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American Journal of Kidney Diseases

We Can Finally Stop Worrying About SGLT2 Inhibitors and Acute Kidney Injury

  • Vikas S. Sridhar
    Affiliations
    Toronto General Hospital Research Institute, UHN, Toronto, Canada

    Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Canada
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  • Katherine R. Tuttle
    Affiliations
    Division of Nephrology, Department of Medicine, University of Washington, Spokane, WA
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  • David Z.I. Cherney
    Correspondence
    Address for Correspondence: David Z.I. Cherney, MD CM, PhD, FRCP(C), Toronto General Hospital, 585 University Ave, 8N-845, Toronto, Ontario, M5G 2N2.
    Affiliations
    Toronto General Hospital Research Institute, UHN, Toronto, Canada

    Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

    Department of Physiology, University of Toronto, Toronto, Canada

    Banting and Best Diabetes Centre, Toronto, Canada
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      Related article, p. 471
      Sodium glucose transporter 2 (SGLT2) inhibitors, originally approved solely as antihyperglycemic agents for the treatment of type 2 diabetes mellitus (T2DM), are increasingly recognized for their distinctive kidney and cardiovascular protective properties.
      • Lytvyn Y.
      • Bjornstad P.
      • van Raalte D.H.
      • Heerspink H.L.
      • Cherney D.Z.I.
      The new biology of diabetic kidney disease-mechanisms and therapeutic implications.
      From a kidney perspective, in people with T2DM in the CREDENCE trial with estimated glomerular filtration rate (eGFR) of 30 to <90 mL/min/1.73 m2 and severe albuminuria, canagliflozin led to a 30% reduction in the composite risk for kidney failure (sustained eGFR < 15 mL/min/1.73 m2 or treatment with dialysis or transplantation), a doubling of serum creatinine level, or death from kidney or cardiovascular causes.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      These benefits generally mirrored reductions in kidney and cardiovascular end points observed in cardiovascular safety studies with SGLT2 inhibitors.
      • Lytvyn Y.
      • Bjornstad P.
      • van Raalte D.H.
      • Heerspink H.L.
      • Cherney D.Z.I.
      The new biology of diabetic kidney disease-mechanisms and therapeutic implications.
      Recently, the DAPA-CKD study (ClinicalTrials.gov identifier NCT03036150) involving participants with severe albuminuria and eGFR of 25 to <75 mL/min/1.73 m2 with or without T2DM was stopped early due to the overwhelming efficacy of dapagliflozin. Although these observations demonstrate that SGLT2 inhibitors are disease-modifying in chronic kidney disease, it is equally important to consider the safety profile of these therapies. In an article in this issue of AJKD, Rampersad et al
      • Rampersad C.
      • Kraut E.
      • Whitlock R.H.
      • et al.
      Acute kidney injury events in patients with type 2 diabetes using SGLT2 inhibitors versus other glucose-lowering drugs: a retrospective cohort study.
      assess the risk for acute kidney injury (AKI) with the use of SGLT2 inhibitors compared with other glucose-lowering agents.
      Aside from an increase in risk for mycotic genital infections and a small risk for diabetic ketoacidosis, SGLT2 inhibitors have favorable safety profiles. Interestingly, despite a large body of safety-related evidence, the previous literature has had a major focus on whether these agents increase the risk for AKI.
      • Lytvyn Y.
      • Bjornstad P.
      • van Raalte D.H.
      • Heerspink H.L.
      • Cherney D.Z.I.
      The new biology of diabetic kidney disease-mechanisms and therapeutic implications.
      This concern around AKI arose for several reasons.
      First, SGLT2 inhibitors induce a modest but acute decline in eGFR by approximately 3 to 5 mL/min/1.73 m2, reminiscent of the glomerular hemodynamic effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which may be confused with AKI in clinical practice and trial settings. This characteristic eGFR “dip” has been commonly attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback, leading to reversible intrarenal hemodynamic effects, including afferent vasoconstriction.
      • Lytvyn Y.
      • Bjornstad P.
      • van Raalte D.H.
      • Heerspink H.L.
      • Cherney D.Z.I.
      The new biology of diabetic kidney disease-mechanisms and therapeutic implications.
      ,
      • van Bommel E.J.M.
      • Lytvyn Y.
      • Perkins B.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.
      Second, from a mechanistic perspective, physicians and physiologists have been taught to think of medication-related afferent arteriolar constriction to be harmful by definition, based on how nonsteroidal anti-inflammatory drugs (NSAIDs) act in the kidney. As described later, SGLT2 inhibitors are clearly not NSAIDs, and drawing parallels between these classes of drugs is both clinically and physiologically incorrect.
