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Cited by 123Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesAcute Kidney Injury Research

SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation

Open access
Tuttle, Katherine R., Brosius, Frank C., Cavender, Matthew A., Fioretto, Paola, Fowler, Kevin J., Heerspink, Hiddo J.L., Manley, Tom, McGuire, Darren K. +9 more·2021·Diabetes
DOI 10.2337/dbi20-0040PMC PMC8162454
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Abstract

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

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Crossref · 10.2337/dbi20-0040

Cites

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Claims the paper makes

0 of 158 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Preclinical data suggest that tubuloglomerular feedback may also occur by locally produced adenosine binding receptors that activate vasodilation in the efferent arteriole.

    “Notably, preclinical data suggest that tubuloglomerular feedback may also occur by locally produced adenosine binding receptors that activate vasodilation in the efferent arteriole (25).”
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    • cites [25] Ren, 2001, Efferent arteriole tubuloglomerular feedback in the renal nephron, Kidney Int source

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  • Premisenone given

    SGLT2 inhibitors improve glomerular hemodynamic function.

    “SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    When sodium chloride enters the macula densa, vasoactive substances such as adenosine are locally formed and released.

    “When sodium chloride enters the macula densa, vasoactive substances such as adenosine are locally formed and released.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Heerspink, 2016, Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications, Circulation source

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    • cites [20] Vallon, 2017, Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition, Diabetologia source

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  • Premisecitation

    Empagliflozin reduced the risk for secondary kidney disease endpoints including albuminuria progression, serum creatinine doubling, kidney failure, and death.

    “Empagliflozin also reduced the risk for secondary kidney disease end points (albuminuria progression, serum creatinine doubling, kidney failure, and death) (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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  • Interpretationcitation

    The kidney benefits of SGLT2 inhibitors appear largely independent of glycemic control.

    “The kidney benefits of SGLT2 inhibitors appear to be largely independent of glycemic control based on a growing series of observations.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source

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    • cites [15] Cannon, 2020, Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c &lt;7%: results from the CREDENCE Trial, Circulation source

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    • cites [16] McMurray, 2019, The Dapagliflozin in Heart Failure with Reduced Ejection Fraction Trial (DAPA-HF): outcomes in patients with CKD and effects on renal function

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  • May combine two claims. 36
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    In cardiovascular safety trials of SGLT2 inhibitors in type 2 diabetes, secondary kidney endpoints and cardiovascular events were consistently reduced.

    “In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

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    • cites [13] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med source

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    Premisecitation

    EMPA-REG OUTCOME was the first cardiovascular outcome trial to demonstrate safety of an SGLT2 inhibitor and the first to show clear benefit of a glucose-lowering agent for major adverse cardiovascular events in type 2 diabetes with atherosclerotic cardiovascular disease.

    “The first reported cardiovascular disease (CVD) outcome trial (CVOT) to demonstrate safety of an SGLT2 inhibitor, the EMPA-REG OUTCOME trial, was also the first to show clear benefit of a particular glucose-lowering agent for protection against major adverse cardiovascular events (MACE) in people with T2DM and ASCVD.”
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    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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    Premisecitation

    Different BOLD-MRI techniques lead to varying results and current technology is not sufficiently sensitive to identify tubular segments.

    “Different BOLD-MRI techniques lead to varying results and current technology is not sufficiently sensitive to identify tubular segments.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Yin, 2012, Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI, Eur J Radiol source

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  • May combine two claims.

    Interpretationreasoning

    By reducing sodium and glucose reabsorption, SGLT2 inhibitors reduce tubular workload and mitigate hypoxia in the proximal tubule.

    “By reducing sodium and glucose reabsorption, SGLT2 inhibitors reduce tubular workload and mitigate hypoxia in the proximal tubule.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The resulting increased glucose and sodium reabsorption increases oxygen demand, rendering the proximal tubule relatively hypoxic.

