, which can reduce extracellular volume, blood pressure,serum uric acid levels and body weight. These changes may have beneficial effects on both the renal and cardiovascular systems; (4) SGLT2 may be functionally linked to NHE3, such thatSGLT2 inhibition may also inhibit NHE3 in the proximal tubule, with implications on the natriuretic, GFR and blood pressure effect; (5) SGLT2 inhibition reduces insulin levels and the needfor therapeutic and/or endogenous insulin, and increases glucagon levels. As a consequence, lipolysis and hepatic gluconeogenesis are elevated. These metabolic adaptations reduce fattissue/body weight and hypoglycemia risk, and result in mild ketosis, potentially having beneficial effects on both the renal and cardiovascular systems; (6) SGLT2 inhibition may alsoenhance renal HIF content, which may have renal protective effects. White text boxes indicate affected variables, gray text boxes indicate processes that link SGLT2 inhibition to thereduction in GFR. Green arrows demonstrate consequences, red arrows indicate changes in associated variables (increase/decrease). ECV = extracellular volume; GFR = glomerular filtrationrate; HIF = hypoxia-inducible factor; MD = macula densa; NHE3 = sodium-hydrogen exchanger 3; PBow = hydrostatic pressure in Bowman space; SGLT2 = sodium-glucose co-transporter 2.Reproduced with permission [29].

6 J. A. DAVIDSON

Association of Clinical Endocrinologists and American Collegeof Endocrinology refer to a potential benefit of empagliflozinon renal outcomes, in addition to CV benefits [81].Furthermore, the latest diabetes management guidelinesfrom the American Diabetes Association recommend thatSGLT2 inhibitors be considered for patients with T2DM andCKD who require add-on therapy to metformin, on the basis ofrecent CVOTs indicating that these agents may reduce the riskof CKD progression and CVD events [82]. Although the effectof SGLT2 inhibition on HbA1c reduction declines with progres-sive reductions in eGFR, the CV and renal benefits of therapyappear to be maintained regardless of eGFR level (down to30 mL/min/1.73 m2) [63]. The preservation of a blood pres-sure-lowering effect with SGLT2 inhibitor therapy in patientswith T2DM and CKD indicates that this effect could furthercontribute to a reduced renal burden in these patients[51,63,68]. Furthermore, SGLT2 inhibitors might offer synergis-tic effects with other blood pressure-lowering agents [83] ordiuretics [61] in patients with T2DM and CKD. It is possible,therefore, that SGLT2 inhibitors could have a role in patientswith T2DM for uses other than glucose lowering, and mayhave a future role in patients with eGFR levels below thelevel at which clinically relevant HbA1c reductions would beexpected due to their potential CV and renal benefits [63].

5. Conclusion

SGLT2 inhibitors have an important role in the management ofT2DM, adding to the currently available treatment optionsthat can assist with individualization of therapy. The pleiotro-pic effects of SGLT2 inhibitors have the potential to produce

benefits beyond blood glucose control, and there is increasingevidence to indicate that these agents may reduce the risk ofprogression of renal impairment in patients with T2DM. Thefindings of ongoing and future clinical trials will help shedfurther light on the role of SGLT2 inhibitors in the long-termprotection of renal and CV function in patients with T2DM.

Funding

This article was supported by Boehringer Ingelheim Pharmaceuticals, Inc.(BIPI). The author meets criteria for authorship as recommended by theInternational Committee of Medical Journal Editors (ICMJE) and was fullyresponsible for all content and editorial decisions, was involved at allstages of manuscript development, and approved the final version thatreflects the author’s interpretations and conclusions. The author receivedno direct compensation related to the development of the manuscript.Writing support was provided by Jennifer Garrett, MBBS, of ElevateScientific Solutions, which was contracted and compensated by BIPI forthis service.

Declaration of interest

The author has no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict with thesubject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties. Peer reviewerson this manuscript have no relevant financial relationships to disclose.

References

1. Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and pre-valence of chronic kidney disease among patients with type 2

Table 1. Ongoing trials of SGLT2 inhibitors with renal outcomes.

