CoChat
Sign Up
Cited by 161Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesAcute Kidney Injury Research

A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

Open access
Sen, Taha, Heerspink, Hiddo J.L.·2021·Cell Metabolism
DOI 10.1016/j.cmet.2021.02.016
Open this paper in CoChat — free accountOpen PDF

Abstract

Sodium glucose co-transporter (SGLT) 2 inhibitors reduce the risk of kidney failure in patients with and without type 2 diabetes (T2D). Although the precise underlying mechanisms for these nephroprotective effects are incompletely understood, various hypotheses have been proposed including reductions in intraglomerular pressure through restoration of tubuloglomerular feedback, blood pressure reduction and favorable effects on vascular function, reduction in tubular workload and hypoxia, and metabolic effects resulting in increased autophagy. Here, we review these mechanisms, which may also explain the beneficial effects of SGLT2 inhibitors on kidney function in patients without T2D.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2021.02.016

Cites

81 of 81 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 78 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § SUMMARY · p. 2

    In individuals with or without type 2 diabetes, SGLT2 inhibitors cut the likelihood of progressing to kidney failure.

    “Sodium glucose co-transporter (SGLT) 2 inhibitors reduce the risk of kidney failure in patients with and without type 2 diabetes (T2D).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Perkovic et al., 2019 source

      Not checked in the free run.

    • cites Heerspink et al., 2020 source

      Not checked in the free run.

  • Premisecitation
    § INTRODUCTION · p. 2

    Better glycemic control is consistently linked with improved microvascular outcomes.

    “Improved glycemic control has been consistently associated with improved microvascular outcomes (Zoungas et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zoungas et al., 2017 source

      Not checked in the free run.

  • Study design and conductcitation
    § BLOOD PRESSURE EFFECTS · p. 3

    Prior clinical studies of natriuresis and osmotic diuresis did not record or standardize sodium intake.

    “Although clinical studies demonstrated natriuretic/osmotic diuretic effects of SGLT2 inhibitors, it should be mentioned that these studies did not record or standardize sodium intake (Tanaka et al., 2017; Iijima et al., 2015; Wilcox et al., 2018; Mordi et al., 2020; Griffin et al., 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Tanaka et al., 2017 source

      Not checked in the free run.

    • cites Iijima et al., 2015 source

      Not checked in the free run.

    • cites Wilcox et al., 2018 source

      Not checked in the free run.

  • Premisenone given
    § BLOOD PRESSURE EFFECTS · p. 3

    SGLT2 inhibitors lower systolic and diastolic blood pressure by about 4 and 2 mmHg.

    “SGLT2 inhibitors decrease systolic and diastolic blood pressure by approximately 4 and 2 mmHg, respectively.”
    Quote in the paperSubstantial claim
  • Premisecitation
    § BLOOD PRESSURE EFFECTS · p. 3

    In type 2 diabetes patients with preserved kidney function on a strict standardized sodium diet, dapagliflozin significantly lowered 24 h blood pressure without obvious changes in sodium excretion.

    “A recent study in patients with T2D and preserved kidney function who adhered to a strict standardized sodium diet showed that the SGLT2 inhibitor dapagliflozin significantly decreased 24 h blood pressure without obvious changes in sodium excretion (Scholtes et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Scholtes et al., 2021 source

      Not checked in the free run.

  • May combine two claims. 34
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation
    § INTRODUCTION · p. 2

    SGLT2 inhibitors lower the proximal tubule's capacity to reabsorb glucose, producing acute glycosuria and better glycemic control over time.

    “Studies with inhibitors of the SGLT2 transporter indeed showed that these drugs decrease the glucose reabsorption capacity of the proximal tubule, thereby acutely increasing glycosuria and improving glycemic control over time (DeFronzo et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites DeFronzo et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § INTRODUCTION · p. 2

    SGLT2 inhibitors also lower blood pressure, body weight, and albuminuria.

    “However, more importantly, SGLT2 inhibitors also decrease other cardiovascular risk factors, such as blood pressure, body weight, and albuminuria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § INTRODUCTION · p. 2

    SGLT2 is mainly found in the proximal tubule and handles 80%-90% of renal glucose reabsorption, while SGLT1 takes up the remaining 10%-20%.

