SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis
Open accessAbstract
Background The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. Methods We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin–angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). Findings From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE–TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52–0·86, p=0·0019), an effect consistent across studies ( I 2 =0%, p heterogeneity =0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53–0·81, p<0·0001), and acute kidney injury (0·75, 0·66–0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (p trend =0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30–45 mL/min per 1·73 m 2 (RR 0·70, 95% CI 0·54–0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (p trend =0·66) and use of RAS blockade (p heterogeneity =0·31). Interpretation SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. Funding None.
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Claims the paper makes
18 of 31 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The mechanism for the effect on kidney haemodynamics has only been studied in patients with type 1 diabetes with whole-kidney hyperfiltration and at an individual nephron level in animal models.
“the mechanism for the effect on kidney haemodynamics has only been studied in patients with type 1 diabetes with whole-kidney hyperfiltration and at an individual nephron level in animal models; 39”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Kidokoro, 2019, Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging, Circulation source
The Discussion (page unavailable) reports prior whole-kidney haemodynamic measurements in patients with type 1 diabetes, and the Conclusions describe this paper’s single-nephron findings in diabetic mice. The paper does not establish the claim’s exclusive “only been studied” limit; it also mentions an empagliflozin study in children with type 2 diabetes, though not a direct study of the mechanism. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
RAS blockade is the only other treatment effective in slowing the progression of diabetic kidney disease.
“the only other treatment effective in slowing the progression of diabetic kidney disease”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Tuttle, 2017, Back to the future: glomerular hyperfiltration and the diabetic kidney, Diabetes source
- Premisecitation
A plausible mechanistic explanation for the renoprotective effect of SGLT2 inhibitors is correction of aberrant glomerular haemodynamics induced by hyperglycaemia, which drive progressive nephron loss.
“A plausible mechanistic explanation for the renoprotective effect of SGLT2 inhibitors is correction of aberrant glomerular haemodynamics induced by hyperglycaemia, which drive progressive nephron loss.34,35”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [34] Alicic, 2017, Diabetic kidney disease: challenges, progress, and possibilities, Clin J Am Soc Nephrol source
The Pathophysiology of DKD passage (page unavailable) links hyperglycemia and SGLT2-mediated glucose reabsorption to altered tubuloglomerular feedback, high intraglomerular pressure, and hyperfiltration. A later passage reports that the SGLT2 inhibitor empagliflozin slowed diabetic kidney disease progression, but our copy does not explicitly say that correcting those hemodynamics explains its benefit or that they drive progressive nephron loss. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [35] Tonneijck, 2017, Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment, J Am Soc Nephrol source
- Interpretationcitation
The absence of effect modification by baseline albuminuria contrasts with findings from trials of RAS blockade.
“The absence of effect modification by baseline albuminuria contrasts with the findings from trials of RAS blockade.[31][32][33]”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [31] Jafar, 2001, Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data, Ann Intern Med source
- cites [32] Kent, 2007, Progression risk, urinary protein excretion, and treatment effects of angiotensin-converting enzyme inhibitors in nondiabetic kidney disease, J Am Soc Nephrol source
- cites [33] Molitch, 2015, Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes, Kidney Int source
The Abstract says the benefit of RAAS blockade for CKD progression in people without increased albumin excretion is unclear, while BP management reports benefits in several trials involving hypertensive diabetic patients. This supports a contrast in the evidence across patient groups, but the paper does not report that baseline albuminuria itself modified the treatment effect; the groups also differ in blood pressure status. Page numbers are not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Interpretationreasoning
The absolute benefits of SGLT2 inhibition are likely to be at least as large for people with eGFR lower than 45 as for those with higher eGFRs.
“the absolute benefits of SGLT2 inhibition are likely to be at least as large as those for people with higher eGFRs.30”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Gansevoort, 2011, Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts, Kidney Int source
The Discussion reports substantially higher risk of end-stage renal disease at lower eGFR, supporting the claim’s premise that people with lower eGFR have more kidney risk. The paper does not study SGLT2 inhibition or compare its absolute benefits across eGFR groups, so it cannot establish the treatment-benefit comparison. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Individuals with eGFR lower than 45 are at much greater risk of kidney failure than those with higher eGFRs.
“Because these individuals are at much greater risk of kidney failure than those with higher eGFRs”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Gansevoort, 2011, Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts, Kidney Int source
- Premisecitation
Large-scale cardiovascular outcome trials of SGLT2 inhibitors have shown promising effects on a range of albuminuria and serum creatinine-based kidney outcomes in patients with, or at high risk of, atherosclerotic cardiovascular disease.
“Large-scale cardio vascular outcome trials [10][11][12][13][14][15] of SGLT2 inhibitors, which were originally designed to meet regulatory requirements and ensure cardiovascular safety, have shown promising effects on a range of albuminuria and serum creatinine-based kidney outcomes in patients with, or at high risk of, atherosclerotic cardiovascular disease.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [10] Perkovic, 2018, Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials, Lancet Diabetes Endocrinol source
- cites [11] Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med source
- cites [12] Neuen, 2018, Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program, Circulation source
- Findingown data
The effect of SGLT2 inhibitors on substantial loss of kidney function, end-stage kidney disease, or death due to cardiovascular or kidney disease varies across studies, primarily because of the EMPA-REG OUTCOME trial (I2=60.3%, p heterogeneity=0.056).
“The overall effect of SGLT2 inhibitors on substantial loss of kidney function, endstage kidney disease, death due to cardiovascular or kidney disease (overall 29% reduction; figure 2) varied across studies, primarily because of the EMPA-REG OUTCOME trial, in which a greater magnitude of effect on death due to cardiovascular disease was observed (I²=60•3%, p heterogeneity =0•056).”
Quote in the paperNot a substantial claim - Findingown data
SGLT2 inhibitor treatment reduces the risk of end-stage kidney disease by 35% compared with placebo.
“SGLT2 inhibitor treatment reduced the risk of end-stage kidney disease by 35% (figure 2), with no differences in treatment effect across studies (I²=0•0%, p heterogeneity =0•41).”
Quote in the paperSubstantial claim - Findingown data
SGLT2 inhibitor treatment lowers the risk of acute kidney injury by 25% compared with placebo.
“Treatment with SGLT2 inhibitors also lowered the risk of acute kidney injury by 25% (figure 3), with no evidence of differences between studies (I²=0%, p heterogeneity =0•68).”
Quote in the paperSubstantial claim - Findingown data
There is no evidence of differences between studies in the effect of SGLT2 inhibitors on substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease (I2=0.0%, p heterogeneity=0.49).
“The use of SGLT2 inhibitors also reduced the risk of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease by 42% (figure 2), with no evidence of differences between studies (I²=0•0%, p heterogeneity =0•49).”
Quote in the paperNot a substantial claim - Findingown data
The effect of SGLT2 inhibitors on the composite outcome of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease is consistent between users and non-users of RAS blockade at baseline (p heterogeneity=0.31).
“The effect of SGLT2 inhibitors was also consistent between users and non-users of RAS blockadebased treatments at baseline (p heterogeneity =0•31; figure 5C).”
Quote in the paperNot a substantial claim - Findingreasoning
The greatest absolute benefit of SGLT2 inhibitors in terms of eGFR decline was seen in the CREDENCE trial (2.74 mL/min per 1.73 m2 per year, 95% CI 2.37-3.11).
“As a result, annual placebo-subtracted differences in eGFR also differed, with the greatest absolute benefit in terms of eGFR decline seen in the CREDENCE trial (2•74 mL/min per 1•73 m² per year, 95% CI 2•37-3•11).”
Quote in the paperNot a substantial claim - Findingown data
There is no evidence of differences between studies in the effect of SGLT2 inhibitors on acute kidney injury (I2=0%, p heterogeneity=0.68).
“Treatment with SGLT2 inhibitors also lowered the risk of acute kidney injury by 25% (figure 3), with no evidence of differences between studies (I²=0%, p heterogeneity =0•68).”
Quote in the paperNot a substantial claim - Findingown data
SGLT2 inhibitor treatment reduces the risk of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease by 42% compared with placebo.
“The use of SGLT2 inhibitors also reduced the risk of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease by 42% (figure 2), with no evidence of differences between studies (I²=0•0%, p heterogeneity =0•49).”
Quote in the paperSubstantial claim - Findingown data
SGLT2 inhibitor treatment reduces the risk of dialysis, transplantation, or death due to kidney disease by 33% compared with placebo.
“SGLT2 inhibitor treatment reduced the risk of dialysis, transplantation, or death due to kidney disease by 33% (figure 1) compared with placebo.”
Quote in the paperSubstantial claim - Findingown data
The effect of SGLT2 inhibitors on the composite outcome of dialysis, transplantation, or death due to kidney disease is consistent across studies (I2=0%, p heterogeneity=0.53).