Trial acronym/titleClinicalTrials.gov identifier Primary study aims

Number ofpatientsenrolled

Estimatedcompletion date

CREDENCEEvaluation of the Effects of Canagliflozin on Renaland Cardiovascular Outcomes in Participants WithDiabetic Nephropathy [73]

NCT02065791 To assess whether canagliflozin has a renal andvascular protective effect in reducing theprogression of renal impairment relative to placeboin participants with T2DM, stage 2 or 3 CKD andmacroalbuminuria, who are receiving standard ofcare (including a maximum tolerated daily dose ofan angiotensin-converting enzyme inhibitor orangiotensin receptor blocker).

4401 June 2019

DAPA-HF [66]Study to Evaluate the Effect of Dapagliflozin onthe Incidence of Worsening Heart Failure orCardiovascular Death in Patients With ChronicHeart Failure

NCT03036124 To evaluate the effect of dapagliflozin on theincidence of worsening heart failure or CV death inpatients with chronic heart failure with reducedejection fraction.

4744 December 2019

EMPEROR trialsEMPagliflozin outcomE tRial in Patients WithchrOnic heaRt Failure (EMPEROR) With ReducedEjection Fraction (EMPEROR-Reduced) [77] andWith Preserved Ejection Fraction (EMPEROR-Preserved) [78]

NCT03057977NCT03057951

To investigate the safety and efficacy of empagliflozinversus placebo on top of guideline-directedmedical therapy in patients with heart failure withreduced ejection fraction (EMPEROR-Reduced) orpreserved ejection fraction (EMPEROR-Preserved).

28504126

June 2020

DAPA-CKD [76]Study to Evaluate the Effect of Dapagliflozin onRenal Outcomes and Cardiovascular Mortality inPatients With Chronic Kidney Disease

NCT03036150 To evaluate the effect of dapagliflozin versus placebo,once daily in addition to standard of care, toprevent the progression of CKD or CV/renal death.

4000 November 2020

EMPA-KIDNEY [80]The Study of Heart and Kidney Protection WithEmpagliflozin

NCT03594110 To investigate the effect of empagliflozin on kidneydisease progression or CV death versus placebo ontop of standard of care in patients with pre-existingCKD.

5000 June 2022

POSTGRADUATE MEDICINE 7

diabetes mellitus in the United States. Clin Ther.2009;31:2608–2617.

2. De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotran-sporter 2 inhibitors and prevention of diabetic nephropathy: tar-geting the renal tubule in diabetes. Am J Kidney Dis.2014;64:16–24.

3. Murphy D, McCulloch CE, Lin F, et al. Trends in prevalence ofchronic kidney disease in the United States. Ann Intern Med.2016;165:473–481.

4. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease andincreased mortality risk in type 2 diabetes. J Am Soc Nephrol.2013;24:302–308.

5. Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glo-merular filtration rate and subsequent risk of end-stage renal dis-ease and mortality. JAMA. 2014;311:2518–2531.

6. Kim JJ, Hwang BH, Choi IJ, et al. A prospective two-center study onthe associations between microalbuminuria, coronary atherosclero-sis and long-term clinical outcome in asymptomatic patients withtype 2 diabetes mellitus: evaluation by coronary CT angiography.Int J Cardiovasc Imaging. 2015;31:193–203.

7. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardio-vascular events, death, and heart failure in diabetic and nondia-betic individuals. JAMA. 2001;286:421–426.

8. World Health Organization [Internet]. Global report on diabetes;2016 cited 2018 Jul 9; Available from: http://www.who.int/diabetes/global-report/en/

9. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetesand diabetes complications in the elderly: an emerging publichealth burden. Curr Diab Rep. 2013;13:805–813.

10. Saran R, Robinson B, Abbott KC, et al. US renal data system 2017annual data report: epidemiology of kidney disease in the UnitedStates. Am J Kidney Dis. 2018;71:S1–S672.

11. Vupputuri S, Kimes TM, Calloway MO, et al. The economic burdenof progressive chronic kidney disease among patients with type 2diabetes. J Diabetes Complications. 2014;28:10–16.

