• 1.

    Tang H, et al. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: A meta-analysis of randomised controlled trials. Diabetologia 2016; 59:25462551. doi: 10.1007/s00125-016-4101-6

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Ray EC, et al. SGLT2 inhibitors for treatment of refractory hypomagnesemia: A case report of 3 patients. Kidney Med 2020; 2:359364. doi: 10.1016/j.xkme.2020.01.010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Blau JE, et al. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight 2018; 3:e99123. doi: 10.1172/jci.insight.99123

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Dominguez Rieg JA, et al. Tubular effects of sodium-glucose cotransporter 2 inhibitors: Intended and unintended consequences. Curr Opin Nephrol Hypertens 2020; 29:523530. doi: 10.1097/MNH.0000000000000632

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Davies MJ, et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2015; 17:426429. doi: 10.1111/dom.12439

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Kristensen KB, et al. Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis. Diabetologia 2021; 64:15631571. doi: 10.1007/s00125-021-05424-4

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Refardt J, et al. A randomized trial of empagliflozin to increase plasma sodium levels in patients with the syndrome of inappropriate antidiuresis. J Am Soc Nephrol 2020; 31:615624. doi: 10.1681/ASN.2019090944

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Schork A, et al. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: A prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 2019; 18:46. doi: 10.1186/s12933-019-0852-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Oshima M, et al. Effects of canagliflozin on anemia in patients with type 2 diabetes and chronic kidney diseaase: A post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol 2020; 8:903914. doi: 10.1016/S2213-8587(20)30300-4

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Marathias KP, et al. Competing effects of renin angiotensin system blockade and sodium-glucose cotransporter-2 inhibitors on erythropoietin secretion in diabetes. Am J Nephrol 2020; 51:349356. doi: 10.1159/000507272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: Modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol 2018; 314:F969F984. doi: 10.1152/ajprenal.00551.2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Maruyama T, et al. Canagliflozin improves erythropoiesis in diabetes pateints with anemia of chronic kidney disease. Diabetes Technol Ther 2019; 21:713720. doi: 10.1089/dia.2019.0212

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Griffin M, et al. Empagliflozin in heart failure: Diuretic and cardiorenal effects. Circulation 2020; 142:10281039. doi: 10.1161/CIRCULATIONAHA.120.045691

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kimura Y, et al. Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats. J Diabetes Investig 2019; 10:933946. doi: 10.1111/jdi.13009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Menne J, et al. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med 2019; 16:e1002983. doi: 10.1371/journal.pmed.1002983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Rampersad C, et al. Acute kidney injury events in patients with type 2 diabetes using SGLT2 inhibitors versus other glucose-lowering drugs: A retrospective cohort study. Am J Kidney Dis 2020; 76:471479. doi: 10.1053/j.ajkd.2020.03.019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Iskander C, et al. Use of sodium-glucose cotrans-porter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: A population-based cohort study. CMAJ 2020; 192:E351E360. doi: 10.1503/cmaj.191283

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Kraus BJ, et al. Characterization and implications of the initial estimated glomerular filtration rate ‘dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial. Kidney Int 2021; 99:750762. doi: 10.1016/j. kint.2020.10.031

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Patel N, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors & kidney transplantation: What are we waiting for? Kidney360 [published ahead of print April 22, 2021]. doi: 0.34067/KID.0000732021; https://kidney360.asnjournals.org/content/early/2021/04/22/KID.0000732021

    • Search Google Scholar
    • Export Citation
  • 20.

    Halden TAS, et al. Efficacy and safety of empagliflozin in renal transplant recipients with posttranspplant diabetes mellitus. Diabetes Care 2019; 42:10671074. doi: 10.2337/dc19-0093

    • Crossref
    • Search Google Scholar
    • Export Citation

Beyond Heart and Kidney Protection: Potential Uses of SGLT2 Inhibitors

  • 1 Jefferson L. Triozzi, MD, is a nephrology fellow at Vanderbilt University Medical Center in Nashville, TN. L. Parker Gregg, MD, MSCS, is an Assistant Professor at Baylor College of Medicine and is with the Michael E. DeBakey VA Medical Center and Veterans Affairs Health Services Research and Development Center for Innovations in Quality, Effectiveness and Safety in Houston, TX.
Full access

Sodium-glucose cotransporter-2 (SGLT2) inhibitors demonstrate multiple effects beyond improving cardiovascular and kidney outcomes. Although much remains to be learned about the underlying mechanisms, early data suggest possible roles for SGLT2 inhibitors in the management of hypomagnesemia, nephrolithiasis, hyponatremia, anemia, cardiorenal syndrome, and in kidney transplant recipients (Figure 1).