“The effect of SGLT2 inhibitors on this outcome was consistent across studies (I²=0%, p heterogeneity =0•53).”
Quote in the paperNot a substantial claim - Findingown data
There is no evidence of differences in treatment effect of SGLT2 inhibitors on the composite outcome of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease across UACR subgroups (p trend=0.66).
“We identified no evidence of differences in treatment effect for the composite outcome across UACR subgroups (p trend =0•66; figure 5B).”
Quote in the paperSubstantial claim - Findingown data
The rate of eGFR decline in participants treated with placebo varied between trials, from -0.85 mL/min per 1.73 m2 per year in the CANVAS Program to -4.59 mL/min per 1.73 m2 per year in the CREDENCE trial.
“The rate of eGFR decline in participants treated with placebo varied between trials, from -0•85 mL/min per 1•73 m² per year in the CANVAS Program to -4•59 mL/min per 1•73 m² per year in the CREDENCE trial.”
Quote in the paperSubstantial claim - Findingown data
There are no differences in the effect of SGLT2 inhibitors on end-stage kidney disease across studies (I2=0.0%, p heterogeneity=0.41).
“SGLT2 inhibitor treatment reduced the risk of end-stage kidney disease by 35% (figure 2), with no differences in treatment effect across studies (I²=0•0%, p heterogeneity =0•41).”
Quote in the paperNot a substantial claim - Findingown data
The magnitude of benefit of SGLT2 inhibitors on the composite outcome of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease might be attenuated across progressively lower eGFR subgroups (p trend=0.073).
“We identified some evidence that the magnitude of benefit might be attenuated across progressively lower eGFR subgroups (p trend =0•073; figure 5A).”
Quote in the paperNot a substantial claim - Findingown data
SGLT2 inhibitors reduce the risk of acute kidney injury (RR 0.58, 95% CI 0.51-0.66).
“0•58 (0•51-0•66)”
- Also stated in: § Discussion · plain
“Protection against acute kidney injury is a welcome finding”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
The magnitude of relative (but not absolute) benefit might attenuate somewhat across progressively lower eGFR subgroups.
“Although our findings suggest that the magnitude of relative (but not absolute) benefit might attenuate somewhat across progressively lower eGFR subgroups”
Quote in the paperSubstantial claim - Findingown data
Renoprotection was achieved across the entire spectrum of eGFR levels studied to date, down to an eGFR of 30 mL/min per 1.73 m2.
“these results clearly show that renoprotection was achieved across the entire spectrum of eGFR levels studied to date, down to an eGFR of 30 mL/min per 1•73 m².”
Quote in the paperSubstantial claim - Findingreasoning
Renoprotection with SGLT2 inhibitors is consistent irrespective of baseline use of RAS blockade.
“Furthermore, renoprotection with SGLT2 inhibitors seems consistent, irrespective of baseline use of RAS blockade.”
Quote in the paperSubstantial claim - Findingown data
Clear and consistent benefits of SGLT2 inhibitors were apparent when participants were subdivided into those with an eGFR below 60 mL/min per 1.73 m2 and those with an eGFR of 60 mL/min per 1.73 m2 or higher (p heterogeneity=0.33).
“Clear and consistent benefits were also apparent when participants were subdivided into those with an eGFR below 60 mL/min per 1•73 m² and those with an eGFR of 60 mL/min per 1•73 m² or higher (p heterogeneity =0•33; appendix p 14).”
Quote in the paperSubstantial claim - Findingown data
There is an absence of effect modification by baseline albuminuria.
“The absence of effect modification by baseline albuminuria”
Quote in the paperSubstantial claim - Findingown data
SGLT2 inhibitors reduce the risk of dialysis, transplantation, or death due to kidney disease (RR 0.67, 95% CI 0.52-0.86).
“0•67 (0•52-0•86)”
Quote in the paperSubstantial claim - Findingown data
SGLT2 inhibitors reduce the risk of major kidney outcomes (RR 0.75, 95% CI 0.66-0.85; p<0.0001).
“0•75 (0•66-0•85; p<0•0001)”
Quote in the paperSubstantial claim - Study design and conductown data
The prespecification of outcomes, requirements for changes in kidney function to be confirmed on repeated measurement, and adjudication procedures differed across the included studies.
“The prespecification of outcomes, requirements for changes in kidney function to be confirmed on repeated measurement, and adjudication procedures differed across the studies (appendix pp 4-5).”
Quote in the paperNot a substantial claim - Study design and conductown data
Kidney endpoints were defined and reported differently across the included studies.
“Kidney endpoints were also defined and reported differently across the studies (appendix pp 6-9).”
Quote in the paperNot a substantial claim - Interpretationown data
The protective effect of SGLT2 inhibitors against acute kidney injury allays early concerns about the risk of adverse effects resulting from the haemodynamic mechanism of action of this class of drugs.
“Additionally, the protective effect of SGLT2 inhibitors against acute kidney injury allays early concerns about the risk of adverse effects resulting from the haemodynamic mechanism of action of this class of drugs.”
Quote in the paperNot a substantial claim - Interpretationown data
The benefits of SGLT2 inhibitors are cumulative with those of RAS blockade.
“Furthermore, the inclusion of CREDENCE, a trial that mandated the use of RAS blockade, further supported that the benefits of SGLT2 inhibitors are cumulative with those of RAS blockade.”
Quote in the paperNot a substantial claim - Study design and conductcitation
The early stopping of CREDENCE might increase the risk of overestimating treatment effects.
“which might increase the risk of overestimating treatment effects.43”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Viele, 2016, Interpretation of clinical trials that stopped early, JAMA source
- Interpretationreasoning
Mechanisms other than those associated with albuminuria reduction might also be important for the renoprotective effect of SGLT2 inhibitors.
“These data suggest that mechanisms other than those associated with albuminuria reduction might also be important.”
Quote in the paperSubstantial claim - Interpretationreasoning
Many more individuals at high risk of major kidney outcomes are likely to benefit from SGLT2 inhibitor treatment.
“suggesting that many more individuals at high risk of major kidney outcomes are likely to benefit from treatment”
Quote in the paperSubstantial claim - Study design and conductnone given
No evidence of substantive heterogeneity exists.
“although no evidence of substantive hetero geneity exists”
Quote in the paperSubstantial claim - Interpretationreasoning
SGLT2 inhibition can reduce the risk of dialysis, transplantation, or death due to kidney disease in people with type 2 diabetes and a broad range of risk for kidney outcomes.
“In conclusion, SGLT2 inhibition can reduce the risk of dialysis, transplantation, or death due to kidney disease in people with type 2 diabetes and a broad range of risk for kidney outcomes.”
Quote in the paperSubstantial claim - Study design and conductnone given
The CREDENCE trial alone was specifically powered for kidney outcomes.
“Because the CREDENCE trial alone was specifically powered for kidney outcomes”
Quote in the paperSubstantial claim - Premisecitation
Too few participants with baseline eGFR lower than 60 mL/min per 1.73 m2 were included in that meta-analysis to adequately assess trend by eGFR.
“However, too few participants with baseline eGFR lower than 60 mL/min per 1•73 m² were included in that meta-analysis to adequately assess trend by eGFR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Zelniker, 2018, SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials, Lancet source
- Interpretationreasoning
The restrictions on SGLT2 inhibitor use in people with eGFR <45 are called into question by evidence of renoprotection.
“With evidence of renoprotection now available from the accumulated trials, these restrictions are called into question”
Quote in the paperSubstantial claim - Interpretationreasoning
SGLT2 inhibition should provide benefit for a broader patient population.
“Taken together, these findings suggest that SGLT2 inhibition should provide benefit for a broader patient population.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
The consistency with the results from the other trials reduces the risk of overestimating treatment effects.
“However, the consistency with the results from the other trials reduces that risk and is an important finding of this analysis.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The consistency of effects among other SGLT2 inhibitors remains somewhat uncertain.
“the consistency of effects among other SGLT2 inhibitors remains somewhat uncertain”
Quote in the paperSubstantial claim - Study design and conductown data
A substantial proportion of the data were derived from a single study of canagliflozin (CREDENCE) that was stopped early.
“A substantial proportion of the data were derived from a single study of canagliflozin (CREDENCE) that was stopped early”
Quote in the paperSubstantial claim - Interpretationreasoning
These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent clinically important kidney outcomes in individuals with type 2 diabetes.
“These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent clinically important kidney outcomes in individuals with type 2 diabetes.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 12
- May combine two claims. 23
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationTwo authors independently extracted all data using a standardised data form and assessed risk of bias at the study level using the Cochrane risk-of-bias tool.