    “The resulting increased glucose and sodium reabsorption increases oxygen demand, which in turn renders the proximal tubule relatively hypoxic (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Layton, 2018, SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism, Am J Physiol Renal Physiol source

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    Interpretationreasoning

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

    “Thus, although the acute reduction in GFR is consistent in patients with T1DM and T2DM, the underlying glomerular hemodynamic effectors may differ.”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    Lack of a compensatory increase in heart rate suggests commensurate blunting of sympathetic nervous system activity, which may also contribute to salutary effects of SGLT2 inhibitors compared with other diuretics.

    “Lack of a compensatory increase in heart rate suggests commensurate blunting of sympathetic nervous system activity, which may also contribute to salutary effects of SGLT2 inhibitors compared with other diuretics (36,37).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Sano, 2019, Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects, Circulation source

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    • cites [37] Scheen, 2019, Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure, Curr Cardiol Rep source

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    Premisecitation

    Participants receiving canagliflozin had lower plasma levels of inflammatory and fibrotic mediators compared with those receiving glimepiride despite similar levels of glycemia, suggesting a glucose-independent effect.

    “Although the mechanism for reduced inflammation with SGLT2 inhibition is unknown, study participants receiving canagliflozin had lower plasma levels of inflammatory and fibrotic mediators compared with those receiving glimepiride despite similar levels of glycemia, suggesting a glucose-independent effect (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Heerspink, 2019, Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease, Diabetologia source

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    Premisecitation

    The cardiovascular outcome trials and CREDENCE were comparable in key aspects: type 2 diabetes participants, placebo controls, SGLT2 inhibitor dose not based on glycemia, all participants treated by standard of care, and similarly defined and adjudicated outcomes.

    “The CVOTs designed to test safety and a CKD trial (CREDENCE) were comparable in key aspects: participants with T2DM, placebo controls, SGLT2 inhibitor dose not based on glycemia, all participants treated by standard of care, and similarly defined and adjudicated outcomes.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

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    • cites [13] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med source

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    • cites [14] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source

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    • cites [15] Cannon, 2020, Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c &lt;7%: results from the CREDENCE Trial, Circulation source

      Not checked in the free run.

    • cites [16] McMurray, 2019, The Dapagliflozin in Heart Failure with Reduced Ejection Fraction Trial (DAPA-HF): outcomes in patients with CKD and effects on renal function

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    • cites [35] Zinman, 2015, Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes, N Engl J Med source

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  • May combine two claims.

    Interpretationcitation

    Reduction in interstitial fluid in the kidney and reduced proximal tubular energy requirements may alleviate cortical and outer medullary hypoxia.

    “Reduction in interstitial fluid in the kidney and reduced proximal tubular energy requirements may alleviate cortical and outer medullary hypoxia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hyperuricemia may induce kidney inflammation and has been reported as a risk factor for incident diabetic kidney disease in type 2 diabetes.

    “Hyperuricemia may induce kidney inflammation and has been reported to be a risk factor for incident DKD in T2DM (43).”
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    • cites [43] Zoppini, 2012, Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function, Diabetes Care source

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    Premisecitation

    In DECLARE-TIMI 58, the point estimate of efficacy was numerically lower in participants with atherosclerotic cardiovascular disease (HR 0.90; 95% CI 0.79-1.02) than in those without (HR 1.01; 95% CI 0.86-1.20), but neither subgroup achieved statistical significance nor was the interaction significant.

    “The point estimate of efficacy was numerically lower in participants with ASCVD (HR, 0.90; 95% CI, 0.79–1.02) than in those without ASCVD (HR, 1.01; 95% CI, 0.86–1.20), but results in neither subgroup achieved statistical significance nor was the interaction significant.”
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    • cites [13] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med source

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    Premisecitation

    In CREDENCE, risk for 3-point major adverse cardiovascular events was significantly reduced with canagliflozin versus placebo overall (HR 0.80; 95% CI 0.67-0.95) and in the primary prevention cohort for atherosclerotic cardiovascular disease (HR 0.68; 95% CI 0.49-0.94), and was numerically similar in the secondary prevention cohort (HR 0.85; 95% CI 0.69-1.06).

