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Sodium glucose cotransporter-2 inhibitors protect the cardiorenal axis: Update on recent mechanistic insights related to kidney physiology

  • Author Footnotes
    1 These authors contributed equally to this work.
    Charlotte C. van Ruiten
    Correspondence
    Corresponding author.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Anne C. Hesp
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland
    Search for articles by this author
  • Daniël H. van Raalte
    Affiliations
    Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland

    Department of Vascular Medicine Amsterdam University Medical Center, Location VU University Medical Center, Amsterdam, the Netherland
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:April 09, 2022DOI:https://doi.org/10.1016/j.ejim.2022.03.031

      Highlights

      • SGLT2 inhibitors are important in the treatment of type 2 diabetes, chronic kidney disease and heart failure.
      • SGLT2 inhibitors improve cardiovascular outcomes and end-stage kidney disease.
      • This review describes the mechanisms by which SGLT2 inhibitors improve kidney outcomes.
      • This review describes the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors.

      Abstract

      Sodium glucose cotransporter-2 (SGLT2) inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. SGLT2 inhibitors lower glucose levels by inducing glycosuria. In addition, SGLT2 inhibitors improve cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but remain poorly understood.
      In this review, we first summarize recent trial evidence and subsequently focus on (1) the mechanisms by which SGLT2 inhibitors improve kidney outcomes and (2) the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors.

      Keywords

      Abbreviations:

      DKD (Diabetic kidney disease), T2D (Type 2 diabetes), ESKD (End-stage kidney disease), RAAS (renin angiotensin aldosterone system), CVD (cardiovascular disease), SGLT2 (Sodium-glucose contransporter 2), GFR (glomerular filtration rate), UACR (urinary albumin-to-creatinine ratio), CVOTs (Cardiovascular outcome trials)

      1. Diabetic kidney disease: a global burden

      Diabetic kidney disease (DKD) is a common complication of diabetes, affecting ∼ 40% of patients with type 2 diabetes (T2D) [
      • Alicic R.Z.
      • Rooney M.T.
      • Tuttle K.R.
      Diabetic kidney disease: challenges, progress, and possibilities.
      ]. DKD is characterized by increased urinary albumin excretion and/or impaired glomerular filtration rate (GFR) [
      • National Kidney F.
      KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
      ]. DKD is a multifactorial disease, and obesity, systemic and glomerular hypertension, dyslipidemia, and smoking are well-known contributing factors on top of hyperglycemia. Current therapies to prevent or slow the progression of DKD are based on reducing these kidney risk factors, such as blood glucose and blood pressure control, the latter by blockers of the renin angiotensin aldosterone system (RAAS) [
      • Muskiet M.H.
      • Tonneijck L.
      • Smits M.M.
      • Kramer M.H.
      • Heerspink H.J.
      • van Raalte D.H.
      Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.
      ]. However, those therapies are only partially effective and the residual risk to develop end-stage kidney disease (ESKD) remains high [
      • Alicic R.Z.
      • Rooney M.T.
      • Tuttle K.R.
      Diabetic kidney disease: challenges, progress, and possibilities.
      ]. As such, the prevalence of DKD has become the leading cause for ESKD and kidney replacement therapy worldwide [
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      ]. The number of DKD-related ESKD is lower than expected based on DKD prevalence, which is due to the fact that DKD very strongly increases cardiovascular disease (CVD) and cardiovascular death [
      • Afkarian M.
      • Sachs M.C.
      • Kestenbaum B.
      • Hirsch I.B.
      • Tuttle K.R.
      • Himmelfarb J.
      • et al.
      Kidney disease and increased mortality risk in type 2 diabetes.
      ]. These facts emphasize the unmet medical need to reduce the kidney burden in people living with diabetes. However, previous studies have shown that improvement in kidney outcomes has proven difficult, with studies showing either no benefit or increased side effects [
      • Mann J.F.
      • Schmieder R.E.
      • McQueen M.
      • Dyal L.
      • Schumacher H.
      • Pogue J.
      • et al.
      Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
      ,
      • Lewis E.J.
      • Lewis J.B.
      • Greene T.
      • Hunsicker L.G.
      • Berl T.
      • Pohl M.A.
      • et al.
      Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.
      ,
      • Packham D.K.
      • Wolfe R.
      • Reutens A.T.
      • Berl T.
      • Heerspink H.L.
      • Rohde R.
      • et al.
      Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy.
      ,
      • de Zeeuw D.
      • Akizawa T.
      • Audhya P.
      • Bakris G.L.
      • Chin M.
      • Christ-Schmidt H.
      • et al.
      Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
      ].