“Two authors (BLN and TY) independently extracted all data using a standardised data form and assessed risk of bias at the study level using the Cochrane risk-of-bias tool.18”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Higgins, 2011, The Cochrane Collaboration's tool for assessing risk of bias in randomised trials, BMJ source
May combine two claims.
PremisecitationIn 2019, the results of the CREDENCE trial were reported; it was the first study designed to specifically assess the effect of an SGLT2 inhibitor (canagliflozin) on a primary kidney outcome in people with established diabetic kidney disease.
“In 2019, the results of the CREDENCE trial 17 -the first study designed to specifically assess the effect of an SGLT2 inhibitor (canagliflozin) on a primary kidney outcome in people with established diabetic kidney disease-were reported.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med source
May combine two claims.
PremisecitationSGLT2 inhibitors are not currently indicated for people with an eGFR lower than 45 mL/min per 1.73 m2 in most countries, largely because of insufficient glycaemic efficacy.
“SGLT2 inhibitors are not currently indicated for people with an eGFR lower than 45 ml/min per 1•73 m² in most countries, largely because of insufficient glycaemic efficacy.29”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [29] Toyama, 2019, Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and meta-analysis, Diabetes Obes Metab source
The Introduction (page unavailable) says SGLT2 inhibitors were not approved below an eGFR of 45 mL/min/1.73 m² for empagliflozin and canagliflozin, and below 60 for dapagliflozin and ertugliflozin. It also says glucose-lowering efficacy declines with kidney function, while the Abstract identifies that dependence as the primary reason use in CKD has been limited. The copy does not establish the claim’s geographic qualifier, “in most countries,” or explicitly make insufficient glycaemic efficacy the reason for the stated approval thresholds. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationTreatment with ACE inhibitors or ARBs prevents major adverse kidney outcomes in people with diabetes and is recommended by clinical practice guidelines for people with type 2 diabetes who have or are at high risk of kidney disease.
“Treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been shown to prevent major adverse kidney outcomes in people with diabetes, and these drugs are recommended by clinical practice guidelines for the treatment of people with type 2 diabetes who have, or are at high risk of, kidney disease.[4][5][6][7][8]”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [4] Lewis, 1993, The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy, N Engl J Med source
- cites [5] Lewis, 2001, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes, N Engl J Med source
The Results report fewer primary composite events with irbesartan, an ARB, than with placebo or amlodipine in patients with type 2 diabetes and overt nephropathy. The Discussion cautions against assuming ACE inhibitors have equivalent effects in this population. The paper does not establish prevention in people merely at high risk of kidney disease or state a clinical-practice-guideline recommendation. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [6] Brenner, 2001, Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, N Engl J Med source
The Discussion (p. 4) reports that losartan, an ARB, reduced end-stage renal disease and doubling of serum creatinine in patients with type 2 diabetes and established nephropathy. The paper does not establish the same major kidney-outcome benefit for ACE inhibitors in this population, address people merely at high risk of kidney disease, or report the claimed clinical-practice guideline recommendation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationThe effect of SGLT2 inhibitors parallels that seen with RAS blockade, suggesting similarities in mechanisms of action based on reducing intraglomerular pressure.
“The effect parallels that seen with RAS blockade, the only other treatment effective in slowing the progression of diabetic kidney disease, and suggests some similarities in mechanisms of action based on reducing intraglomerular pressure”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Tuttle, 2017, Back to the future: glomerular hyperfiltration and the diabetic kidney, Diabetes source
May combine two claims.
PremisecitationThe haemodynamic effect of SGLT2 inhibitors results in an early fall in eGFR, followed by protection against decline in kidney function, with reversal on drug cessation.
“This haemodynamic effect results in an early fall in eGFR, but is followed by protection against decline in kidney function, with reversal of the haemodynamic effect achieved on drug cessation.12,37”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [12] Neuen, 2018, Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program, Circulation source
The Discussion describes an acute fall in eGFR after SGLT2 inhibition begins, followed by stabilization and preservation of kidney function. The Results report an early fall and a slower subsequent decline with canagliflozin, but although they mention off-treatment measurements, the passages do not state that the haemodynamic effect reversed after drug cessation. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [37] Fioretto, 2018, Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3a): the DERIVE Study, Diabetes Obes Metab source
May combine two claims.
PremisecitationBlocking sodium reuptake in the proximal tubule restores delivery of sodium to the macula densa, leading to afferent arteriolar constriction and a reduction in intraglomerular pressure.
“Blocking sodium reuptake in the proximal tubule has been suggested to restore delivery of sodium to the macula densa, leading to afferent arteriolar constriction and a reduction in intraglomerular pressure.36”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [36] Cherney, 2014, Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus, Circulation source
May combine two claims. The quote only partly states this claim.
Findingown dataThe systematic review and meta-analysis included four studies comprising five individual trials, with a total of 38,723 randomly assigned participants from six continents.
“Our systematic review and meta-analysis summarises and pools data from four studies including a total of 38 723 participants across six continents.”
- Also stated in: § Results · plain
“Our meta-analysis included data for a total of 38 723 randomly assigned participants from six continents.”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
May combine two claims.
Findingown dataSGLT2 inhibitors provide clear, separately significant benefit on the composite outcome of substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease for all eGFR subgroups, including a 30% relative risk reduction in participants with baseline eGFR lower than 45 mL/min per 1.73 m2.
“However, clear, separately significant evidence of benefit was apparent for all eGFR subgroups, including for participants with a baseline eGFR lower than 45 mL/min per 1•73 m², in whom a 30% relative risk reduction was identified (figure 5A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe results for tests of heterogeneity altered slightly in different sensitivity analyses, but the evidence of clear separate benefit for all eGFR subgroups remained constant.
“The results for tests of heterogeneity altered slightly in the different sensitivity analyses (appendix p 11), but the evidence of clear separate benefit for all eGFR subgroups remained constant.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most participants with baseline eGFR lower than 60 mL/min per 1.73 m² reported without more granular categories were likely to have an eGFR between 45 and <60 mL/min per 1.73 m².
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataAcute kidney injury events, both serious and non-serious, were reported variably across individual trials and were not adjudicated.
“Acute kidney injury events, both serious and non-serious, were reported variably across individual trials and were not adjudicated (appendix p 9).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBecause of the small number of eligible trials, publication bias was not assessed.
“Because of the small number of eligible trials, we did not assess publication bias.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataRenoprotection with SGLT2 inhibitors is achieved across all levels of baseline kidney function, down to an eGFR of 30 mL/min per 1.73 m2, with clear benefits in the subgroup with baseline eGFR between 30 and 45 mL/min per 1.73 m2.
“Importantly, renoprotection was achieved across all levels of baseline kidney function, down to an eGFR of 30 mL/min per 1•73 m², with clear benefits seen even for the subgroup with baseline eGFR between 30 and 45 mL/min per 1•73 m², for whom these drugs are not currently approved for use in most countries.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe risk of bias was low for all indicators in the included studies; all participants and investigators were masked to treatment allocation, with complete reporting of outcomes.
“The risk of bias was low for all indicators; all participants and investigators were masked to treatment allocation, with complete reporting of outcomes (appendix p 3).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe review protocol was registered with PROSPERO before the analyses were initiated and completed.
“The protocol for this review was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) for registration before the analyses were initiated (on April 10, 2019), and the study was registered before the analyses were completed (PROSPERO registration number CRD42019131774).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDiscrepancies in data extraction or risk-of-bias assessment were resolved in consultation with a third author.
“Any discrepancies in data extraction or risk-of-bias assessment were resolved in consultation with a third author (MJJ).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn the 2018 meta-analysis, less than a sixth of participants had baseline eGFR lower than 60 mL/min per 1.73 m2, limiting the ability to robustly assess effect modification by kidney function.
“However, less than a sixth of participants in the analysis had baseline eGFR lower than 60 mL/min per 1•73 m² and thus, the ability to robustly assess effect modification by kidney function was limited.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Zelniker, 2018, SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials, Lancet source
May combine two claims.
PremisereasoningMost participants in the cardiovascular outcome trials of SGLT2 inhibitors were at low risk of clinically important kidney outcomes, and event rates for kidney failure were low.
“Most participants in these trials were at low risk of clinically important kidney outcomes and, as a result, event rates for kidney failure were low, with few participants requiring dialysis or kidney transplantation, or dying from kidney disease, in each trial.”
Quote in the paperSubstantial claimMay combine two claims.
PremisereasoningVery few participants with baseline eGFR lower than 45 mL/min per 1.73 m2 were assessed in the cardiovascular outcome trials of SGLT2 inhibitors, so whether these patients derive protection against kidney failure outcomes has been unclear.
“Additionally, because very few participants with baseline eGFR lower than 45 mL/min per 1•73 m² were assessed in the cardiovascular outcome trials of SGLT2 inhibitors, whether these patients derive protection against kidney failure outcomes has also been unclear, given that the glycaemic efficacy of SGLT2 inhibitors is substantially attenuated in this population.”