    “Risk for 3-point MACE was significantly reduced with canagliflozin versus placebo overall (HR, 0.80; 95% CI, 0.67–0.95) and in the primary prevention cohort for ASCVD (HR, 0.68; 95% CI, 0.49–0.94), and was numerically similar in the secondary prevention cohort (HR, 0.85; 95% CI, 0.69–1.06) (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Mahaffey, 2019, Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups, Circulation source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Mitochondrial dysfunction may further aggravate ATP deficiency and hypoxia, which could conceivably be alleviated by SGLT2 inhibition.

    “Mitochondrial dysfunction may further aggravate ATP deficiency and hypoxia, which could conceivably be alleviated by SGLT2 inhibition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Formal interaction testing did not identify statistically significant differences in the effect of canagliflozin in patients with or without established atherosclerotic cardiovascular disease; HRs were 0.82 (95% CI 0.72-0.95) and 0.98 (95% CI 0.74-1.30), respectively.

    “Although formal interaction testing did not identify statistically significant differences in the effect of canagliflozin in patients with or without established ASCVD, HRs in participants with and without ASCVD were 0.82 (95% CI, 0.72–0.95) and 0.98 (95% CI, 0.74–1.30), respectively (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Mahaffey, 2018, Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study), Circulation source

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  • May combine two claims.

    Premisecitation

    Higher urinary levels of tricarboxylic acid cycle metabolites predict kidney disease progression, and higher glucose metabolic flux promotes proximal tubular mitochondrial dysfunction.

    “Moreover, higher urinary levels of tricarboxylic acid cycle metabolites predict kidney disease progression, and higher glucose metabolic flux promotes proximal tubular mitochondrial dysfunction (32).”
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    • cites [32] Sas, 2016, Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications, JCI Insight source

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    Premisecitation

    Reductions in hospitalizations for heart failure were seen in EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, including patients with and without prevalent atherosclerotic cardiovascular disease and those with and without a history of heart failure.

    “Reductions in hospitalizations for HF were seen in EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, including patients with and without prevalent ASCVD and those with and without a history of HF.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

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    • cites [13] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with type 2 diabetes are at high risk for atherosclerotic cardiovascular disease and heart failure compared with nondiabetic individuals.

    “Patients with T2DM are at high risk for ASCVD and HF compared with nondiabetic individuals (50,53).”
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    • cites [50] Rawshani, 2017, Mortality and cardiovascular disease in type 1 and type 2 diabetes, N Engl J Med source

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    • cites [53] Cavender, 2015, Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) Registry, Circulation source

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    Premisecitation

    The effect on new-onset albuminuria was observed in CANVAS and DECLARE-TIMI-58, but not in the EMPA-REG OUTCOME trial.

    “This effect was observed in CANVAS (12) and DECLARE-TIMI-58 (67), but not in the EMPA-REG OUTCOME trial (11).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

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    • cites [67] Raz, 2019, Effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: a predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial source

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    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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    Interpretationcitation

    Particularly plausible mechanisms for cardiovascular benefit include effects on volume status, natriuresis, expansion of red blood cell mass, and myocardial energetics.

    “Those that appear particularly plausible include effects on volume status, natriuresis, expansion of red blood cell mass, and myocardial energetics (34,36,59,62,64).”
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    • cites [34] Lambers Heerspink, 2013, Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes, Diabetes Obes Metab source

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    • cites [36] Sano, 2019, Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects, Circulation source

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    • cites [59] Inzucchi, 2018, How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial, Diabetes Care source

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    • cites [62] Verma, 2018, SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review, Diabetologia source

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    • cites [64] Mazer, 2020, Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease, Circulation source

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  • May combine two claims.

    Premisecitation

    In CREDENCE, 29.8% of participants had a baseline eGFR of 30 to 45 mL/min/1.73 m2, and kidney benefits did not differ from those in patients with higher eGFR.

    “In CREDENCE, 29.8% (1,313/4,401) of participants had a baseline eGFR of 30 to 45 mL/min/1.73 m2, and kidney benefits did not differ from those in patients with higher eGFR (14,69).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source

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    • cites [69] Neuen, 2019, SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis, Lancet Diabetes Endocrinol source

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  • May combine two claims.

    Interpretationreasoning

    The albuminuria-lowering effect occurs within weeks after initiation of treatment and is presumably due to glomerular hemodynamic effects.