12. Mujais SK, Story K, Brouillette J, et al. Health-related quality of life inCKD patients: correlates and evolution over time. Clin J Am SocNephrol. 2009;4:1293–1301.

13. Zhou Z, Chaudhari P, Yang H, et al. Healthcare resource use, costs,and disease progression associated with diabetic nephropathy inadults with type 2 diabetes: a retrospective observational study.Diabetes Ther. 2017;8:555–571.

14. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintainsglycaemic control while reducing weight and body fat mass over 2years in patients with type 2 diabetes mellitus inadequately con-trolled on metformin. Diabetes Obes Metab. 2014;16:159–169.

15. Cefalu WT, Stenlof K, Leiter LA, et al. Effects of canagliflozin onbody weight and relationship to HbA1c and blood pressurechanges in patients with type 2 diabetes. Diabetologia.2015;58:1183–1187.

16. Roden M, Merker L, Christiansen AV, et al. Safety, tolerability andeffects on cardiometabolic risk factors of empagliflozin monother-apy in drug-naive patients with type 2 diabetes: a double-blindextension of a phase III randomized controlled trial. CardiovascDiabetol. 2015;14:154.

17. Stenlof K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety ofcanagliflozin monotherapy in patients with type 2 diabetes inade-quately controlled with diet and exercise: findings from the52-week CANTATA-M study. Curr Med Res Opin. 2014;30:163–175.

18. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces bloodpressure in patients with type 2 diabetes and hypertension.Diabetes Care. 2015;38:420–428.

19. American Diabetes Association. Pharmacologic approaches to gly-cemic treatment: standards of medical care in diabetes - 2019.Diabetes Care. 2019;42:S90–S102.

20. Sjostrom CD, Johansson P, Ptaszynska A, et al. Dapagliflozin lowersblood pressure in hypertensive and non-hypertensive patients withtype 2 diabetes. Diab Vasc Dis Res. 2015;12:352–358.

21. US Food and Drug Administration [Internet]. Highlights of prescrib-ing information: FARXIGA®; 2014 cited 2018 Jul 31. Available from:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202293s012lbl.pdf

22. US Food and Drug Administration [Internet]. Highlights of prescrib-ing information: INVOKANA®; 2017 cited 2018 Jul 31. Availablefrom: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204042s026lbl.pdf

23. US Food and Drug Administration [Internet]. Highlights of prescrib-ing information: JARDIANCE®; 2018 cited 2019 Jan 31. Availablefrom: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf

24. US Food and Drug Administration [Internet]. Highlights of prescrib-ing information: STEGLATRO®; 2018 cited 2019 Jan 17. Availablefrom: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209803s001lbl.pdf

25. US Food and Drug Administration [Internet]. Highlights of prescrib-ing information: INVOKANA®; 2018 cited 2019 Jan 10. Availablefrom: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf

26. Heerspink HJL, Kosiborod M, Inzucchi SE, et al. Renoprotectiveeffects of sodium-glucose cotransporter-2 inhibitors. Kidney Int.2018;94:26–39.

27. Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reab-sorption: a novel strategy for achieving glucose control in type 2diabetes mellitus. Endocr Pract. 2008;14:782–790.

28. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys inglucose homeostasis: a new path towards normalizing glycaemia.Diabetes Obes Metab. 2012;14:5–14.

29. Vallon V, Thomson SC. Targeting renal glucose reabsorption totreat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.Diabetologia. 2017;60:215–225.

30. Wang MY, Yu X, Lee Y, et al. Dapagliflozin suppresses glucagonsignaling in rodent models of diabetes. Proc Natl Acad Sci USA.2017;114:6611–6616.

31. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucosecotransporter 2 inhibitors for type 2 diabetes: a systematic reviewand meta-analysis. Ann Intern Med. 2013;159:262–274.

32. Vallon V. The mechanisms and therapeutic potential of SGLT2inhibitors in diabetes mellitus. Annu Rev Med.2015;66:255–270.

33. Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical useof SGLT2 inhibitors in patients with type 2 diabetes mellitus andchronic kidney disease. Clin Pharmacokinet. 2015;54:691–708.

34. Scheen AJ. Pharmacokinetic and pharmacodynamic profile ofempagliflozin, a sodium glucose co-transporter 2 inhibitor. ClinPharmacokinet. 2014;53:213–225.

35. Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokineticsand pharmacodynamics of dapagliflozin, a selective inhibitor ofsodium-glucose co-transporter type 2. Clin Pharmacokinet.2014;53:17–27.

36. Lamos EM, Younk LM, Davis SN. Canagliflozin, an inhibitor ofsodium-glucose cotransporter 2, for the treatment of type 2 dia-betes mellitus. Expert Opin Drug Metab Toxicol. 2013;9:763–775.

37. Levey AS, de Jong PE, Coresh J, et al. The definition, classification,and prognosis of chronic kidney disease: a KDIGO controversiesconference report. Kidney Int. 2011;80:17–28.

38. Zhang L, Zhang M, Lv Q, et al. Efficacy and safety ofsodium-glucose cotransporter 2 inhibitors in patients with type 2diabetes and moderate renal function impairment: a systematicreview and meta-analysis. Diabetes Res Clin Pract.2018;140:295–303.

39. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patientswith type 2 diabetes and moderate renal impairment shows thatdapagliflozin reduces weight and blood pressure but does notimprove glycemic control. Kidney Int. 2014;85:962–971.

40. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozinover 52 weeks in patients with type 2 diabetes mellitus and chronickidney disease. Diabetes Obes Metab. 2014;16:1016–1027.

41. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety ofempagliflozin added to existing antidiabetes treatment in patientswith type 2 diabetes and chronic kidney disease: a randomised,

8 J. A. DAVIDSON

double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol.2014;2:369–384.

42. Grunberger G, Camp S, Johnson J, et al. Ertugliflozin in patientswith stage 3 chronic kidney disease and type 2 diabetes mellitus:the VERTIS RENAL randomized study. Diabetes Ther. 2018;9:49–66.

43. US Food and Drug Administration [Internet]. Risk evaluation andmitigation strategies (REMS) review: NDA 202293 (dapagliflozintablets, 5 and 10 mg); 2011 cited 2018 Jul 5. Available from:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000RiskR.pdf

44. US Food and Drug Administration [Internet]. Risk evaluation andmitigation strategies (REMS) review: NDA 204042 (canagliflozintablets, 100 and 300 mg); 2013 cited 2018 Jul 5. Available from:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000RiskR.pdf

45. US Food and Drug Administration [Internet]. FDA drug safetycommunication: FDA strengthens kidney warnings for diabetesmedicines canagliflozin (Invokana, Invokamet) and dapagliflozin(Farxiga, Xigduo XR); 2016 cited 2018 Jul 31. Available from:https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm

46. Seidu S, Kunutsor SK, Cos X, et al. SGLT2 inhibitors and renaloutcomes in type 2 diabetes with or without renal impairment:a systematic review and meta-analysis. Prim Care Diabetes.2018;12:265–283.

47. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagli-flozin versus glimepiride in patients with type 2 diabetes inade-quately controlled with metformin (CANTATA-SU): 52 week resultsfrom a randomised, double-blind, phase 3 non-inferiority trial.Lancet. 2013;382:941–950.

48. Takashima H, Yoshida Y, Nagura C, et al. Renoprotective effects ofcanagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2diabetes patients with chronic kidney disease: a randomizedopen-label prospective trial. Diab Vasc Dis Res. 2018;15:469–472.

49. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamiceffect of sodium-glucose cotransporter 2 inhibition in patients withtype 1 diabetes mellitus. Circulation. 2014;129:587–597.

50. Ruggenenti P, Porrini EL, Gaspari F, et al. Glomerular hyperfiltrationand renal disease progression in type 2 diabetes. Diabetes Care.2012;35:2061–2068.

51. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascularoutcomes, and mortality in type 2 diabetes. N Engl J Med.2015;373:2117–2128.

52. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progres-sion of kidney disease in type 2 diabetes. N Engl J Med.2016;375:323–334.

53. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovas-cular and renal events in type 2 diabetes. N Engl J Med.2017;377:644–657.

54. Perkovic V, Zeeuw D, Mahaffey KW, et al. Canagliflozin and renaloutcomes in type 2 diabetes: results from the CANVAS programrandomised clinical trials. Lancet Diabetes Endocrinol.2018;6:691–704.

55. Cannon CP, McGuire DK, Pratley R, et al. Design and baselinecharacteristics of the eValuation of ERTugliflozin effIcacy and safetycardiovascular outcomes trial (VERTIS-CV). Am Heart J.2018;206:11–23.

56. US Food and Drug Administration [Internet]. FDA news release:FDA approves Jardiance to reduce cardiovascular death in adultswith type 2 diabetes; 2016 cited 2017 Mar 8. Available from:h t t p s : / / w w w . f d a . g o v / N e w s E v e n t s / N e w s r o o m /PressAnnouncements/ucm531517.htm

57. Wanner C, Inzucchi SE, Zinman B. Empagliflozin and progression ofkidney disease in type 2 diabetes. N Engl J Med.2016;375:1801–1802.

58. Verma S, Mazer CD, Fitchett D, et al. Empagliflozin reduces cardio-vascular events, mortality and renal events in participants withtype 2 diabetes after coronary artery bypass graft surgery:

subanalysis of the EMPA-REG OUTCOME® randomised trial.Diabetologia. 2018;61:1712–1723.

59. Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomesand safety of empagliflozin in patients with type 2 diabetes melli-tus and peripheral artery disease: a subanalysis of EMPA-REGOUTCOME. Circulation. 2018;137:405–407.

60. Wanner C, Heerspink HJL, Zinman B, et al. Empagliflozin and kidneyfunction decline in patients with type 2 diabetes: a slope analysisfrom the EMPA-REG OUTCOME trial. J Am Soc Nephrol.2018;29:2755–2769.

61. Mordi NA, Mordi IR, Singh JS, et al. Renal and cardiovascular effectsof sodium-glucose cotransporter 2 (SGLT2) inhibition in combina-tion with loop diuretics in diabetic patients with chronic heartfailure (RECEDE-CHF): protocol for a randomised controlleddouble-blind cross-over trial. BMJ Open. 2017;7:e018097.

62. Rastogi A, Bhansali A. SGLT2 inhibitors through the windows ofEMPA-REG and CANVAS trials: a review. Diabetes Ther.2017;8:1245–1251.

63. Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal out-comes with canagliflozin according to baseline kidney function:data from the CANVAS Program. Circulation. 2018;138:1537–1550.

64. Fioretto P, Stefansson BV, Johnsson E, et al. Dapagliflozin reducesalbuminuria over 2 years in patients with type 2 diabetes mellitusand renal impairment. Diabetologia. 2016;59:2036–2039.

65. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascularoutcomes in type 2 diabetes. N Engl J Med. 2018. Epub ahead ofprint. DOI:10.1056/NEJMoa1812389.

66. AstraZeneca [Internet]. Study to evaluate the effect of dapagliflozinon the incidence of worsening heart failure or cardiovascular deathin patients with chronic heart failure (Dapa-HF). ClinicalTrials.govrecord: NCT03036124; 2018 cited 2018 Jul 31. Available from:https : //c l in icaltr ia ls .gov/ct2/show/NCT03036124?term=NCT03036124

67. Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozinon the urinary albumin-to-creatinine ratio in patients with type 2diabetes and established cardiovascular disease: an exploratoryanalysis from the EMPA-REG OUTCOME randomised,placebo-controlled trial. Lancet Diabetes Endocrinol.2017;5:610–621.

68. Hung SC, Kuo KL, Peng CH, et al. Volume overload correlates withcardiovascular risk factors in patients with chronic kidney disease.Kidney Int. 2014;85:703–709.

69. Ceriello A, Genovese S, Mannucci E, et al. Glucagon and heart intype 2 diabetes: new perspectives. Cardiovasc Diabetol. 2016.DOI:10.1186/s12933-016-0440-3.

70. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empa-gliflozin on arterial stiffness and heart rate variability in subjectswith uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol.2014. DOI:10.1186/1475-2840-13-28.

71. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin onblood pressure and markers of arterial stiffness and vascular resis-tance in patients with type 2 diabetes. Diabetes Obes Metab.2015;17:1180–1193.

72. Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin aglucose-regulating drug with diuretic properties in subjects withtype 2 diabetes. Diabetes Obes Metab. 2013;15:853–862.

73. Jardine MJ, Mahaffey KW, Neal B, et al. The canagliflozin and renalendpoints in diabetes with established nephropathy clinical eva-luation (CREDENCE) study rationale, design, and baselinecharacteristics. Am J Nephrol. 2017;46:462–472.

74. Janssen Pharmaceuticals Inc. [Internet]. Phase 3 CREDENCE renaloutcomes trial of INVOKANA® (canagliflozin) is being stopped earlyfor positive efficacy findings; 2018 cited 2018 Jul 30. Available from:https://www.janssen.com/phase-3-credence-renal-outcomes-trial-invokanar-canagliflozin-being-stopped-early-positive-efficacy

75. AstraZeneca [Internet]. A study to evaluate the effect of dapagli-flozin with and without saxagliptin on albuminuria, and to

POSTGRADUATE MEDICINE 9

investigate the effect of dapagliflozin and saxagliptin on HbA1c inpatients with type 2 diabetes and CKD. ClinicalTrials.gov record:NCT02547935; 2018 cited 2018 Jul 31. Available from: https://clinicaltrials.gov/ct2/show/NCT02547935?term=NCT02547935

76. AstraZeneca [Internet]. A study to evaluate the effect of dapagliflozinon renal outcomes and cardiovascular mortality in patients withchronic kidney disease (Dapa-CKD). ClinicalTrials.gov record:NCT03036150; 2018 cited 2018 Jul 31. Available from: https://clinicaltrials.gov/ct2/show/NCT03036150?term=NCT03036150

77. Boehringer Ingelheim [Internet]. Empagliflozin outcome trial inpatients with chronic heart failure with reduced ejection fraction(EMPEROR-Reduced). ClinicalTrials.gov record: NCT03057977; 2018cited 2018 Jul 31. Available from: https://clinicaltrials.gov/ct2/show/NCT03057977?term=NCT03057977

78. Boehringer Ingelheim [Internet]. Empagliflozin outcome trial inpatients with chronic heart failure with preserved ejection fraction(EMPEROR-Preserved). ClinicalTrials.gov record: NCT03057951; 2018cited 2018 Jul 31. Available from: https://clinicaltrials.gov/ct2/show/NCT03057951?term=NCT03057951

79. Boehringer Ingelheim [Internet]. Boehringer Ingelheim and Lillyannounce an academic collaboration with University of Oxford

to investigate the effects of empagliflozin in people with chronickidney disease; 2018 cited 2018 Apr 16. Available from: https://www.boehringer-ingelheim.com/EMPA-KIDNEY

80. Boehringer Ingelheim [Internet]. EMPA-KIDNEY (the study ofheart and kidney protection with empagliflozin). ClinicalTrials.gov record: NCT03594110; 2018 cited 2018 Jul 31. Availablef rom: ht tps : / /www.c l in ica l t r ia l s .gov/ct2/show/record/NCT03594110?view=record

81. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statementby the american association of clinical endocrinologists andAmerican College of endocrinology on the comprehensive type 2diabetes management algorithm - 2018 executive summary.Endocr Pract. 2018;24:91–120.

82. American Diabetes Association. Microvascular complications andfoot care: standards of medical care in diabetes - 2019. DiabetesCare. 2019;42:S124–S138.

83. Weber MA, Mansfield TA, Cain VA, et al. Blood pressure and glycaemiceffects of dapagliflozin versus placebo in patients with type 2 diabeteson combination antihypertensive therapy: a randomised, double-blind,placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol.2016;4:211–220.

10 J. A. DAVIDSON