Quote in the paperSubstantial claim- Rests on an assumption: The glycaemic efficacy of SGLT2 inhibitors is substantially attenuated in patients with baseline eGFR lower than 45 mL/min per 1.73 m².
May combine two claims.
Premisenone givenMost participants in cardiovascular outcome trials of SGLT2 inhibitors had normal albuminuria, so the consistency of treatment effect across different levels of albuminuria is unclear.
“Similarly, most participants in cardiovascular outcome trials of SGTL2 inhibitors had normal albuminuria and, therefore, the consistency of treatment effect across different levels of albuminuria is unclear.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThe large number of events and consistency of effect across the trials gives confidence to the finding that SGLT2 inhibitors provide protection against acute kidney injury.
“the large number of events and consistency of effect across the trials is striking and gives confidence to the finding that SGLT2 inhibitors provide protection against acute kidney injury.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenSerious and non-serious acute kidney injury events were investigator reported, collected variably, and not adjudicated.
“Although serious and non-serious acute kidney injury events were investigator reported, collected variably, and not adjudicated”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSGLT2 inhibitors are glucose-lowering drugs that also lower blood pressure, bodyweight, and albuminuria and might have direct haemodynamic effects on the kidney.
“Sodium-glucose co-transporter-2 (SGLT2) inhibitors are glucose-lowering drugs that also lower blood pressure, bodyweight, and albuminuria and might have direct haemodynamic effects on the kidney. 9”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Heerspink, 2016, Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications, Circulation source
Classified as probably not a substantial claim.
PremisecitationA 2018 meta-analysis of cardiovascular outcome trials suggested that the effect of SGLT2 inhibitors on kidney outcomes attenuates with declining eGFR.
“The results of a 2018 meta-analysis 14 of cardiovascular outcome trials suggested that the effect of SGLT2 inhibitors on kidney outcomes attenuates with declining eGFR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Zelniker, 2018, SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials, Lancet source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe glycaemic efficacy of SGLT2 inhibitors is directly proportional to glomerular filtration rate.
“The glycaemic efficacy of SGLT2 inhibitors is directly proportional to glomerular filtration rate, 9,28”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Heerspink, 2016, Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications, Circulation source
- cites [28] Heerspink, 2018, Renoprotective effects of sodium-glucose cotransporter-2 inhibitors, Kidney Int source
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenThe broader generalisability of these results might be somewhat affected by the characteristics of participants in the included studies.
“The broader generalisability of these results might also be somewhat affected by the characteristics of participants in the included studies”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningThe cardiovascular outcome trials of SGLT2 inhibitors were not explicitly designed to provide definitive information on renoprotective effects, so kidney endpoints were not always prespecified or adjudicated and the distinction between acute and chronic reductions in eGFR was not possible in all studies.
“Because these trials were also not explicitly designed to provide definitive information on renoprotective effects, kidney endpoints were not always prespecified or adjudicated and the distinction between acute and chronic reductions in estimated glomerular filtration rate (eGFR) was not possible in all studies.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThese findings strengthen those of a previous meta-analysis of SGLT2 inhibitor cardiovascular outcome trials.
“These findings strengthen those of a previous meta-analysis 16 of SGLT2 inhibitor cardiovascular outcome trials.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Gilbert, 2019, Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: a meta-analysis of cardiovascular outcome trials, Diabetes Obes Metab source
May combine two claims.
PremisecitationAlthough these trials have collectively suggested protection against acute kidney injury, the safety of SGLT2 inhibitors in patients at high risk of adverse kidney outcomes has not been well established.
“Although these trials have collectively suggested protection against acute kidney injury, 16 the safety of SGLT2 inhibitors in patients at high risk of adverse kidney outcomes has not been well established.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Gilbert, 2019, Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: a meta-analysis of cardiovascular outcome trials, Diabetes Obes Metab source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenThe validity of these overview results is reinforced by the high quality of the included studies.
“The validity of these overview results is reinforced by the high quality of the included studies”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningData for acute kidney injury might be less robust than those for other endpoints, because of variances in the collection and reporting of this outcome.
“Data for acute kidney injury might be less robust than those for other endpoints, because of variances in the collection and reporting of this outcome.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
SGLT2 inhibitors are not approved for use in patients with eGFR lower than 45 mL/min per 1.73 m² in most countries, mainly because their glucose-lowering effect is substantially dependent on kidney function.
“Additionally, SGLT2 inhibitors are not approved for use in patients with estimated glomerular filtration rate (eGFR) lower than 45 mL/min per 1•73 m² in most countries, mainly because their glucose-lowering effect is substantially dependent on kidney function.”
The paper relies on this without support.
The glycaemic efficacy of SGLT2 inhibitors is substantially attenuated in patients with baseline eGFR lower than 45 mL/min per 1.73 m².
“given that the glycaemic efficacy of SGLT2 inhibitors is substantially attenuated in this population.”
The authors state this as an assumption.
Most participants with baseline eGFR lower than 60 mL/min per 1.73 m² reported without more granular categories were likely to have an eGFR between 45 and <60 mL/min per 1.73 m².
“on the assumption that most of these participants were likely to have an eGFR within this range (on the basis of trial exclusion criteria).”
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?
Several large randomized controlled trials enrolling over 8000 people showed that SGLT2 inhibitors significantly reduce cardiovascular death or worsening heart failure and improve symptoms, physical limitations, and quality of life in people with heart failure with reduced ejection fraction.
“Several large RCTs, which in combination enrolled over 8000 persons, have demonstrated that SGLT2is significantly reduce the risk of CV death or worsening HF and improve symptoms, physical limitations, and QoL in persons with heart failure with reduced ejection fraction (HFrEF).”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [457]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe benefits of SGLT2 inhibitors were highly consistent in people with and without type 2 diabetes.
“The benefits were highly consistent in persons both with and without T2D; however, because persons with T2D had higher absolute risk, they experienced a greater absolute benefit with SGLT2is vs placebo.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [457]
The Discussion reports kidney benefits from SGLT2 inhibitors in people with type 2 diabetes. It says trials enrolling people with and without type 2 diabetes were still underway, so this paper does not establish that benefits were highly consistent between those groups. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSubgroup meta-analyses based on participants' kidney function indicated that the salutary effects of SGLT2i on MACE, cardiovascular death or hospitalization for heart failure, and a composite kidney outcome do not significantly differ among subgroups based on eGFR.
“Subgroup meta-analyses based on participants ' kidney function indicated that the salutary effects of SGLT2i on MACE, cardiovascular death or HHF, and a composite kidney outcome (substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease) do not signi fi cantly differ among subgroups based on eGFR (142,252).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [252]
The Overall section reports benefits for the composite kidney outcome across eGFR subgroups, with no significant heterogeneity in the below-60 versus 60-or-higher comparison (p=0.33), although it notes a possible trend toward smaller relative benefits at lower eGFR. The paper does not report corresponding eGFR-subgroup findings for MACE or cardiovascular death or hospitalization for heart failure. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients with chronic kidney disease and type 2 diabetes have high residual cardiorenal morbidity and mortality, despite current therapies.
“Patients with chronic kidney disease (CKD) and type 2 diabetes have high residual cardiorenal morbidity and mortality, despite current therapies,1–5”
From Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis (2022) · cites this paper as [4]
The Introduction says that residual kidney risk remains high despite recommended ACE inhibitor or ARB treatment for people with type 2 diabetes who have, or are at risk of, kidney disease. The Results include cardiovascular or kidney death in a composite outcome, but the paper does not establish the claimed high residual cardiovascular morbidity and mortality in patients with both CKD and type 2 diabetes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEvidence from combined major SGLT2 inhibitor trials suggests kidney and cardiovascular benefits are consistent irrespective of baseline albuminuria, including in patients with normal albumin excretion.
“Evidence from combined major SGLT2i trials, however, suggests that kidney and cardiovascular benefits are consistent irrespective of baseline albuminuria (56), including in patients with normal albumin excretion, as reflected in the KDIGO recommendation and consensus statement supporting SGLT2i use in most patients with T2D and CKD (2).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [56]
The Overall results report no evidence that the effect on the composite kidney outcome differed across baseline albuminuria groups. The Data analysis section includes a normal-albuminuria group (UACR <30 mg/g). The cited analysis does not establish that cardiovascular benefits were consistent across those groups. (LLM, conf=0.88)
Experimental — accuracy not yet measured
SGLT2 inhibitors have been observed to have consistent efficacy and safety across studied ranges of eGFR.