      2. SGLT2 inhibition: novel glucose-lowering agents

      Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of blood glucose-lowering drugs developed for the management of hyperglycemia in people with T2D. Under normoglycemic conditions, all tubular glucose is reabsorbed preventing urinary glucose loss. SGLTs in the proximal tubule are responsible for glucose reabsorption. SGLT2 reabsorbs ∼90% of the filtered glucose [low-affinity, high-capacity transporter], whereas the remaining ∼10% is reabsorbed by the more distal located SGLT1 [high-affinity, low-capacity transporter] [
      • Wilding J.P.
      The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors.
      ]. When plasma glucose levels rise above the maximal reabsorptive capacity, glycosuria occurs. In T2D, the maximum reabsorptive capacity for glucose is increased, and the threshold for plasma glucose at which glycosuria occurs is also increased [
      • DeFronzo R.A.
      • Hompesch M.
      • Kasichayanula S.
      • Liu X.
      • Hong Y.
      • Pfister M.
      • et al.
      Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes.
      ], which is likely due to SGLT2 upregulation. SGLT2 inhibitors reduce plasma glucose by directly blocking sodium-coupled glucose reabsorption, in an insulin independent fashion. Glucose lowering efficacy is directly related to the filtered glucose load, and therefore related to the degree of hyperglycemia and glomerular filtration rate (GFR) [
      • Yale J.F.
      • Bakris G.
      • Cariou B.
      • Yue D.
      • David-Neto E.
      • Xi L.
      • et al.
      Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease.
      ,
      • Barnett A.H.
      • Mithal A.
      • Manassie J.
      • Jones R.
      • Rattunde H.
      • Woerle H.J.
      • et al.
      Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial.
      ]. Because of this mechanism and the fact that SGLT2 inhibitors do not increase insulin secretion, SGLT2 inhibitors usually do not cause hypoglycemia. In addition to lowering of blood glucose concentrations, SGLT2 inhibitors improve several kidney risk factors which, remarkably, is independent of GFR and degree of hyperglycemia. As such, SGLT2 inhibitors induce weight loss (2, 3 kg), reduce systolic blood pressure (2, 3 mmHg), reduce plasma uric acid concentrations, reduce markers for systemic low-grade inflammation [
      • Bonnet F.
      • Scheen A.J.
      Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease.
      ], and lower urinary albumin‐to‐creatinine ratio (UACR) [
      • Petrykiv S.
      • Sjostrom C.D.
      • Greasley P.J.
      • Xu J.
      • Persson F.
      • Heerspink H.J.L.
      Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function.
      ], which will be discussed below. The most important side effect of SGLT2 inhibition is the occurrence of genital mycotic infections which can be treated with topical antimycotic agents. Less frequent side effects include dehydration and hypotension, particularly occurring in elderly and usually in combination with diuretic therapy. Ketoacidosis has been reported in people with low endogenous insulin secretion [
      • Rosenstock J.
      • Ferrannini E.
      Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.
      ] (Fig. 1).
      Fig 1
      Fig. 1Various hypotheses have been put forward to explain the beneficial effects of SGLT2 inhibition on kidney outcomes. The central hypothesis relies on the restoration of aberrant kidney hemodynamics, which alleviates the kidney from hyperfiltration-induced hypoxia an barotrauma. An increase in EPO levels and ketone production can also improve kidney oxygenation. Additionally, small systemic effects including a reduction in HbA1c, uric acid, weight, and blood pressure can further contribute to kidney preservation.

      3. SGLT2 inhibition: effects on hard CV and kidney outcomes

      While clinicians have responded enthusiastically to this new glucose-lowering drug class, it was the outcome of large-sized outcome trials with SGLT2 inhibitors that has changed guidelines. Although SGLT2 improve cardiovascular and kidney risk factors, the improvements in cardiovascular and renal outcomes by SGLT2 inhibitors have nevertheless been a surprise to the scientific community and remain mechanistically incompletely understood as detailed below.
      Three cardiovascular outcome trials (CVOTs) EMPA‐REG OUTCOME (empagliflozin) [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ], CANVAS Program (canagliflozin) [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ], and DECLARE‐TIMI 58 (dapagliflozin) [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ] reported a reduction in major cardiovascular events (3-MACE) and CV mortality and/or in the risk of hospitalization for heart failure in patients with T2D and at high risk of CV disease [with most patients having established CVD]. In the most recent CVOT, VERTIS CV (ertugliflozin) [
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • et al.
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ], only showed non inferiority for the primary 3-MACE outcome, but consistently with the results of the other CVOTs, reduced the rates of hospitalization for heart failure (hazard ratio (HR), 0.70; 95% CI, 0.45–0.90). In addition, the first thee large CVOTs, SGLT2 inhibition reduced the renal composite outcome (worsening of renal function, end-stage renal disease, or renal death) by 44% in people with established atherosclerotic disease (HR, 0.56; 95% CI, 0.47–0.67; P < 0.0001), and by 46% in people with multiple CV risk factors (HR, 0.54; 95% CI, 0.42‐0.71;  P < 0 .0001) [
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Bonaca M.P.
      • et al.
      SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      ]. In VERTIS CV, the effect of ertugliflozin on the renal composite outcome did not reach statistical significance (HR, 0.81, 95% CI 0.63–1.04) (Table 1) [
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • et al.
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ,
      • Cherney D.Z.I.
      • Charbonnel B.
      • Cosentino F.
      • Dagogo-Jack S.
      • McGuire D.K.
      • Pratley R.
      • et al.
      Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial.
      ]. However, the chosen threshold for eGFR decline was greater (≥ 57%, based on doubling of serum creatinine) than in the other three CVOTs (≥ 30–50%). If, similar to other CVOT results, the definition of kidney function decline was set as > 40%, ertugliflozin treatment in VERTIS CV significantly reduced kidney function loss and the renal composite consistently as with the other three CVOTs [
      • Cherney D.Z.I.
      • Charbonnel B.
      • Cosentino F.
      • Dagogo-Jack S.
      • McGuire D.K.
      • Pratley R.
      • et al.
      Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial.
      ]. The indicated CVOTs however, were not powered to study renal outcomes and the percentage of people with chronic kidney disease (CKD) were relatively low. In addition, surrogate renal outcomes were measured in these studies, instead of hard renal outcomes. Thus, dedicated kidney trials were initiated. In the CREDENCE trial [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ], 4401 T2D patients with mean HbA1c of 8.3 (± 1.3) %, eGFR of 56.2 (± 18.2) ml/min/1.73 m2, with macroalbuminuria (median ACR 927 mg/g), all on a background therapy of a stable dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARB), were randomized to canagliflozin or placebo. Approximately 60% of included patients had an eGFR 30 to <60 ml/min/1.73 m2. The primary composite outcome (kidney failure, doubling of serum creatinine, or renal or cardiovascular death) was improved with a relative risk reduction of 29% (HR, 0.70; 95% CI, 0.59–0.82; P < 0.001) and corresponding number needed to treat (NNT) of 23 for the duration of the trial (Table 1) [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]. The secondary composite outcome (kidney failure, doubling of serum creatinine, or renal death) was improved with a relative risk reduction of 34% (HR, 0.66; 95% CI, 0.53–0.81; P < 0.001) and corresponding NNT of 31 for the duration of the trial (Table 1) [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]. Beside the risk reduction of the composite outcome, the hard renal outcome of ESKD was also improved with a relative risk reduction of 31% (HR, 0.68; 95% CI, 0.54–0.86; P 0.002) and corresponding NNT of 46. In DAPA-CKD (dapagliflozin), 4304 patients, with (n = 2906) or without T2D, with a mean eGFR of 43.1 ± 12.4 ml/min/1.73 m2, and with macroalbuminuria (median ACR 949 mg/g), on a stable background therapy with ACE inhibitors or ARBs, were included. DAPA-CKD in contrast to CREDENCE and the other CVOTs, also included patients with an eGFR below 30 ml/min/1.73 m2 (14.5%) and included people with CKD without diabetes. In DAPA-CKD [
      • Heerspink H.J.L.
      • Stefansson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ], dapagliflozin improved the renal composite outcome (sustained ≥ 50% eGFR decline, end stage kidney disease, or death from renal or cardiovascular causes) with a relative risk reduction of 39% (HR, 0.61; 95% CI, 0.51–0.72, P < 0.001) and corresponding NNT of 19 (Table 1), independent of the presence of diabetes [
      • Heerspink H.J.L.
      • Stefansson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ]. The risk reduction of dapagliflozin of the primary composite outcome was generally consistent across prespecified including baseline eGFR. The secondary composite (sustained ≥ 50% eGFR decline, end stage kidney disease, or renal death) was improved with a relative risk reduction of 43 % (HR, 0.56; 95% CI, 0.45–0.68, P < 0.001) and corresponding NNT 21 for the duration of the trial (Table 1). In addition, the hard renal outcome of ESKD was improved with a relative risk reduction of 34% (HR, 0.64; 95% CI, 0.50–0.82) and corresponding NNT of 42 for the duration of the study. Altogether, confirming that the kidney protective effects of SGLT2 inhibitors extend to a broad population of persons with CKD with and without T2D. Moreover, the ongoing EMPA-KIDNEY trial (NCT03594110) includes beside patients with an eGFR ≥45 to <90 mL/min/1.73 m² and macroalbuminuria, also patients with an eGFR ≥20 to <45 mL/min/1.73 m² without macroalbuminuria. This will elucidate if the kidney protective effects of empagliflozin will also apply for this specific population.
      Table 1Renal outcomes in large trials with SGLT2 inhibitors.
      TrialYear of completionSGLT2 inhibitorPatient populationNumber of patientsMedian follow-up (years)Renal outcomeHazard ratio (95% CI)Number needed to treat
      EMPA-REG OUTCOME2015EmpagliflozinT2D with established CVD70203.1Secondary: composite of macroalbuminuria, dSCr, ESKD, renal death0.61 (0.53–0.70)16
      CANVAS Program2017CanagliflozinT2D with or at high risk for atherosclerotic CVD10,1423.6Secondary: composite of dSCr, ESKD, new onset macroalbuminuria, renal death0.58 (0.50–0.67)83 *
      DECLARE-TIMI 582018DapagliflozinT2D with or at high risk for atherosclerotic CVD17,1604.2Secondary: composite of ≥40% decrease in eGFR to <60 mL/min per 1.73 m2, ESKD, renal death0.53 (0.43-0.66)77
      VERTIS CV2020ErtugliflozinT2D and atherosclerotic CVD82463.0Secondary: composite of dSCr, ESKD, renal death0.81 (0.63–1.04)134 **
      CREDENCE trial2019CanagliflozinT2D and nephropathy