    “The albuminuria-lowering effect occurs within weeks after initiation of treatment and is presumably due to glomerular hemodynamic effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the cardiovascular outcome trials and CREDENCE, kidney-protective effects are consistent overall and in participants with different levels of glycemic control (HbA1c below 7% or above 9%) or eGFR strata (above 90, 60-90, or 30-60 mL/min/1.73 m2).

    “In the CVOTs and CREDENCE, kidney-protective effects are consistent overall (Fig. 6) (69) and in participants with different levels of glycemic control (HbA1c <7% or >9%) or eGFR strata (>90, 60–90, or 30–60 mL/min/1.73 m2) (11,12,14,70).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

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    • cites [14] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source

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    • cites [70] Mosenzon, 2019, Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial, Lancet Diabetes Endocrinol source

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  • May combine two claims.

    Premisecitation

    After the first 4 weeks of treatment during which eGFR declined with empagliflozin, eGFR stabilized in the empagliflozin groups and declined steadily in the placebo group.

    “Importantly, after the first 4 weeks of treatment during which eGFR declined with empagliflozin, eGFR stabilized in the empagliflozin groups and declined steadily in the placebo group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source

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  • May combine two claims.

    Premisenone given

    Treatment with SGLT2 inhibitors increases the likelihood to regress from severely to moderately increased albuminuria or normal albuminuria and from moderately increased albuminuria to normal albuminuria.

    “Treatment with SGLT2 inhibitors also increases the likelihood to regress from severely to moderately increased albuminuria or normal albuminuria and from moderately increased albuminuria to normal albuminuria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DAPA-HF was the first clinical trial of an SGLT2 inhibitor to assess heart failure events as the primary outcome and to include participants with and without diabetes.

    “DAPA-HF was the first clinical trial of an SGLT2 inhibitor to assess HF events as the primary outcome and to include participants with and without diabetes (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Rawshani, 2017, Mortality and cardiovascular disease in type 1 and type 2 diabetes, N Engl J Med source

      Not checked in the free run.

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

    Premisenone given

    SGLT2 inhibitors were initially approved for type 2 diabetes as glucose-lowering agents without increased risk for hypoglycemia.

    “SGLT2 inhibitors were initially approved for T2DM as glucose-lowering agents without increased risk for hypoglycemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients with eGFR below 45 mL/min/1.73 m2, SGLT2 inhibitors have nominal effects on glycemia, although reductions in eGFR decline, blood pressure, and body weight are maintained.

    “This observation is clinically relevant because in patients with eGFR <45 mL/min/1.73 m2, SGLT2 inhibitors have nominal effects on glycemia, although reductions in eGFR decline, blood pressure, and body weight are maintained (72,73).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [72] Kohan, 2014, Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control, Kidney Int source

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    • cites [73] Neuen, 2018, Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function, Circulation source

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  • May combine two claims.

    Premisecitation

    Higher amputation and fracture risks were not seen in cardiovascular outcome trials of other SGLT2 inhibitors or with canagliflozin in CREDENCE.

    “Higher risks for amputation and fracture were not observed in CVOTs of other SGLT2 inhibitors or with canagliflozin in the CREDENCE trial (14,69,95).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source

      Not checked in the free run.

    • cites [69] Neuen, 2019, SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis, Lancet Diabetes Endocrinol source

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    • cites [95] Donnan, 2019, Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis, BMJ Open source

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  • May combine two claims.

    Premisecitation

    That model predicted that empagliflozin plus standard care would raise out-of-pocket costs but extend survival by 2.1 life-years.

    “The model predicted that although patients would incur increased out-of-pocket cost, empagliflozin in addition to standard of care would result in longer survival by 2.1 life-years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Kansal, 2019, Cost-effectiveness analysis of empagliflozin treatment in people with Type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial, Diabet Med source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Dapagliflozin and sotagliflozin also have regulatory approval in Europe as glucose-lowering agents adjunctive to insulin for type 1 diabetes.