    “SGLT1 is predominantly found in the gastrointestinal tract, while SGLT2 is primarily expressed in the proximal tubule and accounts for 80%-90% of glucose reabsorption with the remaining 10%-20% reabsorbed by SGLT1 (Wright et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wright et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § INTRODUCTION · p. 2

    Large cardiovascular outcome trials first showed that SGLT2 inhibitors slow kidney function decline and reduce kidney outcomes in type 2 diabetes patients, most of whom had relatively preserved kidney function.

    “Large cardiovascular outcome trials provided initial proof that SGLT2 inhibitors slow the progression of kidney function decline and reduce the risks of kidney outcomes in patients with T2D of whom the majority had relatively preserved kidney function (Wiviott et al., 2019; Neal et al., 2017; Zinman et al., 2015; Mosenzon et al., 2019).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Wiviott et al., 2019 source

      Not checked in the free run.

    • cites Neal et al., 2017 source

      Not checked in the free run.

    • cites Zinman et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Cell · p. 3

    The acute eGFR drop is associated with long-term kidney function preservation during continued treatment and reverses soon after SGLT2 inhibitor discontinuation.

    “Importantly, this drop in eGFR is associated with a preservation of long-term kidney function during prolonged treatment and is reversible soon after discontinuation of SGLT2 inhibitors (Wanner et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wanner et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    This ketogenic mechanism may cooperate with other SGLT2 inhibitor mechanisms and produce a synergistic kidney-protective effect.

    “This mechanism would cooperate with other SGLT2 inhibitorinduced mechanisms, as described above, and would provide a powerful synergistic effect that could ultimately protect kidney function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § OTHER PROTECTIVE MECHANISMS · p. 5

    Hyperuricemia is associated with kidney inflammation, and observational studies show a strong linear association between higher plasma uric acid and progressive kidney function loss.

    “Hyperuricemia has been associated with kidney inflammation, and various observational studies documented a strong linear association between higher plasma uric acid levels and progressive kidney function loss (Zoppini et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zoppini et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § BLOOD PRESSURE EFFECTS · p. 3

    In non-diabetic mice, empagliflozin inhibited NHE3 activity and decreased urinary pH and bicarbonate excretion.

    “In non-diabetic mice, SGLT2 inhibition with empagliflozin inhibited NHE3 activity and decreased urinary pH and bicarbonate excretion (Figure 1) (Onishi et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Onishi et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § WORKLOAD AND HYPOXIA · p. 3

    By reducing glucose and sodium reabsorption, SGLT2 inhibitors lower tubular workload and oxygen consumption and alleviate hypoxia, which may explain reductions in proximal AKI biomarkers and AKI events.

    “By decreasing glucose and sodium reabsorption, SGLT2 inhibitors decrease tubular workload and oxygen consumption and alleviate hypoxia, which may explain why SGLT2 inhibitors decrease proximal biomarkers of AKI such as kidney injury molecule-1 and decrease the risk of AKI events (Neuen et al., 2019; Dekkers et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Neuen et al., 2019 source

      Not checked in the free run.

    • cites Dekkers et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § BLOOD PRESSURE EFFECTS · p. 3

    The blood pressure-lowering effect of SGLT2 inhibitors does not depend on starting blood pressure and is independent of concomitant blood pressure-lowering drugs.

    “In contrast to other blood pressure-lowering agents (Law et al., 2003), the blood pressure-lowering effect does not depend on starting blood pressure levels and is also independent of the use of other concomitant blood pressure-lowering agents (Ye et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ye et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § BLOOD PRESSURE EFFECTS · p. 3

    Human trials show SGLT2 inhibitors improve arterial stiffness, vascular resistance, endothelial function, and blood pressure variability.

    “Human clinical trials have shown that SGLT2 inhibitors exert favorable effects on arterial stiffness, vascular resistance, and endothelial and blood pressure variability (Kario et al., 2018; Chilton et al., 2015; Cherney et al., 2014a; Cooper et al., 2019).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kario et al., 2018 source

      Not checked in the free run.

    • cites Chilton et al., 2015 source

      Not checked in the free run.