      eGFR 30 to 90 mL/min/1.73m² + UACr >300-5000
      44012.6Primary: composite of composite of kidney failure, dSCr, renal death, cardiovascular death

      Secondary: composite of kidney failure, dSCr, renal death
      0.70 (0.59–0.82)

      0.66 (0.53–0.81)


      23

      31

      DAPA-CKD2020DapagliflozinChronic Kidney Disease with or

      without T2D

      eGFR 27 to 75 mL/min/1.73 m² + UACr 200-5000
      4304

      2.4Primary composite of sustained ≥ 50% eGFR decline, ESKD, renal and cardiovascular death

      Secondary composite of sustained ≥ 50% eGFR decline, ESKD, renal death

      0.61 (0.51–0.72)

      0.56 (0.45–0.68)


      19

      21

      EMPA-KIDNEYOngoing

      (estimated completion Dec. 2022)
      Empagliflozin- eGFR ≥45 to <90 mL/min/1.73 m² + macroalbuminuria

      - eGFR ≥20 to <45 mL/min/1.73 m² without macroalbuminuria
      NANAComposite of ESKD, a sustained decline in eGFR to <10 mL/min/1.73 m², renal death, or a sustained decline of ≥40% in eGFR from randomization), cardiovascular deathNANA
      Relative Risk Reductions are calculated per 1000 patient years (or 100 patient years for DAPA-CKD). The number of participants needed to be treated (NNT) to prevent one outcome event are calculated for the duration of the study, except for * CANVAS Program which is calculated per 1000 patient years. In CANVAS Program the renal composite without new onset of macroalbuminuria was also significant (HR 0.53, 95% CI 0.33–0.84). ** In VERTIC CV, the chosen threshold for eGFR decline was ≥ 57%, based on doubling of serum creatinine, which is larger than in the other three CVOTs (≥ 30-50%). If the definition of kidney function decline was set as > 40%, ertugliflozin treatment in VERTIS CV significantly reduced kidney function loss and the renal composite consistently as with the other three CVOTs [
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • et al.
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ,
      • Cherney D.Z.I.
      • Charbonnel B.
      • Cosentino F.
      • Dagogo-Jack S.
      • McGuire D.K.
      • Pratley R.
      • et al.
      Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial.
      ]. 95 % confidence intervals are calculated based on [PMID12201860] [PMID9804726]. Abbreviations: CVD, cardiovascular disease; ESKD, End Stage Kidney Disease; dSCr, doubling of serum Creatinin; UACR, urinary albumin to creatinin ratio.
      Dedicated trials have also been conducted to confirm the effects of SGLT2 inhibition on heart failure outcomes. Thus, three large studies have been reported in people with clinically established heart failure with either preserved [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      ] or reduced ejection fraction [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Kober L.
      • Kosiborod M.N.
      • Martinez F.A.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ]. Importantly, the majority of the patients were treated according to guidelines with RAAS blocker, beta-blocker and mineralocorticoid receptor antagonist. In DAPA-HF, dapagliflozin improved the primary composite outcome (worsening of heart failure, death from cardiovascular causes) with a relative risk reduction of 26% (HR, 0.74; 95% CI 0.65–0.86) and corresponding NNT of 20 for the duration of the study [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Kober L.
      • Kosiborod M.N.
      • Martinez F.A.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]. In EMPEROR-Reduced, empagliflozin reduced the primary composite (cardiovascular death or hospitalizations for heart failure) with a relative risk reduction of 25% (HR, 0.75; 95% CI, 0.65–0.86) and corresponding NNT of 19 [
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ]. In EMPEROR-Preserved, irrespective of the presence of diabetes, empagliflozin reduced the primary composite (cardiovascular death or hospitalizations for heart failure) with a relative risk reduction of 21% (HR, 0.79; 95% CI, 0.69–0.90) and corresponding NNT of 31 [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      ]. This was the first study in which a drug improved heart failure in patients with a preserved ejection fraction (HFpEF) [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      ]. Kidney outcomes (eGFR slope, or composite kidney outcomes (sustained decline in the eGFR of ≥ 40–50%, ESKD, sustained dialysis, renal transplantation, or renal death)) remained similar or were also improved in these trials [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Kober L.
      • Kosiborod M.N.
      • Martinez F.A.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ].

      4. Mechanisms of kidney protection

      The central hypothesis of direct kidney hemodynamic effects
      Various hypotheses have been put forward to explain the beneficial effects of SGLT2 inhibition on kidney outcomes. The central hypothesis relies on the correction of aberrant glomerular hemodynamic function. Early in the course of diabetes, a supraphysiological increase in GFR, termed glomerular hyperfiltration, has been reported and predisposes to diabetic kidney disease [
      • Tonneijck L.
      • Muskiet M.H.
      • Smits M.M.
      • van Bommel E.J.
      • Heerspink H.J.
      • van Raalte D.H.
      • et al.
      Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.
      ]. This adverse hemodynamic profile is thought to be a consequence of an imbalance in vasoactive factors, coined “the vascular theory“, or abnormal interactions between the tubule and glomerulus following hyperglycemia-induced SGLT2 upregulation, termed “the tubular theory“. According to the latter, the upregulation of SGLT2 receptors increases the reabsorption of both glucose and sodium in the proximal tubule. Subsequently, a decreased sodium/chloride load is presented to the macula densa which interprets this as inadequate kidney perfusion. GFR is therefore maladaptively increased via repression of the tubuloglomerulofeedback (TGF) system through afferent (preglomerular) vasodilation and efferent (postglomerular) vasoconstriction. This increment in GFR can be detrimental to the glomerulus through increased pressure and associated barotrauma, and through excessive kidney oxygen requirement associated with the increased workload associated with hyperfiltration.
      SGLT2 inhibition has been shown to restore kidney hemodynamic function by inhibition of sodium reabsorption via SGLT2 as well as via the functionally linked Na+/H+ exchanger (NHE) [
      • Vallon V.
      • Thomson S.C.
      Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.
      ]. Indeed, a remarkable feature of SGLT2 inhibition is an acute decrease in eGFR independent of glycemic effects, as seen in both experimental settings [
      • van Bommel E.J.M.
      • Muskiet M.H.A.
      • van Baar M.J.B.
      • Tonneijck L.
      • Smits M.M.
      • Emanuel A.L.
      • et al.
      The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.
      ] as well as in the large cohorts of patients of the CVOTs. The observed eGFR drop is reversible after cessation of SGLT2 inhibition and therefore indicates a direct kidney hemodynamic effect. The exact mechanisms underlying the decline however seem to differ according to diabetes etiology. In type 1 diabetes, empagliflozin has been reported to reduce measured GFR during clamped euglycemia in young lean type 1 diabetic patients whom exhibited hyperfiltration (GFR ≥135 mL/min/1.73 m2). In combination with reduced effective renal plasma flow (ERPF) and increased renal vascular resistance (RVR), it was observed that an increase in afferent arteriolar vasoconstriction underlied the GFR drop in this group [
      • Cherney D.Z.
      • Perkins B.A.
      • Soleymanlou N.
      • Maione M.
      • Lai V.
      • Lee A.
      • et al.
      Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
      ]. However, this hyperfiltering group was post-hoc selected and may not represent people with type 1 diabetes without hyperfiltration and people with type 2 diabetes. Indeed, in the indicated study, no such effects were observed in people with type 1 diabetes that did not hyperfilter. Also, in a population with on average middle-aged and overweight type 2 diabetes patients, the same GFR reduction following dapagliflozin treatment during clamped euglycemia was observed, however without changes in RVR, which rather indicates efferent arteriolar vasodilation [
      • van Bommel E.J.M.
      • Muskiet M.H.A.
      • van Baar M.J.B.
      • Tonneijck L.
      • Smits M.M.
      • Emanuel A.L.
      • et al.
      The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.
      ,
      • van Bommel E.J.M.
      • Lytvyn Y.
      • Perkins B.A.
      • Soleymanlou N.
      • Fagan N.M.
      • Koitka-Weber A.
      • et al.
      Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function.
      ]. This finding was more recently confirmed by another group showing that in people with T2D, empagliflozin-linagliptin combination therapy reduced GFR by inducing postglomerular vasodilation [
      • Ott C.
      • Jung S.
      • Korn M.
      • Kannenkeril D.
      • Bosch A.
      • Kolwelter J.
      • et al.
      Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine.
      ]. These studies underline that an initial GFR reduction following SGLT2 inhibition is observed across a broad range of individuals, although it appears of different underlying physiology.