    “Dapagliflozin and sotagliflozin also have regulatory approval in Europe as glucose-lowering agents adjunctive to insulin for T1DM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fournier gangrene is rare (about 1 in 10,000 patients) but serious and has been reported in FDA post-market safety reports.

    “Among putative side effects of SGLT2 inhibitors, Fournier gangrene is rare (1 in 10,000 patients) but serious and has been reported in post–market approval safety reports to the FDA (93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Dave, 2019, Association of sodium-glucose cotransporter 2 inhibitor treatment with risk of hospitalization for Fournier gangrene among men, JAMA Intern Med source

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

    Premisecitation

    In EMPA-REG OUTCOME, 1,827 participants (26%) were not receiving metformin.

    “For example, in the EMPA-REG OUTCOME trial, 1,827 (26%) participants were not treated with metformin (84).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Harrington, 2018, Should metformin remain first-line medical therapy for patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease? An alternative approach, Curr Diab Rep source

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  • May combine two claims.

    Premisenone given

    Important adverse effects of SGLT2 inhibitors are euglycemic ketoacidosis, genital mycotic infections, and volume depletion.

    “Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent report found that advising daily genital rinsing after voiding and before bedtime significantly reduced genital mycotic infection risk (6/125 vs. 51/125; P = 0.015) and improved SGLT2 inhibitor adherence over 3 years.

    “In a recent report, advice given for daily rinsing of the genital area after voiding and before bedtime significantly lessened the risk for genital mycotic infections (6/125 vs. 51/125; P = 0.015) and improved adherence to SGLT2 inhibitor treatment over a 3-year period (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Williams, 2019, 1224-P: Improving compliance with SGLT2 inhibitors by reducing the risk of genital mycotic infections: the outcomes of personal hygiene advice, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SGLT2 inhibitors do not raise the risks of acute kidney injury or urinary tract infection, and acute kidney injury is less common.

    “Despite theoretical concerns for acute kidney injury and urinary tract infection, SGLT2 inhibitors do not increase these risks and acute kidney injury is less common (69,95).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Neuen, 2019, SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [95] Donnan, 2019, Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis, BMJ Open source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    People with type 1 or type 2 diabetes who take insulin are at especially high risk of ketoacidosis, and the risk is greatest in type 1 diabetes.

    “Patients with either T1DM or T2DM taking insulin are at particular risk, with the greatest risk for ketoacidosis in T1DM.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [89] Ogawa, 2016, Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors, J Diabetes Investig source

      Not checked in the free run.

    • cites [90] Rosenstock, 2015, Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the CANVAS program, canagliflozin was associated with higher risks of lower extremity amputation (mainly toe or metatarsal; 6.3 vs. 3.4 per 1,000 person-years) and fracture (15.4 vs. 11.9 per 1,000 person-years) than placebo.

    “Higher risks for lower extremity amputation, mainly toe or metatarsal (6.3 vs. 3.4 per 1,000 person-years), and fractures (15.4 vs. 11.9 per 1,000 person-years) were reported for canagliflozin versus placebo in the CANVAS program (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although the glucose-lowering effect of SGLT2 inhibitors is attenuated with reduced eGFR, adjustment of concomitant glucose-lowering agents may be required to avoid hypoglycemia if administered with insulin, sulfonylureas, or glinides.

    “Although the glucose-lowering effect of SGLT2 inhibitors is attenuated with reduced eGFR, adjustment of concomitant glucose-lowering agents may be required to avoid hypoglycemia if administered with insulin, sulfonylureas, or glinides.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    The CKD and cardiovascular benefits of SGLT2 inhibitors are largely independent of the SGLT2 inhibitor dose used.

    “Because the CKD and CVD benefits are largely independent of SGLT2 inhibitor dose, preservation of insulin dosing with SGLT2 inhibitor dose reduction is preferable to mitigate the risk for ketoacidosis.”

  • The paper relies on this without support.

    Euglycemic ketoacidosis, genital mycotic infections, and volume depletion are important risks of SGLT2 inhibitors that require consideration in treatment decisions.

    “Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion.”

  • The paper relies on this without support.

    Findings from SGLT2 inhibitor clinical trials in selected populations can be generalized to routine clinical practice when trial entry criteria are met.