      The third main reason for concerns around AKI with SGLT2 inhibitors was based on reports of AKI in the US Food and Drug Administration Adverse Event Report System (FDAERS). This raised clinical awareness of the issue, leading to subsequent analyses around AKI in clinical trials and observational cohort studies.
      • Perlman A.
      • Heyman S.N.
      • Matok I.
      • Stokar J.
      • Muszkat M.
      • Szalat A.
      Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: analysis of the FDA Adverse Event Report System database.
      Despite FDAERS data, in propensity score–matched analyses from electronic medical records, AKI risk was reduced rather than increased in SGLT2 inhibitor users,
      • Nadkarni G.N.
      • Ferrandino R.
      • Chang A.
      • et al.
      Acute kidney injury in patients on SGLT2 inhibitors: a propensity-matched analysis.
      prompting significant confusion surrounding AKI risk with these drugs. Concurrently, cardiovascular outcome trials with empagliflozin and canagliflozin also reported AKI risk (as an adverse event) to be lower with SGLT2 inhibition compared with placebo.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      In the DECLARE TIMI 58 trial with dapagliflozin involving 17,160 participants with T2DM, AKI similarly occurred less frequently with dapagliflozin and adverse events suggestive of volume depletion were similar between groups, irrespective of baseline eGFR, blood pressure, or diuretic use.
      • Cahn A.
      • Raz I.
      • Bonaca M.
      • et al.
      Safety of dapagliflozin in a broad population of patients with type 2 diabetes - analyses from the DECLARE - TIMI 58 study.
      In a recent meta-analysis using data from the EMPA-REG OUTCOME, CANVAS, DECLARE TIMI 58, and CREDENCE trials, Neuen et al
      • Neuen B.L.
      • Young T.
      • Heerspink H.J.L.
      • et al.
      SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
      reported that AKI risk was reduced by 25%, without effect heterogeneity across studies. Risks for serious and nonserious AKI were both reduced, with the caveat that events were not adjudicated in these trials. In another meta-analysis involving 30 clinical trials, SGLT2 inhibition reduced the risk for serious adverse events due to AKI by 36% (P < 0.001) and AKI events of any severity by 25% (P < 0.001).
      • Menne J.
      • Dumann E.
      • Haller H.
      • Schmidt B.M.W.
      Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis.
      Other meta-analyses involving randomized controlled trials have reported similar benefits around AKI risk,
      • Donnan J.R.
      • Grandy C.A.
      • Chibrikov E.
      • et al.
      Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.
      and separate “real-world analyses” comparing SGLT2 inhibitors with DPP4 inhibitors reported that AKI risk was reduced by 53% in SGLT2-inhibitor users.
      • Cahn A.
      • Melzer-Cohen C.
      • Pollack R.
      • Chodick G.
      • Shalev V.
      Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: real-world data analysis.
      With this background, Rampersad et al used a propensity-match design with data from electronic medical records in 6 administrative databases in Manitoba, Canada. They performed an incident user analysis that compared 4,778 patients with a new prescription for an SGLT2 inhibitor with the same number given a new prescription for other glucose-lowering drugs without prior prescriptions for these agents in the preceding 1 year. Consistent with previous work, in their incident user on-treatment analysis, AKI risk tended to be lower in SGLT2-inhibitor users (hazard ratio, 0.64; 95% confidence interval, 0.40-1.03; P = 0.06). Importantly, whether AKI was defined as an administrative code for AKI hospitalization, AKI based on laboratory values, or AKI based on a composite of the 2, AKI risk was lower in patients receiving treatment with SGLT2 inhibitors at 30 and 90 days.
      The authors completed several sensitivity analyses, including: (1) accounting for any new SGLT2 inhibitor initiation without the requirement for a documented 1-year prescription-free period, (2) an “intention-to-treat analysis” approach, (3) an analysis of patients starting the drug after issuance of Food and Drug Administration warnings, and (4) in patients with hemoglobin A1c testing within a year of drug initiation to gauge glycemic control. These sensitivity analyses were all consistent with the primary analysis and did not show any signal for higher AKI risk with SGLT2 inhibitors. Rampersad et al have therefore reported a robust clear clinical message about the kidney safety of SGLT2-inhibitor use in the real world, regardless of the definition of AKI, that is consistent with observations from clinical trials and other recent large retrospective propensity-matched cohort studies.
      • Iskander C.
      • Cherney D.Z.I.
      • Clemens K.K.
      • et al.