      4.1 Potential other renoprotective mechanisms

      Another prominent hypothesis on the renoprotective effect of SGLT2 inhibition indicates an amelioration of kidney hypoxia following SGLT2 inhibition. Sodium reabsorption is an ATP-dependent process and the primary source of oxygen consumption by the kidney [
      • Hesp A.C.
      • Schaub J.A.
      • Prasad P.V.
      • Vallon V.
      • Laverman G.D.
      • Bjornstad P.
      • et al.
      The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?.
      ]. Both the upregulation of SGLT2s as well as glomerular hyperfiltration increase oxygen consumption, which leads to kidney tissue hypoxia when the increase in oxygen demand is not matched by an increase oxygen supply. The “chronic hypoxia hypothesis” states that this process leads to a vicious cycle of hypoxic damage of glomerular capillaries, downstream ischemia, and kidney tissue necrosis [
      • Hesp A.C.
      • Schaub J.A.
      • Prasad P.V.
      • Vallon V.
      • Laverman G.D.
      • Bjornstad P.
      • et al.
      The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?.
      ,
      • Fine L.G.
      • Norman J.T.
      Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.
      ]. SGLT2 inhibition may be a two-edge sword in this respect, as it alleviates oxygen demand by lowering GFR and proximal sodium reabsorption, while it may improve oxygenation through an increase in erythropoietin (EPO) levels and by driving ketone-body production as detailed below.
      The erythropoietic effect of SGLT2 inhibition has been indicated by the increase of hematocrit consistent for all four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) [
      • Sano M.
      • Goto S.
      Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects.
      ]. The proximal sodium reabsorption blockade leads to a downstream shift of sodium reabsorption towards the medullary region [
      • O'Neill J.
      • Fasching A.
      • Pihl L.
      • Patinha D.
      • Franzen S.
      • Palm F.
      Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.
      ]. The subsequent medullary hypoxia increases the production of hypoxia-inducible factor (HIF) which instigates EPO production and results in an increase in hemoglobin production, oxygen delivery, and alleviation of cortical kidney tissue hypoxia. In addition, EPO may contribute to kidney protection by its anti-inflammatory effects [
      • Nairz M.
      • Sonnweber T.
      • Schroll A.
      • Theurl I.
      • Weiss G.
      The pleiotropic effects of erythropoietin in infection and inflammation.
      ]. Clinically, the EPO-induced increment in erythropoiesis was shown to lead to reduced anemia and need for iron preparations in an analysis of the CREDENCE study [
      • Oshima M.
      • Neuen B.L.
      • Jardine M.J.
      • Bakris G.
      • Edwards R.
      • Levin A.
      • et al.
      Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial.
      ]. The differential effects of SGLT2 inhibition on cortical and medullary oxygen availability remains poorly investigated in humans presently.
      Added to its contribution to increased oxygen supply, SGLT2 inhibition may reduce kidney oxygen demand by promotion of ketone body metabolism as an alternative fuel to glucose and free fatty acids. Data supporting the “thrifty substrate hypothesis” demonstrate that an increase of circulating ketone bodies, which are promoted through increased ketogenesis secondary to changes in insulin/glucagon ratio's, offer an oxygen-efficient fuel for ATP production as relatively little oxygen is used to convert ketones to ATP [
      • Ferrannini E.
      • Mark M.
      • Mayoux E.
      CV protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis.
      ]. Again, this theory needs further studies in humans.
      Finally, several other interesting hypotheses have been formulated in recent years with respect to the kidney protective mechanisms of SGLT2 inhibitors, which require future studies. As such, SGLT2 inhibitors may activate the energy sensor SIRT1 (sirtuin-1). SIRT1 may activate factors such as proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mimicking a fasting condition resulting in increased gluconeogenesis and ketogenesis [
      • Packer M.
      Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors.
      ]. Nutrient deprivation sensing has showed several benefits in experimental studies, which has been related to activation of the process of autophagy. Autophagy involves degradation of dysfunction organelles in autolysosomes, thereby improving cellular health and survival [
      • Packer M.
      Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors.
      ]. Metabolic changes related to the energy loss have also been proposed by Marton et al., proposing an aestivation-like response contributing to energy conservation and cellular homeostasis [
      • Marton A.
      • Kaneko T.
      • Kovalik J.P.
      • Yasui A.
      • Nishiyama A.
      • Kitada K.
      • et al.
      Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation.
      ]. Whether these mechanisms contribute to the improved kidney outcomes needs further studies.