    “SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria.”

  • The paper relies on this without support.

    The risks of euglycemic ketoacidosis, genital mycotic infections, and volume depletion apply across the SGLT2 inhibitor class.

    “These risks occur across the SGLT2 inhibitor class.”

  • The paper relies on this without support.

    Even when awareness of SGLT2 inhibitor benefits is greater, their high cost remains a barrier to use.

    “Even with greater awareness of the benefits of SGLT2 inhibitors, their high cost poses a barrier to use.”

  • The paper relies on this without support.

    Most participants in the SGLT2 inhibitor clinical trials were also taking metformin, but some were not.

    “Most participants enrolled in the clinical trials of SGLT2 inhibitors were concomitantly treated with metformin, although some were not.”
6 of 6

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • DAPA-HF description cites an unrelated reference

    Minor

    The sentence introducing DAPA-HF cites reference 50, which is listed as a study of mortality and cardiovascular disease in diabetes. The paper lists the DAPA-HF trial report separately as reference 58.

  • CREDENCE analysis cites a DAPA-HF reference

    Minor

    The CREDENCE cardiovascular analysis is attributed to reference 16, but that reference describes a DAPA-HF presentation, not CREDENCE.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Centers for Disease Control and Prevention, 2020, National Diabetes Statistics Report, 2020
  2. International Diabetes Foundation, 2019, IDF Diabetes Atlas
  3. AstraZeneca . Farxiga phase III DAPA-CKD trial will be stopped early after overwhelming efficacy in patients with chronic kidney disease. Accessed 28 April 2020. Available from https://www.astrazeneca.com/media-centre/press-releases/2020/farxiga-phase-iii-dapa-ckd-trial-will-be-stopped-early-after-overwhelming-efficacy-in-patients-with-chronic-kidney-disease.html

Cited by

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Related

Authors
Tuttle, K. R., Brosius, F. C., Cavender, M. A., Fioretto, P., Fowler, K. J., Heerspink, H. J. L., Manley, T., McGuire, D. K., Molitch, M. E., Mottl, A. K., Perreault, L., Rosas, S. E., Rossing, P., Sola, L., Vallon, V., Wanner, C., & Perkovic, V.
Affiliations
  • University of Washington (US)
  • University of Arizona (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Padua (IT)
  • Elkhart Clinic (US)
  • University of Groningen (NL)
  • National Kidney Foundation (US)
  • The University of Texas Southwestern Medical Center (US)
  • Northwestern University (US)
  • University of Colorado Anschutz (US)
  • Joslin Diabetes Center (US)
  • University of Copenhagen (DK)
  • University of the Republic, Montevideo, Uruguay
  • University of California San Diego (US)
  • Universitätsklinikum Würzburg (DE)
  • UNSW Sydney (AU)
Corresponding author
Tuttle, Katherine R.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2020-10-26
Volume
70
Issue
1
Pages
1-16
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/dbi20-0040
PMC
PMC8162454
OpenAlex
W3093635194
Cited by
123
References
99
Citations by year
2026: 8 · 2025: 24 · 2024: 19 · 2023: 21 · 2022: 34 · 2021: 16 · 2020: 1
FWCI
2.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • Padua Research Archive (University of Padova) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
  • Amgen
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Gilead Sciences
  • Edwards Lifesciences
  • University of Michigan
  • CSL Behring
  • Boston Scientific Corporation
  • Ironwood Pharmaceuticals, Incorporated
  • Providence Health Care
  • Steno Diabetes Center Copenhagen (SDCC 3.A Complications)
  • Bayer HealthCare
  • Eisai
  • Novo Nordisk
  • Astellas Pharma
  • Esperion Therapeutics
  • National Institutes of Health
  • Centers for Disease Control and Prevention
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Duke Clinical Research Institute
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, chronic kidney disease, cardiovascular disease, type 2 diabetes, canagliflozin, albuminuria, renal failure, glomerular hemodynamics, euglycemic diabetic ketoacidosis, genital mycotic infections, hypovolemia, risk mitigation, implementation strategies, CREDENCE trial
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Education, Humans, 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.

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