      Use of sodium–glucose cotransporter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: a population-based cohort study.
      The consistency of this analysis is a major strength and should provide reassurance to both health care providers and patients.
      Although the safety around AKI with SGLT2 inhibitors is now well understood, it is less clear why SGLT2 inhibitors may reduce AKI risk in people with T2DM. Several factors may contribute to kidney protection with SGLT2 inhibitors. First, in nondiabetic experimental models, SGLT2 inhibition increases nitric oxide–dependent vasodilatation, reducing ischemia-reperfusion injury, which could protect against AKI.
      • Sayour A.A.
      • Korkmaz-Icoz S.
      • Loganathan S.
      • et al.
      Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation.
      Other reported beneficial kidney effects include suppression of kidney fibrosis, decreased peritubular hemorrhage and fibrosis, reduced hypoxia, and increased renal vascular endothelial growth factor A expression in response to ischemia-reperfusion injury, which could preserve intrarenal perfusion and attenuate ischemic injury.
      • Zhang Y.
      • Nakano D.
      • Guan Y.
      • et al.
      A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice.
      As reviewed elsewhere, the reduction in ischemia-reperfusion risk may have a variety of causes, which remain mainly hypothetical and merit further investigation.
      • van Raalte D.H.
      • Cherney D.Z.I.
      Sodium glucose cotransporter 2 inhibition and renal ischemia: implications for future clinical trials.
      With the benefit of hindsight, FDAERS reports of AKI may have reflected: (1) expected changes in eGFR on the basis of known hemodynamic effects and (2) higher risk for AKI in people with diabetes taking SGLT2 inhibitors on the basis of confounding AKI risk factors, including advanced age, greater proportion of men, and higher rates of renin-angiotensin-aldosterone system inhibitor and diuretic use.
      • Desai M.
      • Yavin Y.
      • Balis D.
      • et al.
      Renal safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus.
      Subsequent analyses that have addressed these confounders, either through randomization or through propensity score matching, as in the analysis by Rampersad et al, have found that these drugs do not increase but rather reduce AKI risk over time.
      Although the data for AKI risk are reassuring overall, the question of whether these agents should be withheld during high-risk clinical situations remains unaddressed. Accordingly, it is prudent to follow local guidelines around sick-day management, temporarily withholding SGLT2 inhibitors along with diuretics, metformin, NSAIDs, and agents that block the renin-angiotensin-aldosterone system under conditions of intercurrent illness, or procedures involving contrast materials. This approach is reasonable given the minimal clinical downside to discontinuing these agents for a few days until the patient is back to his or her baseline state.
      In conclusion, data from clinical trials and propensity-matched analyses of data from clinical practice both unambiguously demonstrate that SGLT2 inhibitors are “kidney safe” and do not predispose to AKI. Based on data from the 3 cardiovascular outcome trials, and especially CREDENCE, these therapies protect against diabetic kidney disease progression and, as the first new treatment to combat this condition in the last 20 years, represent a victory for the nephrology community and for patients with diabetes-related kidney and/or cardiovascular disease. Beyond the efficacy of SGLT2 inhibitors for the treatment of diabetic kidney disease, we can now be confident that these agents do not augment the risk for AKI.

      Article Information

      Authors’ Full Names and Academic Degrees

      Vikas S. Sridhar, MD, Katherine R. Tuttle, MD, and David Z. I. Cherney, MD CM, PhD, FRCP(C).

      Support

      Dr Cherney is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the Canadian Institutes of Health Research, Diabetes Canada, the Heart and Stroke Richard Lewar Centre of Excellence, and the Heart and Stroke Foundation of Canada. Dr Sridhar is funded by the Clinician Scientist Training Program at the University of Toronto.

      Financial Disclosure

      Dr Cherney has received consulting fees or speaking honoraria or both from Janssen, Bayer, Boehringer Ingelheim, Eli Lilly & Co, AstraZeneca, Merck & Co Inc, Prometic, and Sanofi and has received operating funds from Janssen, Boehringer Ingelheim, Eli Lilly & Co, Sanofi, AstraZeneca, and Merck & Co Inc. Dr Tuttle has received consulting fees or speaking honoraria or both from Eli Lilly & Co, Boehringer Ingelheim, AstraZeneca, Bayer, Gilead, Goldfinch Bio, Janssen, and Novo Nordisk. Dr Sridhar declares that he has no relevant financial interests.

      Peer Review

      Received April 29, 2020, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form May 26, 2020.

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