“Moreover, SGLT2i have been observed to have consistent efficacy and safety across studied ranges of eGFR (56).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [56]
The Overall section reports kidney benefits in every studied eGFR subgroup, although the relative benefit might attenuate at lower eGFR. It does not establish consistent safety across eGFR ranges: the reported reduction in acute kidney injury is an overall result, not an eGFR-subgroup safety analysis. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDirect evidence supporting initiation of an SGLT2 inhibitor for patients with T2D and eGFR 20-29 mL/min/1.73 m2 is strongest for patients with concomitant albuminuria or heart failure, though efficacy and safety are generally consistent among trial participants with or without these conditions.
“Based on these results, direct evidence supporting initiation of an SGLT2i for patients with T2D and eGFR 20–29 mL/min/1.73 m2 is strongest for patients with concomitant albuminuria or HF, though the efficacy and safety of SGLT2i are generally consistent among trial participants with or without these conditions (56,61,62).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [56]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn the CREDENCE trial and most earlier cardiovascular outcome trials of SGLT2 inhibitors, the lower inclusion cutoff for estimated GFR was 30 ml/min/1.73 m2.
“In that trial, as in most previous cardiovascular outcome trials of SGLT2 inhibitors, the lower estimated GFR cutoff for inclusion was 30 ml per minute per 1.73 m 2 .16”
From Dapagliflozin in Patients with Chronic Kidney Disease (2020) · cites this paper as [16]
Consistency is moderate to high, with consistency of kidney benefit across the trials and by baseline eGFR and albuminuria groups.
“Consistency is moderate to high, with consistency of kidney bene fi t across the trials and by baseline eGFR and albuminuria groups.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
An updated 2019 meta-analysis of EMPA-REG, CANVAS, CREDENCE, and DECLARE-TIMI 58, including nearly 39,000 participants with T2D, found that SGLT2i significantly reduced the risk of dialysis, kidney transplant, or death from kidney causes by 33% (RR 0.67; 95% CI 0.52-0.86).
“found that SGLT2i signi fi cantly reduced the risk of dialysis, kidney transplant, or death from kidney causes by 33% (RR: 0.67; 95% CI: 0.52 -0.86).”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
The updated 2019 meta-analysis found a reduction in kidney failure and AKI with SGLT2i.
“There was also reduction in kidney failure and AKI.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
The benefits of SGLT2i on kidney outcomes were seen across all eGFR subgroups, including those with an eGFR of 30-45 ml/min per 1.73 m2.
“The bene fi ts of SGLT2i on kidney outcomes were seen across all eGFR subgroups, 97 including those with an eGFR of 30 -45 ml/min per 1.73 m 2 .”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
Pooled results of the 4 large RCTs that published results on kidney outcomes also demonstrated that risk of AKI is significantly lower with SGLT2i treatment.
“Pooled results of the 4 large RCTs that published results on kidney outcomes also demonstrated that risk of AKI is signi fi cantly lower with SGLT2i treatment.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
Despite this theoretical concern, clinical trials have shown that the incidence of AKI is decreased with SGLT2i, compared with placebo.
“Despite this theoretical concern, clinical trials have shown that the incidence of AKI is decreased with SGLT2i, compared with placebo.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [97]
SGLT2 inhibitor use appears to protect patients from acute kidney injury.
“In fact, SGLT2i use appears to protect patients from AKI (56).”
In the EMPEROR-REDUCED trial, empagliflozin significantly reduced the risk of cardiovascular death or heart failure hospitalization by 25%.
“In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, dapagliflozin reduced the primary endpoint of CV death or worsening HF by 26%, whereas in EMPEROR-REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly reduced the risk of CV death or hospitalization for HF by 25%.457,470”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [457]
The Results section identifies EMPA-REG OUTCOME, not EMPEROR-REDUCED, as the empagliflozin trial included in this kidney-outcomes meta-analysis. Searches for EMPEROR-REDUCED and for the claimed 25% reduction in cardiovascular death or heart-failure hospitalization found no passage reporting that result; the copy does not address the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn the DAPA-HF trial, dapagliflozin reduced the primary endpoint of cardiovascular death or worsening heart failure by 26%.
“In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, dapagliflozin reduced the primary endpoint of CV death or worsening HF by 26%, whereas in EMPEROR-REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly reduced the risk of CV death or hospitalization for HF by 25%.457,470”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [457]
The Results section identifies DECLARE-TIMI 58, not DAPA-HF, as the included dapagliflozin trial. Searches for DAPA-HF and the claimed 26% reduction found no passage reporting that trial’s cardiovascular-death-or-worsening-heart-failure endpoint; page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredDapagliflozin reduced the risk of worsening heart failure or cardiovascular death in people with heart failure with reduced ejection fraction regardless of diabetes status.
“Dapagliflozin also has shown in people with HFrEF reduced risk of worsening HF or death from CV causes regardless of the presence or absence of DM.457”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [457]
The Results describe dapagliflozin in a trial of people with type 2 diabetes, while the Discussion mentions trials recruiting people with and without diabetes for kidney outcomes. Searches for worsening heart failure, reduced ejection fraction, and the claimed cardiovascular-death composite found no passage reporting that result in people with HFrEF regardless of diabetes status. (LLM, conf=0.75)
Experimental — accuracy not yet measuredEven with current therapies available, patients with T2DM and CKD still experience significant cardiovascular and renal morbidity and mortality.
“Even with current therapies available [6–10], patients with T2DM and chronic kidney disease (CKD) still experience a significant cardiovascular and renal morbidity and mortality.”
Large trials have shown that SGLT2 inhibitors reduce the risk of kidney disease progression in patients with type 2 diabetes and proteinuric chronic kidney disease.
“Large trials have also shown that SGLT2 inhibitors reduce the risk of kidney disease progression in patients with type 2 diabetes and proteinuric chronic kidney disease,1, 6, 7, 8”
Another limitation of previous meta-analyses was the inability to standardise between-trial differences in the thresholds of eGFR decrease used to define kidney disease progression within categorical composite outcomes.
“Another limitation of previous meta-analyses was the inability to standardise between-trial differences in the thresholds of eGFR decrease used to define kidney disease progression within categorical composite outcomes (appendix p 9).1, 6”
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).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [69]
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).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [69]
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).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [69]
Large clinical trials and meta-analyses show SGLT2 inhibitors reduce AKI incidence.
“On the contrary, large clinical trials and meta-analyses have demonstrated that SGLT2 inhibitors reduce the incidence of AKI (Neuen et al., 2019).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Neuen et al., 2019
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).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Neuen et al., 2019
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Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury
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Self-citationBack to the future: glomerular hyperfiltration and the diabetic kidney
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Are SGLT2 Inhibitors Ready for Prime Time for CKD?
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Self-citationSodium glucose co-transporter 2 inhibition: a new avenue to protect the kidney
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Self-citationCorrection: Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury
Chang, Y.-K., Choi, H., Jeong, J. Y., Na, K.-R., Lee, K. W., Lim, B. J., & Choi, D. E. (2016) · PLOS ONE · doi:10.1371/journal.pone.0160478
Angiotensin-Converting Enzyme Inhibition in Type I Diabetic Nephropathy
Lewis, E. J. (n.d.) · Contributions to Nephrology · doi:10.1159/000425095
MOSENZON, O., WIVIOTT, S. D., ZELNIKER, T. A., HEERSPINK, H. L., DWYER, J. P., CAHN, A., GAUSE-NILSSON, I. A., LANGKILDE, A. M., SABATINE, M. S., & RAZ, I. (2019) · Diabetes · doi:10.2337/db19-236-or
Self-citationHerrington, W. G., Preiss, D., Haynes, R., von Eynatten, M., Staplin, N., Hauske, S. J., George, J. T., Green, J. B., Landray, M. J., Baigent, C., et al. (2019) · Clinical Kidney Journal · doi:10.1093/ckj/sfz009
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- Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes—authors reply, N Engl J Med, 375, 1801, 10.1056/NEJMoa1515920 · DOI · Paper page
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Dapagliflozin in Patients with Chronic Kidney Disease
Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F.-F., Mann, J. F. E., McMurray, J. J. V., Lindberg, M., Rossing, P., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2024816 · Cited by 5,618 · see citing works
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“Subgroup meta-analyses based on participants’ kidney function indicated that the salutary effects of SGLT2i on MACE, cardiovascular death or HHF, and a composite kidney outcome (substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease) do not significantly differ among subgroups ba…”
BackgroundZannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filippatos, G., Brueckmann, M., Ofstad, A. P., Pfarr, E., Jamal, W., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31824-9 · Cited by 1,408 · see citing works
KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease
de Boer, I. H., Caramori, M. L., Chan, J. C. N., Heerspink, H. J. L., Hurst, C., Khunti, K., Liew, A., Michos, E. D., Navaneethan, S. D., Olowu, W. A., et al. (2020) · Kidney International · doi:10.1016/j.kint.2020.06.019 · Cited by 1,399 · see citing works
Self-citationKDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
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“Of note, the beneficial kidney effects of canagliflozin, dapagliflozin and empagliflozin were also evident for hard kidney outcomes including chronic dialysis and kidney transplantation [252].”