      4.2 Systemic effects

      Beside its intrarenal effects, SGLT2 inhibition has been indicated to exert systemic beneficial effects. These have the potential to contribute to kidney protection, although the small changes in these outcomes are unlikely account for the full renoprotective effect. First, the adjusted mean HbA1c-lowering potency of SGLT2- inhibition is approximately 0.7% across different background therapies and compared to placebo [
      • Heerspink H.J.
      • Perkins B.A.
      • Fitchett D.H.
      • Husain M.
      • Cherney D.Z.
      Sodium Glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.
      ], which could reduce kidney glucose toxicity. SGLT2 inhibition also exerts a uric acid lowering effect of 10 to 15%. As serum uric acid levels have been related to kidney disease, possibly by increasing RAAS activity or by induction of endothelial dysfunction and inflammatory cascades [
      • Jalal D.I.
      • Maahs D.M.
      • Hovind P.
      • Nakagawa T.
      Uric acid as a mediator of diabetic nephropathy.
      ], this reduction could lead to kidney function preservation. However, no clinical trial thus far has demonstrated a direct beneficial effect of uric acid lowering on kidney outcomes and the causal relation remains controversial. Next, a body weight reduction of about 1 to 3 kg is likely to benefit the intrarenal milieu by amelioration of glomerular hyperfiltration [
      • Chagnac A.
      • Weinstein T.
      • Herman M.
      • Hirsh J.
      • Gafter U.
      • Ori Y.
      The effects of weight loss on renal function in patients with severe obesity.
      ] and reduction of inflammatory markers and oxidative stress [
      • Ramos L.F.
      • Shintani A.
      • Ikizler T.A.
      • Himmelfarb J.
      Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD.
      ]. Lastly, the reduction in systolic blood pressure which has been observed may contribute to kidney outcomes, independent of weight loss and background antihypertensive therapy [
      • Heerspink H.J.
      • Perkins B.A.
      • Fitchett D.H.
      • Husain M.
      • Cherney D.Z.
      Sodium Glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.
      ,
      • Thomas M.C.
      • Cherney DZI.
      The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.
      ]. The reduction in incoming blood pressure oscillations, especially when beyond the window of autoregulatory control, could contribute to kidney preservation. Nevertheless, given (1) the early onset of kidney benefit and (2) the lack of impressive kidney protective effects of glucose-lowering, weight loss interventions and blood pressure control, it is likely that mitigation of these kidney risk factors play a less important role than the direct kidney effects of SGLT2 inhibitors.

      5. SGLT2 inhibition: changes in kidney physiology driving cardiovascular outcomes?

      As stated above, the beneficial effects of SGLT2 inhibition on 3-MACE as well as heart failure outcomes was largely unexpected. Not surprisingly, the mechanism(s) that drive(s) these CV benefits are uncertain and have led to a wide range of hypotheses that have been reviewed elsewhere (e.g. [
      • Packer M.
      Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors.
      ,
      • Cowie M.R.
      • Fisher M.
      SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control.
      ,
      • Packer M.
      Molecular, cellular, and clinical evidence that sodium-glucose cotransporter 2 inhibitors act as neurohormonal antagonists when used for the treatment of chronic heart failure.
      ]). A central hypothesis is based on SGLT2 inhibitor-induced volume contraction, as mediation analyses from the EMPAREG OUTCOME study showed that hematocrit was the best predictor for CV benefit [
      • Inzucchi S.E.
      • Zinman B.
      • Fitchett D.
      • Wanner C.
      • Ferrannini E.
      • Schumacher M.
      • et al.
      How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial.
      ]. Increased hematocrit has been proposed to serve as a marker for plasma volume. In line, it was shown using radioactively labeled albumin, that dapagliflozin increased plasma volume [
      • Lambers Heerspink H.J.
      • de Zeeuw D.
      • Wie L.
      • Leslie B.
      • List J.
      Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.
      ]. The theory is that this volume contraction is secondary to increased natriuresis. Two earlier studies indeed showed a transient, but small increment in urinary sodium excretion following SGLT2 inhibition, however there was control for dietary sodium intake [
      • Tanaka H.
      • Takano K.
      • Iijima H.
      • Kubo H.
      • Maruyama N.
      • Hashimoto T.
      • et al.
      Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus.
      ,
      • Iijima H.
      • Kifuji T.
      • Maruyama N.
      • Inagaki N.
      Pharmacokinetics, pharmacodynamics, and safety of canagliflozin in japanese patients with type 2 diabetes mellitus.
      ]. In healthy volunteers with a fixed sodium diet (110 mmol/day) dapagliflozin induced a small transient (day 1; 20 mmol) increment in natriuresis, which was much lower than the sodium excretion induced by bumetanide [
      • Wilcox C.S.
      • Shen W.
      • Boulton D.W.
      • Leslie B.R.
      • Griffen S.C.
      Interaction between the sodium-glucose-linked transporter 2 inhibitor dapagliflozin and the loop diuretic bumetanide in normal human subjects.
      ], a drug that is not known to increase hematocrit. A limitation here was uncontrolled fluid intake and low compliance to sodium tablets that can cause nausea and vomiting. In people with heart failure, two studies showed minimal effects of SGLT2 inhibition on markers of sodium homeostasis. Griffin et al. reported increments in fractional sodium excretion (24 h urine not collected, no fixed sodium intake) [
      • Griffin M.
      • Rao V.S.
      • Ivey-Miranda J.
      • Fleming J.
      • Mahoney D.
      • Maulion C.
      • et al.
      Empagliflozin in heart failure: diuretic and cardiorenal effects.
      ], while in contrast no change in 24 h sodium excretion was shown by Mordi et al. In the latter study, an increment in urinary volume was observed, however this is difficult to interpret as sodium and fluid intake were not monitored [
      • Mordi N.A.
      • Mordi I.R.
      • Singh J.S.
      • McCrimmon R.J.
      • Struthers A.D.
      • Lang C.C.
      Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure: the RECEDE-CHF trial.
      ]. In the recent DAPASALT study, people with T2D and normal kidney function were given a standardized diet (150 mmol/day) and urinary volume and natriuresis carefully monitored using multiple 24 h urine collections [
      • Scholtes R.A.
      • Muskiet M.H.A.
      • van Baar M.J.B.
      • Hesp A.C.
      • Greasley P.J.
      • Karlsson C.
      • et al.
      Natriuretic effect of two weeks of dapagliflozin treatment in patients with Type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial.
      ]. Dapagliflozin overall did not change 24 h urine and sodium excretion, although a small increment in sodium excretion was seen in the first day of treatment. Glucose excretion on the other hand was strongly increased while increased fractional lithium excretion confirmed inhibition of proximal tubular function. Plasma volume was not significantly decreased during treatment, but was increased following cessation. Despite these minor effects on natriuresis and plasma volume, systolic blood pressure was reduced by 6 mmHg, indicating that other factors mediate SGLT2 inhibitor-induced blood pressure reduction.
      The kidneys are able to adapt to (drug-induced) changes in tubular physiology enabling them to maintain sodium and water balance. From that point of view, it is unlikely that SGLT2 inhibitors lead to prolonged urinary sodium and water loss. Although there is ongoing inhibition of proximal tubular function and glycosuria, urinary volumes are mostly kept constant through a number of mechanisms. First, SGLT2 inhibitors activate RAAS resulting in distal sodium retention, second, SGLT2 inhibitors reduce free water clearance and increase co-peptin secretion and third, may conserve water through urea metabolism [
      • Marton A.
      • Kaneko T.
      • Kovalik J.P.
      • Yasui A.
      • Nishiyama A.
      • Kitada K.
      • et al.
      Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation.
      ,
      • Eickhoff M.K.
      • Dekkers C.C.J.
      • Kramers B.J.
      • Laverman G.D.
      • Frimodt-Moller M.
      • Jorgensen N.R.
      • et al.
      Effects of dapagliflozin on volume status when added to renin-angiotensin system inhibitors.
      ]. Clinical observations that raise questions marks with volume contraction by SGLT2 inhibitor treatment and its effect on CV outcomes include (1) no influence of baseline eGFR on CV effects [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Heerspink H.J.L.
      • Stefansson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ,
      • Shivakumar O.
      • Sattar N.
      • Wheeler D.C.
      Sodium-glucose cotransporter 2 inhibitor effects on cardiovascular outcomes in chronic kidney disease.
      ] and (2) and the only mildly lower NT-proBNP concentrations that are observed during SGLT2 treatment also seem to play a minor role [
      • Januzzi J.L.
      • Butler J.
      • Jarolim P.
      • Sattar N.
      • Vijapurkar U.
      • Desai M.
      • et al.
      Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes.
      ]. Indeed several other mechanisms have been proposed to underlie the beneficial CV effects of SGLT2 inhibitor treatment, such as mitochondrial dysfunction, reduced oxidative stress, reduced activity of sodium-hydrogen exchanger isoform 3 (NHE3) and altered myocardial substrate metabolism [
      • Packer M.
      Differential pathophysiological mechanisms in heart failure with a reduced or preserved ejection fraction in diabetes.
      ]. An additional interesting observation is that despite reductions in blood pressure and debated hemoconcentration, there is no reciprocal heart rate increment with SGLT2 inhibition. Mechanistically, this may be caused by inhibition of SLGT2 of the sympathetic nervous system as shown in elegant rodent studies [
      • Herat L.Y.
      • Magno A.L.
      • Rudnicka C.
      • Hricova J.
      • Carnagarin R.
      • Ward N.C.
      • et al.
      SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection.
      ]. This may set the SGLT2 drugs apart from conventional diuretics.
      To summarize, the role of changes in kidney sodium handling induced by SGLT2 inhibitors remains enigmatic, in particular its contribution to CV protection that is observed with SGLT2 inhibition. A factor herein is the lack of larger studies that have measured (not estimated) plasma volumes and have conducted rigorous trials where sodium balance is measured across different populations such as heart failure and DKD patients. The reasons why hematocrit is elevated during SGLT2 treatment is currently unclear and could also relate to erythropoiesis as discussed above.