    • cites Cherney et al., 2014a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    Most studies on fuel utilization mechanisms to date are experimental and largely in animal models.

    “It should be mentioned that most of the studies conducted to date are experimental studies largely performed in animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § WORKLOAD AND HYPOXIA · p. 3

    In CREDENCE, canagliflozin markedly reduced anemia risk and initiation of anemia treatments.

    “It is therefore perhaps not a surprise that in a large multi-national kidney outcome trial with canagliflozin (namely, the CREDENCE trial), the risk of anemia, which was an independent predictor of renal and cardiovascular outcomes, and initiation of treatments for anemia were markedly reduced with canagliflozin (Oshima et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oshima et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    Ketonemia promotes glomerular hyperfiltration and has other potential harmful effects.

    “Although the theory on changes in fuel utilization is an attractive hypothesis to explain the mechanism of action of SGLT2 inhibitors, it should be noted that ketonemia promotes glomerular hyperfiltration along with other potential deleterious effects (Nosadini et al., 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nosadini et al., 1989 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § BLOOD PRESSURE EFFECTS · p. 3

    Chronic empagliflozin in Akita mice increased alpha-ketoglutarate, which may drive distal sodium chloride reabsorption to compensate for reduced proximal sodium reabsorption.

    “Notably, chronic empagliflozin treatment in Akita mice increased a -ketoglutarate, which may drive distal sodium chloride reabsorption to compensate for the decreased proximal sodium reabsorption.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Onishi et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § WORKLOAD AND HYPOXIA · p. 3

    Lower medullary oxygen tension stimulates hypoxia-inducible factors, especially HIF-2a, which promotes erythropoietin production and improves red cell mass and oxygen-carrying capacity.

    “Lower medullary oxygen tension in this segment of the tubule stimulates hypoxia-inducible factors, particularly HIF-2 a , which promotes erythropoietin production to improve red cell mass and oxygen-carrying capacity (Layton and Vallon, 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Layton and Vallon, 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    These adaptations include increased endogenous glucose production, partly via higher glucagon, and lower insulin levels.

    “These compensatory mechanisms include an increase in endogenous glucose production, partly through an increase in glucagon, and decrease in insulin levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § INTRODUCTION · p. 2

    Sotagliflozin showed a similar but non-significant kidney failure trend in SCORED, likely because the trial ended early.

    “A similar trend was observed for sotagliflozin, although the effect was not statistically significant in the SCORED trial, probably due to its early termination (Bhatt et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bhatt et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Cell · p. 3

    Tubuloglomerular feedback activation widens the afferent renal arteriole and raises glomerular pressure.

    “TGF activation causes vasodilation of the afferent renal arteriole and leads to increased glomerular hypertension.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Cell · p. 3

    Glomerular hyperfiltration is a common injury pathway in diabetic and non-diabetic settings and is linked to kidney function decline.

    “Glomerular hyperfiltration is a common pathway of kidney injury both in diabetic and non-diabetic settings and is associated with progression of kidney function decline (Helal et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Helal et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Cell · p. 3

    SGLT2 inhibition restores distal sodium delivery, normalizes tubuloglomerular feedback and afferent tone, and lowers intraglomerular pressure.

    “By inhibiting SGLT2, distal sodium delivery is restored, which normalizes TGF and afferent tone, resulting in a reduction in intraglomerular pressure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    Urinary beta-OH-butyrate rises significantly after dapagliflozin, and the rise correlates with changes in erythropoietin and hematocrit in type 2 diabetes and CKD patients.

    “Indeed, urinary b -OH-butyrate concentrations were significantly increased following treatment with the SGLT2 inhib- Perspective itors dapagliflozin, and the rise in b -OH-butyrate correlated with changes in erythropoietin and hematocrit in patients with T2D and CKD (Kim et al., 2019a; Mulder et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kim et al., 2019a

      Not checked in the free run.

    • cites Mulder et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Cell · p. 3

    In Akita mice, SGLT2 inhibition constricts the afferent renal arteriole and lowers intraglomerular pressure and hyperfiltration.