Baigent, C., Emberson, J., Haynes, R., Herrington, W. G., Judge, P., Landray, M. J., Mayne, K. J., Ng, S. Y. A., Preiss, D., Roddick, A. J., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(22)02074-8 · Cited by 1,020 · see citing works
Self-citationde Boer, I. H., Khunti, K., Sadusky, T., Tuttle, K. R., Neumiller, J. J., Rhee, C. M., Rosas, S. E., Rossing, P., & Bakris, G. (2022) · Diabetes Care · doi:10.2337/dci22-0027 · Cited by 919 · see citing works
“Although short-term studies demonstrated added benefit of the combination of ACEi and ARBs in albuminuria reduction, long-term studies showed no benefit and more adverse events, particularly hyperkalemia and AKI, and thus avoidance of this combination is recommended. ns-MRAs The steroidal mineralocorticoid receptor an…”
BackgroundMethodInfluentialDiabetic vascular diseases: molecular mechanisms and therapeutic strategies
Li, Y., Liu, Y., Liu, S., Gao, M., Wang, W., Chen, K., Huang, L., & Liu, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01400-z · Cited by 763 · see citing works
“Upregulated SGLT expression promotes glucose uptake, which affects the tubular-glomerular feedback mechanism, leading to glomerular hypertension.(137,138) Plasma levels of kallikrein, thrombin, and coagulation factors are elevated in hyperglycemic states.”
BackgroundPalmer, S. C., Tendal, B., Mustafa, R. A., Vandvik, P. O., Li, S., Hao, Q., Tunnicliffe, D., Ruospo, M., Natale, P., Saglimbene, V., et al. (2021) · BMJ · doi:10.1136/bmj.m4573 · Cited by 679 · see citing works
Molecular mechanisms and therapeutic targets for diabetic kidney disease
Tuttle, K. R., Agarwal, R., Alpers, C. E., Bakris, G. L., Brosius, F. C., Kolkhof, P., & Uribarri, J. (2022) · Kidney International · doi:10.1016/j.kint.2022.05.012 · Cited by 694 · see citing works
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SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications
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Emerging Targets in Type 2 Diabetes and Diabetic Complications
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Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function
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de Boer, I. H., Khunti, K. K., Sadusky, T., Tuttle, K. R., Neumiller, J. J., Rhee, C. M., Rosas, S. E., Rossing, P. R., & Bakris, G. L. (2022) · Kidney International · doi:10.1016/j.kint.2022.08.012 · Cited by 369 · see citing works
“Although short-term studies demonstrated added benefit of the combination of ACEi and ARBs in albuminuria reduction, long-term studies showed no benefit and more adverse events, particularly hyperkalemia and AKI, and thus avoidance of this combination is recommended. ns-MRAs The steroidal mineralocorticoid receptor an…”
BackgroundMethodInfluentialAnker, S. D., Butler, J., Filippatos, G., Khan, M. S., Marx, N., Lam, C. S. P., Schnaidt, S., Ofstad, A. P., Brueckmann, M., Jamal, W., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051824 · Cited by 352 · see citing works
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“On the basis of pairwise meta-analyses of cardiovascular outcome trials, compared with placebo, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular death and stroke (4), whereas sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduce heart failure hospitalization (5) and end-stage renal disea…”
BackgroundTrajectories of kidney function in diabetes: a clinicopathological update
Oshima, M., Shimizu, M., Yamanouchi, M., Toyama, T., Hara, A., Furuichi, K., & Wada, T. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00462-y · Cited by 349 · see citing works
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Self-citationCardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function
Zannad, F. M., Ferreira, J. P., Pocock, S., Zeller, C., Anker, S. D., Butler, J., Filippatos, G. S., Hauske, S. J., Brueckmann, M., Pfarr, E., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.051685 · Cited by 282 · see citing works
Cherney, D. Z. I., Dekkers, C. C. J., Barbour, S. J., Cattran, D., Abdul Gafor, A. H., Greasley, P. J., Laverman, G. D., Lim, S. K., Di Tanna, G. L., Reich, H. N., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30162-5 · Cited by 283 · see citing works
Self-citationNeuen, B. L., Oshima, M., Agarwal, R., Arnott, C. G., Cherney, D. Z. I., Edwards, R., Langkilde, A. M., Mahaffey, K. W., McGuire, D. K., Neal, B., et al. (2022) · Circulation · doi:10.1161/circulationaha.121.057736 · Cited by 293 · see citing works
Self-citationSodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review
Fonseca-Correa, J. I., & Correa‐Rotter, R. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.777861 · Cited by 282 · see citing works
Ten things to know about ten cardiovascular disease risk factors
Bays, H. E., Taub, P. R., Epstein, E., Michos, E. D., Ferraro, R. A., Bailey, A. L., Kelli, H. M., Ferdinand, K. C., Echols, M. R., Weintraub, H., et al. (2021) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2021.100149 · Cited by 274 · see citing works
Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus
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Gliflozins in the Management of Cardiovascular Disease
Braunwald, E. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2115011 · Cited by 268 · see citing works
Mone, P., Varzideh, F., Jankauskas, S. S., Pansini, A., Lombardi, A., Frullone, S., & Santulli, G. (2022) · Hypertension · doi:10.1161/hypertensionaha.122.19586 · Cited by 224 · see citing works
Yau, K., Dharia, A., Alrowiyti, I., & Cherney, D. Z. I. (2022) · Kidney International Reports · doi:10.1016/j.ekir.2022.04.094 · Cited by 236 · see citing works
“Furthermore, concerns regarding the incidence of acute kidney injury with SGLT2 inhibitors have been allayed by meta-analyses from clinical trials and propensitymatched observational studies, which have found that SGLT2 inhibitors are associated with lower rates of acute kidney injury.(54,56,90) It remains uncertain w…”
BackgroundPacker, M. (2020) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2020.04.016 · Cited by 215 · see citing works
“Additionally, in large-scale randomized placebo-controlled clinical trials, treatment with these drugs have reduced the risk for kidney failure by ~30%.(1) These benefits were seen within 2 to 3 years of treatment and were observed in diabetic patients with both preserved and impaired glomerular function at study entr…”
BackgroundNeuen, B. L., Oshima, M., Agarwal, R., et al. (2022) · UCL Discovery (University College London) · Cited by 213 · see citing works
Self-citationTreatments for NAFLD: State of Art
Mantovani, A., & Dalbeni, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052350 · Cited by 202 · see citing works
“Given that SGLT‐2 inhibitors have documented relevant cardio‐renal benefits in large RCTs enrolling patients with and without T2DM [103,104], they are attractive agents for patients with NAFLD.”
BackgroundRangaswami, J., Bhalla, V., de Boer, I. H., Staruschenko, A., Sharp, J. A., Singh, R. R., Lo, K. B., Tuttle, K., Vaduganathan, M., Ventura, H., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000920 · Cited by 192 · see citing works
Inflammation and Oxidative Stress in Chronic Kidney Disease and Dialysis Patients
Ebert, T., Neytchev, O., Witasp, A., Kublickiene, K. R., Stenvinkel, P., & Shiels, P. G. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8184 · Cited by 190 · see citing works
“Since two recent renal outcome trials with a prespecified primary renal endpoint have confirmed these findings (69a, 163), SGLT2 inhibitors are considered as a novel therapy for CKD due to type 2 diabetes reducing the risk of dialysis, transplantation, or death and protecting against AKI (148).”
Kidney and heart failure outcomes associated with SGLT2 inhibitor use
der Beek, A. B. V. D. A., de Boer, R. A., & Heerspink, H. J. L. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00535-6 · Cited by 183 · see citing works
Self-citationThe New Biology of Diabetic Kidney Disease—Mechanisms and Therapeutic Implications
Lytvyn, Y., Bjornstad, P., van Raalte, D. H., Heerspink, H. J. L., & Cherney, D. Z. I. (2019) · Endocrine Reviews · doi:10.1210/endrev/bnz010 · Cited by 166 · see citing works
Self-citationon behalf of the VERTIS CV Investigators, Cherney, D. Z. I., Charbonnel, B. H., Cosentino, F., Dagogo-Jack, S. E., McGuire, D. K., Pratley, R. E., Shih, W., Frederich, R. C., Maldonado, M., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05407-5 · Cited by 170 · see citing works
“In previous CVOTs, SGLT2 inhibition reduced the risk of important kidney secondary endpoints.”