Figure 1.
Figure 1.

Potential clinical uses for SGLT2 inhibitors

Citation: Kidney News 13, 9

Early data suggest several potential applications and proposed mechanisms for SGLT2 inhibitors beyond their well-known benefits for cardiovascular and kidney protection.

SGLT2 inhibitors may increase magnesium reabsorption in the nephron (Figure 2). In clinical trials, SGLT2 inhibitors led to an approximate 0.04–0.1 mM (0.10–0.24 mg/dL) increase in serum magnesium level when compared to placebo (1). This observed effect was generally within the physiologic range for serum magnesium level, but one case series suggests that SGLT2 inhibitors may have greater effect and therapeutic potential for patients with refractory urinary magnesium wasting (2). By potentially impacting magnesium reabsorption in multiple segments of the nephron, SGLT2 inhibitors may be useful for managing medication-induced urinary magnesium wasting, such as decreased paracellular reabsorption in patients taking loop diuretics or transient receptor potential melastatin type 6 (TRPM6) downregulation in patients taking thiazide diuretics or calcineurin inhibitors.

Figure 2.
Figure 2.

Proposed effects of SGLT2 inhibitors on magnesium handling in the nephron

Citation: Kidney News 13, 9

Several mechanisms potentially contribute to increased reabsorption of magnesium in the nephron. NKCC, sodium-potassium-2 chloride cotransporter; ROMK, renal outer medullary potassium channel; SGLT2, sodium-glucose cotransporter-2; TRPM6, transient receptor potential melastatin type 6.

However, studies have not shown similar effects on handling of urinary calcium, another divalent cation (3). This may be because decreased urinary phosphate excretion in response to SGLT2 inhibition stimulates parathyroid hormone secretion (4). Despite the lack of substantial impact on urinary calcium excretion, the combined effects of SGLT2 inhibitors on urine volume, urinary phosphate excretion, and uric acid homeostasis may decrease the risk of nephrolithiasis (46).

The osmotic diuresis generated by SGLT2 inhibitors increases water excretion and may have a role in the management of hyponatremia. Empagliflozin was shown to raise plasma sodium concentration faster than placebo over 4 days in individuals with the syndrome of inappropriate antidiuretic hormone (SIADH) (7). Studies including more prolonged intervention and longer-term follow-up are needed, as transient changes in urine volume due to SGLT2 inhibitor initiation may not produce sustained effects on net water balance (8).

Clinical trials have shown higher hematocrit concentrations with SGLT2 inhibitors compared to placebo and decreased need for iron supplementation, erythropoiesis-stimulating agents, or blood transfusions in those with concomitant diabetes and chronic kidney disease (9, 10). In patients with type 2 diabetes, hyperglycemia causes maladaptive changes in the kidney that alter hypoxia-inducible factor pathways and impair erythropoiesis (10). Although incompletely understood, SGLT2 inhibitors may stimulate erythropoiesis by decreasing glucose accumulation in the cortical interstitium and by altering oxygen tension in the cortex and outer medulla (1012). Less is known about the therapeutic role of SGLT2 inhibitors for anemia in patients without diabetes.

Given the heart and kidney protective effects of SGLT2 inhibitors, these agents are currently recommended in patients with chronic cardiorenal syndromes. In patients with stable heart failure, natriuresis after initiation of an SGLT2 inhibitor led to decreased blood and plasma volume without the concomitant neurohormonal activation or hypokalemia typically seen after loop diuretic administration (13). Less is known about the use of these drugs in patients with acute cardiorenal syndromes. In rats, SGLT2 inhibition may protect against cardiorenal acute kidney injury by reducing oxidative stress in the kidney (14). In patients with diabetes mellitus, SGLT2 inhibitors were associated with a decreased risk of acute kidney injury compared to other glucose-lowering medications (1517). Understanding these relationships for patients with cardiorenal physiology will require studies incorporating biomarkers of kidney injury other than glomerular filtration rate, which may reflect hemodynamic changes rather than true kidney injury (18). Existing evidence is insufficient to support SGLT2 inhibitor use in cases of acute cardiorenal syndromes.