    “An experimental study in Akita mice (a model of T1D) using in vivo multiphoton microscope imaging techniques demonstrated that SGTL2 inhibition causes afferent renal arterial vasoconstriction and decreases intraglomerular pressure and hyperfiltration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kidokoro et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § WORKLOAD AND HYPOXIA · p. 3

    Shifting sodium reabsorption to the medullary thick ascending limb raises oxygen demand in the outer medulla and makes that segment vulnerable to ischemia.

    “However, shifting sodium reabsorption to the medullary thick ascending limb of the loop of Henle raises oxygen demand in the outer medulla, rendering this tubular segment vulnerable to ischemia (O'Neill et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites O'Neill et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    These inflammatory mediators are important pathways in diabetes-related kidney disease development and progression.

    “These inflammatory mediators represent important pathways of inflammation and may play an important role in the development and progression of kidney disease in the setting of diabetes (Kim et al., 2019b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim et al., 2019b

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § WORKLOAD AND HYPOXIA · p. 3

    Hyperglycemia increases SGLT2 expression, raising glucose and sodium reabsorption and ATP-dependent tubular workload and oxygen demand, which can cause hypoxia.

    “Increased expression of SGLT2 under hyperglycemic conditions increases glucose and sodium reabsorption and therefore increases ATP-dependent tubular workload and oxygen requirements, which can lead to hypoxia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    Ketone bodies inhibit the NLRP3 inflammasome and reduce IL-1beta production in monocytes.

    “Additionally, increased levels of ketone bodies inhibit the Nod -like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and reduce production of interleukin-1 b in monocytes (Youm et al., 2015; Goldberg et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Youm et al., 2015 source

      Not checked in the free run.

    • cites Goldberg et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Cell · p. 3

    Although the acute GFR reduction is consistent in type 1 and type 2 diabetes, the glomerular hemodynamic effectors may differ.

    “Thus, while the acute reduction in GFR is consistent in patients with T1D and T2D, the underlying glomerular hemodynamic effectors may differ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § NUTRIENT DEPRIVATION AND KETOGENESIS · p. 4

    These hormonal changes stimulate ketogenesis and lipolysis and raise circulating ketone bodies, including beta-OH-butyrate, an efficient energy source.

    “These effects stimulate ketogenesis and lipolysis and increase circulating ketone bodies among b -OH-butyrate, which is an efficient energy source in addition to glucose (Mudaliar et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mudaliar et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation
    § SUMMARY AND FUTURE PERSPECTIVES · p. 6

    Implementation of new therapies in clinical practice is a slow process.

    “Unfortunately, history has taught us that implementation of new therapies in clinical practice is a slow process.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tuttle et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § Perspective · p. 7

    Other effects, such as reduction in hypoxia and changes in renal metabolism and transcription factors, may be involved in the protective effects of SGLT2 inhibitors.

    “In addition to the reduction in intraglomerular pressure, other effects such as reduction in hypoxia as well as changes in renal metabolism and transcription factors may be involved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 5

    The absence of a compensatory heart rate increase suggests blunting of sympathetic nervous system activity, which may contribute to SGLT2 inhibitor benefits compared with other diuretics.

    “The lack of a compensatory increase in heart rate suggests there may be commensurate blunting of sympathetic nervous system (SNS) activity, which may contribute to the salutary effects of SGLT2 inhibitors compared with other diuretics (Gueguen et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gueguen et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Perspective · p. 7

    In the authors' view, reduction in intraglomerular pressure is the most important mechanism responsible for the clear effects of SGLT2 inhibitors.

    “In our view, the reduction in intraglomerular pressure is the most important mechanism responsible for the clear effects of SGTL2 inhibitors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 5

    These sympathetic reductions were also seen with acetazolamide but not with insulin or perindopril.

    “These reductions were also observed with another proximal diuretic, namely acetazolamide, but not with insulin or perindopril.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gueguen et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § OTHER PROTECTIVE MECHANISMS · p. 5

    SGLT2 inhibitors lower uric acid, and post hoc trial analyses suggest this reduction at least partly explains their long-term effects.