BackgroundResultInfluentialEuglycemic diabetic ketoacidosis: A missed diagnosis
Nasa, P., CHAUDHARY, S. K., Shrivastava, P. K., & Singh, A. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i5.514 · Cited by 165 · see citing works
Xie, Y., Bowe, B. C., Gibson, A. K., McGill, J. B., Maddukuri, G. S., Yan, Y., & Al‐Aly, Z. (2020) · Diabetes Care · doi:10.2337/dc20-1890 · Cited by 155 · see citing works
A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors
Sen, T., & Heerspink, H. J. L. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.016 · Cited by 161 · see citing works
Self-citationCardoso, R. N., Graffunder, F. P., Ternes, C. M. P., Fernandes, A. D. F., Rocha, A. V., Fernandes, G. C., & Bhatt, D. L. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100933 · Cited by 165 · see citing works
“Renal protection and weight loss may also contribute to improved HF outcomes with SGLT2 inhibitors [44,45].”
BackgroundRenal Gluconeogenesis: An Underestimated Role of the Kidney in Systemic Glucose Metabolism
Legouis, D., Faivre, A., Cippà, P. E., & de Seigneux, S. (2022) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfaa302 · Cited by 151 · see citing works
Bjornstad, P., Dart, A. B., Donaghue, K. C., Dost, A., Feldman, E. L., Tan, G. S. W., Wadwa, R. P., Zabeen, B., & Marcovecchio, M. L. (2022) · Pediatric Diabetes · doi:10.1111/pedi.13444 · Cited by 160 · see citing works
Current and future therapies for type 1 diabetes
von Scholten, B. J., Kreiner, F. F., Gough, S. C. L., & von Herrath, M. (2021) · Diabetologia · doi:10.1007/s00125-021-05398-3 · Cited by 148 · see citing works
Glucose transporters in the kidney in health and disease
Vallon, V. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02361-w · Cited by 144 · see citing works
Renal effects of SGLT2 inhibitors
Nespoux, J., & Vallon, V. (2019) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000584 · Cited by 146 · see citing works
Fang, Y., Chen, B., Gong, A. Y., Malhotra, D. K., Gupta, R., Dworkin, L. D., & Gong, R. (2021) · Kidney International · doi:10.1016/j.kint.2021.06.031 · Cited by 143 · see citing works
SGLT2 Inhibitors: The Star in the Treatment of Type 2 Diabetes?
Saisho, Y. (2020) · Diseases · doi:10.3390/diseases8020014 · Cited by 133 · see citing works
“However, in view of the results of CVOTs showing a renoprotective effect of SGLT2 inhibitors among those with a wide range of renal function [10,11], currently treatment with SGLT2 inhibitors is rather also considered for patients with diabetes and renal dysfunction, i.”
BackgroundTen things to know about ten cardiovascular disease risk factors – 2022
Bays, H. E., Agarwala, A., German, C. A., Satish, P., Iluyomade, A., Dudum, R., Thakkar, A., Rifai, M. A., Mehta, A., Thobani, A., et al. (2022) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2022.100342 · Cited by 136 · see citing works
Tomasoni, D., Fonarow, G. C., Adamo, M., Anker, S. D., Butler, J., Coats, A. J. S., Filippatos, G. S., Greene, S. J., McDonagh, T. A., Ponikowski, P. P., et al. (2021) · European Journal of Heart Failure · doi:10.1002/ejhf.2397 · Cited by 132 · see citing works
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., et al. (2020) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2020.08.003 · Cited by 132 · see citing works
Self-citationTuttle, 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., et al. (2021) · Diabetes · doi:10.2337/dbi20-0040 · Cited by 123 · see citing works
“(69) with permission of the copyright holder; original graphic © 2019 Elsevier Ltd.”
BackgroundResultInfluentialSelf-citationNeuen, B. L., Oshima, M., Perkovic, V., Agarwal, R., Arnott, C. G., Bakris, G. L., Cannon, C. P., Charytan, D. M., Edwards, R., Górriz, J. L., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab497 · Cited by 124 · see citing works
“A 2019 meta-analysis of CREDENCE and cardiovascular outcome trials observed consistent benefits for kidney outcomes regardless of the baseline use of RAAS blockade.(9) For individuals unable to tolerate RAAS blockade due to hyperkalaemia, treatment with an SGLT2 inhibitor alone may be a reasonable alternative, given t…”
BackgroundSelf-citationPacker, M. (2020) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020010010 · Cited by 125 · see citing works
Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease
Zhou, Z., Jardine, M., Li, Q., Neuen, B. L., Cannon, C. P., de Zeeuw, D., Edwards, R., Levin, A., Mahaffey, K. W., Perkovic, V., et al. (2021) · Stroke · doi:10.1161/strokeaha.120.031623 · Cited by 118 · see citing works
Self-citationGyimesi, G., Pujol‐Giménez, J., Kanai, Y., & Hediger, M. A. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02433-x · Cited by 125 · see citing works
Kidney-Protective Effects of SGLT2 Inhibitors
Palmer, B. F., & Clegg, D. J. (2022) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.09380822 · Cited by 124 · see citing works
Liu, L., Bai, F., Song, H., Xiao, R., Wang, Y., Yang, H., Ren, X., Li, S., Gao, L., Ma, C., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102260 · Cited by 114 · see citing works
“However, over the last several decades, only a few drugs such as RAS and SGLT2 inhibitors were used to prevent the progression of DN or to improve renal function [4,5].”
BackgroundYe, N., Jardine, M. J., Oshima, M., Hockham, C., Heerspink, H. J. L., Agarwal, R., Bakris, G., Schutte, A. E., Arnott, C., Chang, T. I., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.048740 · Cited by 115 · see citing works
Self-citationLuna-Marco, C., Iannantuoni, F., Hermo-Argibay, A., Devos, D., Salazar, J. D., Víctor, V. M., & Rovira-Llopis, S. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.01.015 · Cited by 114 · see citing works
Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial
The EMPA-KIDNEY Collaborative Group, Herrington, W. G., Wanner, C., Green, J. B., Hauske, S. J., Judge, P., Mayne, K. J., Ng, S. Y. A., Sammons, E., Zhu, D., et al. (2022) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfac040 · Cited by 110 · see citing works
“Nevertheless, results from meta-analyses of the earlier reported SGLT-2 inhibitor trials in type 2 DM encouragingly suggest renal benefits may extend to people without albuminuria [44], as do eGFR slope-based analyses in the trials among people with heart failure [20, 21, 45, 46].”
Self-citationDocherty, N. G., & le Roux, C. W. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-0323-4 · Cited by 107 · see citing works
Clinical Benefit of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
Zelniker, T. A., & D, E. B. M. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.11.036 · Cited by 107 · see citing works
Pasternak, B., Wintzell, V., Melbye, M., Eliasson, B., Svensson, A., Franzén, S., Guðbjörnsdóttir, S., Hveem, K., Jonasson, C., Svanström, H., et al. (2020) · BMJ · doi:10.1136/bmj.m1186 · Cited by 101 · see citing works
Handelsman, Y., Butler, J., Bakris, G. L., DeFronzo, R. A., Fonarow, G. C., Green, J. B., Grunberger, G., Januzzi, J. L., Klein, S., Kushner, P. R., et al. (2023) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2022.108389 · Cited by 105 · see citing works
State-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications
Vallon, V. (2024) · American Journal of Hypertension · doi:10.1093/ajh/hpae092 · Cited by 115 · see citing works
Applications of SGLT2 inhibitors beyond glycaemic control
O’Hara, D. V., Lam, C. S. P., McMurray, J. J. V., Yi, T. W., HOCKING, S. L., Dawson, J., Raichand, S., Januszewski, A. S., & Jardine, M. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-024-00836-y · Cited by 111 · see citing works
“In a meta-analysis of CVOTs, kidney benefits were consistent regardless of baseline albuminuria ( P value for trend = 0.66) 50 .”
InfluentialSelf-citationZhang, Y., Jiang, L., Wang, J., Wang, T., Chien, C., Huang, W., Fu, X., Xiao, Y., Fu, Q., Wang, S., et al. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01676-5 · Cited by 96 · see citing works
Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk
Scilletta, S., Marco, M. D., Miano, N., Filippello, A., Mauro, S. D., Scamporrino, A., Musmeci, M., Coppolino, G., Barbagallo, F. D. G., Bosco, G., et al. (2023) · Biomolecules · doi:10.3390/biom13050752 · Cited by 112 · see citing works
“[91] confirmed that this class of drugs reduces the risk of dialysis, kidney transplantation, and renal death in patients with DKD and also provides protection against AKI.”