Although kidney transplant recipients were excluded from large SGLT2 inhibitor outcome trials, it is plausible that cardiovascular benefits could be extrapolated to this population in appropriate clinical contexts (19). One placebo-controlled randomized trial showed that empagliflozin lowered hemoglobin A1c by a median of −0.2% and body weight by a median of −2.5 kg in 44 kidney transplant recipients with posttransplant diabetes mellitus (20). Despite their immunosuppressed status, there was no increase in infections among patients receiving SGLT2 inhibitors, with three participants each in the empagliflozin and placebo groups developing urinary tract infections and one participant in the empagliflozin arm with a genital yeast infection. Larger studies are needed to evaluate efficacy and safety of SGLT2 inhibitors in this population and to better understand how these drugs affect allograft perfusion in kidney transplant recipients with impaired autoregulatory mechanisms.

Evidence supporting these potential uses of SGLT2 inhibitors is in early stages. It remains to be determined whether such uses differ among individual SGLT2 inhibitors. More research is needed to assess the mechanisms, durability, and clinical implications of these effects.

References

  • 1.

    Tang H, et al. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: A meta-analysis of randomised controlled trials. Diabetologia 2016; 59:25462551. doi: 10.1007/s00125-016-4101-6

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Ray EC, et al. SGLT2 inhibitors for treatment of refractory hypomagnesemia: A case report of 3 patients. Kidney Med 2020; 2:359364. doi: 10.1016/j.xkme.2020.01.010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Blau JE, et al. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight 2018; 3:e99123. doi: 10.1172/jci.insight.99123

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Dominguez Rieg JA, et al. Tubular effects of sodium-glucose cotransporter 2 inhibitors: Intended and unintended consequences. Curr Opin Nephrol Hypertens 2020; 29:523530. doi: 10.1097/MNH.0000000000000632

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Davies MJ, et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2015; 17:426429. doi: 10.1111/dom.12439

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Kristensen KB, et al. Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis. Diabetologia 2021; 64:15631571. doi: 10.1007/s00125-021-05424-4

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Refardt J, et al. A randomized trial of empagliflozin to increase plasma sodium levels in patients with the syndrome of inappropriate antidiuresis. J Am Soc Nephrol 2020; 31:615624. doi: 10.1681/ASN.2019090944

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Schork A, et al. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: A prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 2019; 18:46. doi: 10.1186/s12933-019-0852-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Oshima M, et al. Effects of canagliflozin on anemia in patients with type 2 diabetes and chronic kidney diseaase: A post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol 2020; 8:903914. doi: 10.1016/S2213-8587(20)30300-4

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Marathias KP, et al. Competing effects of renin angiotensin system blockade and sodium-glucose cotransporter-2 inhibitors on erythropoietin secretion in diabetes. Am J Nephrol 2020; 51:349356. doi: 10.1159/000507272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: Modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol 2018; 314:F969F984. doi: 10.1152/ajprenal.00551.2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Maruyama T, et al. Canagliflozin improves erythropoiesis in diabetes pateints with anemia of chronic kidney disease. Diabetes Technol Ther 2019; 21:713720. doi: 10.1089/dia.2019.0212

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Griffin M, et al. Empagliflozin in heart failure: Diuretic and cardiorenal effects. Circulation 2020; 142:10281039. doi: 10.1161/CIRCULATIONAHA.120.045691

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kimura Y, et al. Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats. J Diabetes Investig 2019; 10:933946. doi: 10.1111/jdi.13009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Menne J, et al. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med 2019; 16:e1002983. doi: 10.1371/journal.pmed.1002983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Rampersad C, et al. Acute kidney injury events in patients with type 2 diabetes using SGLT2 inhibitors versus other glucose-lowering drugs: A retrospective cohort study. Am J Kidney Dis 2020; 76:471479. doi: 10.1053/j.ajkd.2020.03.019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Iskander C, et al. Use of sodium-glucose cotrans-porter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: A population-based cohort study. CMAJ 2020; 192:E351E360. doi: 10.1503/cmaj.191283

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Kraus BJ, et al. Characterization and implications of the initial estimated glomerular filtration rate ‘dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial. Kidney Int 2021; 99:750762. doi: 10.1016/j. kint.2020.10.031

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Patel N, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors & kidney transplantation: What are we waiting for? Kidney360 [published ahead of print April 22, 2021]. doi: 0.34067/KID.0000732021; https://kidney360.asnjournals.org/content/early/2021/04/22/KID.0000732021

    • Search Google Scholar
    • Export Citation
  • 20.

    Halden TAS, et al. Efficacy and safety of empagliflozin in renal transplant recipients with posttranspplant diabetes mellitus. Diabetes Care 2019; 42:10671074. doi: 10.2337/dc19-0093

    • Crossref
    • Search Google Scholar
    • Export Citation
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