      6. Areas of ongoing research

      Several clinical trials are currently ongoing with respect to SGLT2 inhibition. An important question is how SGLT2 inhibition combines with other (potential) kidney protective agents. In the conducted outcomes trials, SGLT2 inhibitors were initiated on top of RAAS blockade. Therefore, the interaction between these drugs remains poorly studied. Two studies have recently been completed in people with type 1 and type 2 diabetes which investigated the interactions between RAAS blockers and SGLT2 inhibitors [NCT04238702; NCT02632747] (Table 2). In addition, the novel mineralocorticoid receptor antagonist (MRA) finerenone was recently shown in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial, to reduce CKD progression in people with type 2 diabetes [
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • Pitt B.
      • Ruilope L.M.
      • Rossing P.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ]. However, MRA have the side effect of hyperkalemia, limiting their use. In this light, it is interesting to note that SGLT2 inhibitors lower the risk for hyperkalemia, without inducing hypokalemia risk [
      • Neuen B.L.
      • Oshima M.
      • Perkovic V.
      • Agarwal R.
      • Arnott C.
      • Bakris G.
      • et al.
      Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.
      ]. The interaction between finerenone and SGLT2 inhibitors are currently ongoing to assess their combined clinical effects and safety profile.
      Table 2Ongoing clinical trials with SGLT2 inhibition.
      TrialNCT numberPatient populationTrial designInterventionPrimary Outcome(s)
      Renohemodynamic Effects of Combined empagliflOzin and LosARtan (RECOLAR)

      NCT04238702Type 2 diabetes patientsRandomized, double-blind, placebo-controlled, 4-armed cross-over mechanistic intervention studyEmpagliflozin 10 mg

      Losartan 50 mg

      Placebo

      -change in mGFR after 7 days of treatment using iohexol

      -change in ERPF after 7 days of treatment using iohexol

      A Double-blind, Placebo Controlled, Cross-over Renal Mechanistic Trial to Assess the Effect of Adding Empagliflozin Versus Placebo on Renal Hyperfiltration on a Background of the Angiotensin Converting Enzyme Inhibitor (ACEi) Ramipril: BETWEEN StudyNCT02632747Type 1 diabetes patients, Type 2 diabetes patients,

      Non-diabetic obese patients
      Randomized, double-blind, double-dummy, placebo-controlled, cross over, 4 week trialEmpagliflozin or placebo on a background of open-label ramiprilGFR under euglycaemic conditions
      Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease

      (FLOW study)
      NCT03819153Type 2 diabetes and CKDRandomized, placebo controlled, event driven intervention trialSemaglutide versus placebo (a lot of participants will use SGLT2 inhibitors as background therapy)Time to first occurrence of a composite primary outcome event (persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease)
      Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD Trial)

      NCT04724837diabetic kidney disease and non-diabetes mellitus CKDMulti-center, randomized, double-blind, placebo-controlled, dose-ranging studyZibotentan

      Dapagiflozin

      placebo
      Change in Log-transformed UACR from baseline to Week 12
      Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance (CROCODILE)

      NCT0407466830 adults with T1D, 20 control subjects without diabetesCross-sectional observational trialnone-Renal oxygenation (BOLD fMRI)

      -Renal perfusion (ASL MRI)

      -Renal oxygen Consumption (11-C Acetate PET/CT)

      -Insulin Sensitivity (Hyperinsulinemic-Euglycemic Clamp)

      -Mitochondrial Function
      Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study (ROCKIES)

      NCT04027530T2DM without CKD and healthy controlsRandomized placebo controlled 4 weeks cross-over trialErtugliflozin 15 mg versus placebo-Renal oxygenation (BOLD-MRI)

      -Renal oxygen consumption (PET/CT-scan using 11C-Acetate)

      -Renal hemodynamics (mGFR and ERPF)

      Adolescent Type 1 Diabetes Treatment With SGLT2i for hyperglycEMia & hyPerfilTration Trial (ATTEMPT)

      NCT04333823100 adolescents and young adults with type 1 diabetesMulti-center, double-blinded, randomized, placebo controlled trialDapagliflozin 5mg versus placebo (in combination with insulin) for 16 weeksChange in mGFR from baseline to the end of the 16-week treatment period
      Dapagliflozin in Non-diabetic Stage IV CKD (ADAPT)

      NCT04794517Non-diabetic Stage-IV CKD

      Proteinuria (0.5 g/24 h)
      Prospective, randomized, double-blind, placebo-controlled, 6 weeks cross-over StudyDapagliflozin 10mg versus placebo-GFR measured by the Iohexol plasma clearance technique

      -24 h urinary protein excretion
      Ongoing trials with SGLT2 inhibition. mGFR, measured Glomerular Filtration Rate; ERPF, Effective Renal Plasma Flow; UACR, Urinary Albumin to Creatinine Ratio.
      In recent years, the glucagon-like peptide (GLP-1) receptor agonists, which lower blood glucose levels through stimulation of insulin secretion, reduction of glucagon production, reduction of gastric emptying and increased satiety, have shown to reduce albuminuria in people with type 2 diabetes [
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • Liu M.
      • Saremi A.
      • Heerspink H.J.L.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      ]. The current FLOW study [NCT03819153] is ongoing to investigate the effects of GLP-1 receptor agonist on kidney outcomes in people with type 2 diabetes, many of which will also be treated with SGLT2 inhibitors, allowing to study their interaction.
      Finally, endothelin-receptor agonists (ERA) have shown to improve kidney outcomes, however, at the expense of increased fluid retention, edema and congestive heart failure [
      • Heerspink H.J.L.
      • Parving H.H.
      • Andress D.L.
      • Bakris G.
      • Correa-Rotter R.
      • Hou F.F.
      • et al.
      Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.
      ]. It may be hypothesized that SGLT2 inhibitors could partly off-set these effects of ERA treatment. This is currently under investigation [NCT04724837]. Thus, the above-indicated studies will help to understand whether (1) combination therapies of SGLT2 inhibition and other kidney protective drugs have additive value and (2) may provide enhanced safety profile through opposing effects on factors such as flood regulation.
      Regarding mechanistic studies, CROCODILE [NCT04074668] is ongoing to investigate renal oxygenation, perfusion and consumption, as well as insulin sensitivity and mitochondrial function in patients with type 1 diabetes and healthy controls. To further investigate the mechanisms of renal damage in type 1 diabetes, renal biopsies are performed. The ongoing ROCKIES study [NCT04027530] will provide insight into the role of renal hypoxia in the diabetic kidney, and will assess the effects of SGLT2 inhibition on renal tissue oxygenation and oxygen consumption, as well as a change in intrarenal hemodynamics and perfusion in type 2 diabetic patients (Table 2).
      The ongoing ATTEMPT trial [NCT04333823] will assess renal mechanistic effects of SGLT2 inhibition on the early onset manifestations and progression of diabetes complications in adolescents with type 1 diabetes. The ADAPT trial [NCT04794517] is ongoing to assess whether dapagliflozin ameliorates hyperfiltration and reduces proteinuria as compared to placebo, in patients with non-diabetic CKD (stage IV CKD) and proteinuria (0.5 g/24 h) (Table 2).

      7. Conclusions

      In conclusion, SGLT2 inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. This is driven by the large cardiovascular and kidney outcome trials conducted in the past few years which have shown surprisingly beneficial results on cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but still remain incompletely understood. Concerning the kidney protective effect of SGLT2i in people with diabetes, several mechanistic studies indicate that a correction of kidney hyperfiltration owing to postglomerual vasodilation in adults with type 2 diabetes following SGLT2i accounts for the protective effect. Another focus of research is the possible alleviation of kidney hypoxia by SGLT2 inhibition, in addition to small beneficial systemic effects. With regards to the cardiac protective effect, it has been long hypothesized that a plasma volume contraction following natriuresis was most likely to be the underlying mechanism. Recent studies carefully scrutinizing this topic have however raised doubts with respect to this concept and future mechanistic trials may shed further light on the mechanism of actions of these drugs. In the meantime, patients with cardiovascular and/or renal disease benefit from these agents in clinical practice.

      Disclosures

      C.C.v.R. and A.C.H. have no conflict of interest. D.H.v.R. serves on advisory boards of Astra Zeneca, Boehringer Ingelheim, Eli Lilly Alliance, Sanofi, Merck Sharp & Dohme (MSD) and Bayer, and received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi, and MSD.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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