    “SGLT2 inhibitors reduce uric acid, and post hoc analyses from SGLT2 inhibitor clinical trials suggest that the reduction in uric acid at least partly explains their long-term effects (Zhao et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhao et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 5

    In a diabetes-induced rabbit model, empagliflozin reduced the hyperactive sympathetic response to levels similar to non-diabetic rabbits and suppressed the renal sympathetic baroreflex.

    “Another study in a diabetes-induced rabbit model demonstrated that the SGLT2 inhibitor empagliflozin reduced the hyperactive sympathetic response caused by diabetes to similar levels as in non-diabetic rabbits and suppressed the renal sympathetic baroreflex (Gueguen et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gueguen et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 5

    In human kidney cells, noradrenaline increased SGLT2 expression and promoted its translocation to the cell membrane.

    “In human kidney cells, the neurotransmitter noradrenaline increased SGLT2 expression and promoted SGLT2 translocation to the cell membrane.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Matthews et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 6

    In a head-to-head study, canagliflozin reduced pro-inflammatory mediators compared with glimepiride at equal glycemic control, suggesting direct anti-inflammatory effects may be involved.

    “In this respect it is interesting to note that a head-to-head study comparing canagliflozin with glimepiride demonstrated that at equal glycemic control canagliflozin reduced pro-inflammatory mediators, suggesting that direct anti-inflammatory effects may be involved (Heerspink et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Heerspink et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § SUMMARY AND FUTURE PERSPECTIVES · p. 6

    The clinical benefits of SGLT2 inhibitors can only be realized if they are now implemented in clinical practice.

    “These clinical benefits can only be realized if SGLT2 inhibitors are now implemented in clinical practice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § SUMMARY AND FUTURE PERSPECTIVES · p. 6

    ACE inhibitors and ARBs were shown to have renoprotective effects in the late 1990s and early 2000s.

    “For example, although the renoprotective effects of ACE inhibitors and ARBs were demonstrated in the late 1990s and early 2000s, only 21% of patients with CKD receive these drugs in the United States (Tuttle et al.,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tuttle et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Figure 1. SGLT2 inhibitors reduce NHE3 transporter activity · p. 5

    Increased SNS activity is well described as related to higher blood pressure and impaired glycemic control.

    “The relation between increased SNS activity and increased blood pressure and impaired glycemic control has been well described (Schlaich et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schlaich et al., 2015 source

      Not checked in the free run.

41 of 41

  • The authors state this as an assumption.

    The exact mechanisms by which SGLT2 inhibitors protect the kidney are not fully known.

    “Although the precise underlying mechanisms for these nephroprotective effects are incompletely understood, various hypotheses have been proposed”

  • The paper relies on this without support.

    Lowering blood pressure protects the kidney.

    “Hypertension is an important risk factor for progressive kidney function loss, and blood pressure lowering has been associated with kidney protection.”

  • The paper relies on this without support.

    The mechanisms of SGLT2 inhibitors are largely independent of improvements in glycemic control.

    “as these mechanisms are largely independent of improvements in glycemic control”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Sen, T., & Heerspink, H. J. L.
Affiliations
University Medical Center Groningen (NL)
Corresponding author
Heerspink, Hiddo J.L.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2021-04
Volume
33
Issue
4
Pages
732-739
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2021.02.016
OpenAlex
W3134370991
Semantic Scholar
ced506fda788e0e800016e27ee2c624d95eff3b7
Cited by
161
References
81
Citations by year
2026: 28 · 2025: 18 · 2024: 33 · 2023: 40 · 2022: 29 · 2021: 13
FWCI
4.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
  • Novo Nordisk
  • Merck
  • AbbVie
  • Janssen Pharmaceuticals
  • Boehringer Ingelheim
  • Bayer
  • Gilead Sciences
  • AstraZeneca
  • Mitsubishi Tanabe Pharma Corporation
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
SGLT2 inhibitors, SGLT2, renal protection, type 2 diabetes, tubuloglomerular feedback, intraglomerular pressure, blood pressure reduction, vascular function, autophagy, renal failure
MeSH terms
Sodium-Hydrogen Exchanger 3, Sodium-Glucose Transporter 2 Inhibitors, Animals, Hypoxia, Blood Pressure, Diabetes Mellitus, Type 2, Humans, Kidney, Vasoconstriction, Renal Insufficiency, Chronic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review