Heerspink, H. J. L., Cherney, D. Z. I., Postmus, D., Stefánsson, B. V., Chertow, G. M., Dwyer, J. P., Greene, T., Kosiborod, M., Langkilde, A. M., McMurray, J. J. V., et al. (2021) · Kidney International · doi:10.1016/j.kint.2021.09.005 · Cited by 92 · see citing works
“Long-term safety data from other cardiovascular outcome trials (starting with the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME] and subsequently endorsed by other cardiovascular outcome trials) have demonstrated the safety of SGLT2 inhibitors with respect to A…”
BackgroundSelf-citationDiabetes: From Research to Clinical Practice
Islam, M. S. (2020) · Advances in experimental medicine and biology · doi:10.1007/5584_2020_553 · Cited by 94 · see citing works
Ravindran, S., & Munusamy, S. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30621 · Cited by 96 · see citing works
“Further, it provided nephroprotection against acute kidney injury (AKI) (Fioretto et al., 2020; Nespoux & Vallon, 2020; Neuen et al., 2019; Perkovic et al., 2019).”
BackgroundNon-invasive molecular imaging of kidney diseases
Klinkhammer, B. M., Lammers, T., Mottaghy, F. M., Kiessling, F. M., Floege, J., & Boor, P. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00440-4 · Cited by 94 · see citing works
Borges, F. A., dos Santos, D. S., Benetti, A., Polidoro, J. Z., Wisnivesky, A. C. T., Crajoinas, R. O., Antônio, E. L., Jensen, L., Caramelli, B., Malnic, G., et al. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020071029 · Cited by 95 · see citing works
Jongs, N., Chertow, G. M., Greene, T., McMurray, J. J. V., Langkilde, A. M., Correa‐Rotter, R., Kashihara, N., Rossing, P. R., Sjöström, C. D., Stefánsson, B. V., et al. (2022) · Journal of the American Society of Nephrology · doi:10.1681/asn.2022030306 · Cited by 95 · see citing works
Self-citationSen, T., Li, J., Neuen, B. L., Neal, B. C., Arnott, C. G., Parikh, C. R., Coca, S. G., Perkovic, V., Mahaffey, K. W., Yavin, Y., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05512-5 · Cited by 91 · see citing works
Self-citationTargeting energy pathways in kidney disease: the roles of sirtuins, AMPK, and PGC1α
Clark, A. J., & Parikh, S. M. (2020) · Kidney International · doi:10.1016/j.kint.2020.09.037 · Cited by 93 · see citing works
Longato, E., Camillo, B. D., Sparacino, G., Gubian, L., Avogaro, A., & Fadini, G. P. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001451 · Cited by 82 · see citing works
GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions
Yu, J. H., Park, S. Y., Lee, D. Y., Kim, N. H., & Seo, J. A. (2022) · Kidney Research and Clinical Practice · doi:10.23876/j.krcp.22.001 · Cited by 93 · see citing works
Giorgino, F., Vora, J. P., Fenici, P., & Solini, A. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01163-9 · Cited by 85 · see citing works
Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories
Levin, A., Perkovic, V., Wheeler, D. C., Hantel, S., George, J. T., von Eynatten, M., Koitka‐Weber, A., Wanner, C., & on behalf of the EMPA-REG OUTCOME Investigators (2020) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.14901219 · Cited by 91 · see citing works
“However, the consistency of effect size across various definitions of kidney outcomes, and across SGLT2 trials, suggests that this limitation may be inconsequential (33,34).”
BackgroundSelf-citationLaursen, J. C., Heinrich, N. S., de Melo, J. M. L., Haddock, B., Rasmussen, I. K. B., Safavimanesh, F., Hansen, C. S., Størling, J., Larsson, H. B. W., Groop, P., et al. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100895 · Cited by 84 · see citing works
“Suggested mechanisms include weight loss, reduction in the systemic or intraglomerular pressure, lowering of uric acid, decreased inflammation, as well as changes in cell metabolism [41,42].”
BackgroundHandelsman, Y., Anderson, J. E., Bakris, G. L., Ballantyne, C. M., Bhatt, D. L., Bloomgarden, Z. T., Bozkurt, B., Budoff, M. J., Butler, J., Cherney, D. Z. I., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155931 · Cited by 93 · see citing works
SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney
Ke, Q., Shi, C., Lv, Y., Wang, L., Luo, J., Jiang, L., Yang, J., & Zhou, Y. (2021) · The FASEB Journal · doi:10.1096/fj.202100909rr · Cited by 86 · see citing works
Screening, identifying, and treating chronic kidney disease: why, who, when, how, and what?
Farrell, D. R., & Vassalotti, J. A. (2024) · BMC Nephrology · doi:10.1186/s12882-024-03466-5 · Cited by 91 · see citing works
“In a meta-analysis, SGLT2is even have kidney protective effects for diabetic patients without albuminuria [86].”
BackgroundSGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes
Zhuo, M., Paik, J. M., Wexler, D. J., Bonventre, J. V., Kim, S. C., & Patorno, E. (2021) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2021.09.015 · Cited by 81 · see citing works
Network Meta-Analysis of Novel Glucose-Lowering Drugs on Risk of Acute Kidney Injury
Zhao, M., Sun, S., Huang, Z., Wang, T., & Tang, H. (2020) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.11220720 · Cited by 86 · see citing works
Koška, J., Gerstein, H. C., Beisswenger, P. J., & Reaven, P. D. (2022) · Diabetes Care · doi:10.2337/dc21-2196 · Cited by 80 · see citing works
“Both ACCORD and VADT were conducted prior to the introduction of newer diabetes medications that have been shown to protect against diabetes nephropathy (38,39).”
MethodNeuen, B. L., Arnott, C., Perkovic, V., Figtree, G., de Zeeuw, D., Fulcher, G., Jun, M., Jardine, M. J., Zoungas, S., Pollock, C., et al. (2021) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14226 · Cited by 78 · see citing works
Self-citationEmpagliflozin in Patients with Chronic Kidney Disease
Neuen, B. L., Fletcher, R. A., & Heerspink, H. J. L. (2023) · New England Journal of Medicine · doi:10.1056/nejmc2301923 · Cited by 72 · see citing works
Self-citationEllagic Acid as a Tool to Limit the Diabetes Burden: Updated Evidence
Amor, A. J., Gómez‐Guerrero, C., Ortega, E., Sala‐Vila, A., & Lázaro, I. (2020) · Antioxidants · doi:10.3390/antiox9121226 · Cited by 74 · see citing works
“Although some glucose-lowering drugs have recently shown promising results in the prevention and management of this chronic complication [99], common antioxidant agents have also been associated with an improvement in early renal damage [100].”
BackgroundIskander, C., Cherney, D. Z. I., Clemens, K. K., Dixon, S. N., Harel, Z., Jeyakumar, N., McArthur, E., Muanda, F. T., Parikh, C. R., Paterson, J. M., et al. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.191283 · Cited by 76 · see citing works
Packer, M. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13961 · Cited by 75 · see citing works
“exert favourable effects on the diabetic kidney in patients who are already receiving inhibitors of the renin-angiotensin system.(1,3)”
BackgroundSGLT2-inhibitors are effective and safe in the elderly: the SOLD study
Lunati, M. E., Cimino, V., Gandolfi, A., Trevisan, M., Montefusco, L., Pastore, I., Pace, C., Betella, N., Favacchio, G., Bulgheroni, M., et al. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106396 · Cited by 77 · see citing works
- Authors
- Neuen, B. L., Young, T., Heerspink, H. J. L., Neal, B., Perkovic, V., Billot, L., Mahaffey, K. W., Charytan, D. M., Wheeler, D. C., Arnott, C., Bompoint, S., Levin, A., & Jardine, M. J.
- Affiliations
- UNSW Sydney (AU)
- University Medical Center Groningen (NL)
- The University of Sydney (AU)
- Stanford Medicine (US)
- NYU Langone Health (US)
- University College London (GB)
- University of British Columbia (CA)
- Concord Repatriation General Hospital (AU)
- Corresponding author
- Jardine, Meg J
- ORCID
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 7
- Issue
- 11
- Pages
- 845-854
- ISSN
- 2213-8587 (ISSN-L)
- OpenAlex
- W2971414122
- Cited by
- 893
- References
- 46
- Citations by year
- 2026: 65 · 2025: 86 · 2024: 104 · 2023: 142 · 2022: 164 · 2021: 185 · 2020: 125 · 2019: 17 · 2017: 1
- FWCI
- 18.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- National Health and Medical Research Council
- AstraZeneca
- University of New South Wales
- Janssen Pharmaceuticals
- Boehringer Ingelheim
- University of Oxford
- 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, type 2 diabetes, renal failure, end-stage renal disease, acute kidney injury, dialysis, kidney transplantation, kidney disease mortality, estimated glomerular filtration rate, albuminuria, renin-angiotensin system blockade, empagliflozin, canagliflozin, dapagliflozin, effect modification
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Diabetic Nephropathies, Humans, Kidney Failure, Chronic, Randomized Controlled Trials as Topic
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