Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect

Sodium-glucose cotransporter-2 (SGLT2) inhibitors were introduced a decade ago for the treatment of type 2 diabetes (T2D) and have emerged as a key therapy for the treatment of chronic kidney disease (CKD). In trials with primary kidney end points, SGLT2 inhibitors reduced the composite of kidney failure, kidney death, and doubling of serum creatinine by 28% to 39%.1Nuffield Department of Population Health Renal Studies GroupSGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.Lancet. 2022; 400: 1788-1801Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Benefits of this class of medication are independent of glycemic lowering, as glucose lowering with other drug classes has not been associated with similar improvements in kidney outcomes. Moreover, patients with advanced CKD (down to an estimated glomerular filtration rate [eGFR] of 20 ml/min per 1.73 m2) in whom SGLT2 inhibitors have little or neutral glucose-lowering effects still derive similar long-term benefit. Furthermore, in nondiabetic patients with CKD, similar kidney benefits are observed.2Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (2474) Google Scholar,3Herrington W.G. Staplin N. Wanner C. et al.Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127Crossref PubMed Scopus (631) Google Scholar These findings have led to a body of research investigating the mechanisms by which SGLT2 inhibitors confer kidney protection. Although CKD is defined by a decrease in glomerular filtration rate (GFR), at early stages, a supraphysiological increase in whole-kidney GFR (i.e., >135 ml/min per 1.73 m2), termed glomerular hyperfiltration, is observed in up to 50% of individuals. Subsequently, compensatory enhanced GFR in single nephrons, termed single-nephron hyperfiltration, is proposed to accelerate decline in kidney function through increments in glomerular pressure and shear stress.4Tonneijck L. Muskiet M.H. Smits M.M. et al.Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.J Am Soc Nephrol. 2017; 28: 1023-1039Crossref PubMed Scopus (496) Google Scholar Although the precise causes for hyperfiltration remain uncertain, kidney hypertrophy, imbalance in vasoactive mediators, including the renin-angiotensin system (RAS), systemic and tubular hyperglycemia, and hyperinsulinemia have been implicated.4Tonneijck L. Muskiet M.H. Smits M.M. et al.Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.J Am Soc Nephrol. 2017; 28: 1023-1039Crossref PubMed Scopus (496) Google Scholar Cumulative evidence suggests that altering glomerular pressure is a mechanism that is central to how SGLT2 inhibitors delay CKD progression. On initiation of an SGLT2 inhibitor, an immediate hemodynamic effect is observed, which corresponds to an ≈3 to 5 ml/min per 1.73 m2 "dip" or decline in eGFR in individuals with eGFR >60 ml/min per 1.73 m2, a change that occurs even after a single dose.5Bjornstad P. Laffel L. Tamborlane W.V. et al.Acute effect of empagliflozin on fractional excretion of sodium and eGFR in youth with type 2 diabetes.Diabetes Care. 2018; 41: e129-e130Crossref PubMed Scopus (29) Google Scholar This initial eGFR dip may reflect the generally transient natriuretic effects of SGLT2 inhibitors. SGLT2 inhibitors block the sodium-glucose cotransporter 2 in the proximal tubule, decreasing glucose and sodium reabsorption.6Thomas M.C. Cherney D.Z.I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.Diabetologia. 2018; 61: 2098-2107Crossref PubMed Scopus (223) Google Scholar The downstream effect is increased distal delivery of sodium to the juxtaglomerular apparatus, which augments tubuloglomerular feedback to the macula densa, leading to adenosine-mediated afferent arteriolar vasoconstriction and efferent arteriolar vasodilation, thereby attenuating glomerular hyperfiltration. This reduction in glomerular hypertension is postulated to confer long-term kidney protective effects and reduces whole-kidney GFR through distinct mechanisms in individuals with type 1 diabetes (T1D) and T2D. This physiological effect is supported by mechanistic studies in individuals with T1D and hyperfiltration. In 27 participants with T1D and whole-kidney hyperfiltration (baseline GFR 172 ± 23 ml/min per 1.73 m2), empagliflozin reduced measured GFR by 33 ml/min per 1.73 m2 by increasing kidney vascular resistance, leading to reduced effective kidney plasma flow, indicating a preglomerular site of action.7Cherney D.Z. Perkins B.A. Soleymanlou N. et al.Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597Crossref PubMed Scopus (1028) Google Scholar In contrast, in people with T1D without whole-kidney hyperfiltration and those with T2D and preserved GFR, different mechanisms of the GFR dip have been reported. In the RED (Renoprotective Effects of Dapagliflozin in Type 2 Diabetes) trial, dapagliflozin reduced measured GFR in individuals with T2D and median eGFR of 85 ± 13 ml/min per 1.73 m2, without inducing preglomerular vasoconstriction, suggesting that postglomerular vasodilation may contribute to the regulation of eGFR, including acute changes in response to SGLT2 inhibition.8van Bommel E.J.M. Muskiet M.H.A. van Baar M.J.B. et al.The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.Kidney Int. 2020; 97: 202-212Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar Kidney hemodynamic effects of SGLT2 inhibitors are maintained even when superimposed on RAS blockade. In people with T1D without whole-kidney hyperfiltration, combination therapy with empagliflozin-ramipril resulted in an 8 ml/min per 1.73 m2 lower measured GFR versus placebo-ramipril treatment, without evidence for preglomerular vasoconstriction.9Lytvyn Y. Kimura K. Peter N. et al.Renal and vascular effects of combined SGLT2 and angiotensin-converting enzyme inhibition.Circulation. 2022; 146: 450-462Crossref PubMed Scopus (22) Google Scholar Similarly, in people with T2D, losartan-empagliflozin combination therapy induced a larger decline in measured GFR than either treatment alone.10Scholtes R.A. Hesp A.C. Mosterd C.M. et al.Kidney hemodynamic effects of angiotensin receptor blockade, sodium-glucose cotransporter-2 inhibition alone, and their combination: a crossover randomized trial in people with type 2 diabetes.Circulation. 2022; 146: 1895-1897Crossref Scopus (4) Google Scholar RAS blockade and SGLT2 inhibitors both resulted in efferent arteriolar vasodilation. However, it was theorized that because dilating smaller postglomerular arterioles yields a greater hemodynamic impact according to the Poiseuille law, postglomerular effects of SGLT2 inhibitors resulted in a greater net reduction in measured GFR.11Denton K.M. Fennessy P.A. Alcorn D. et al.Morphometric analysis of the actions of angiotensin II on renal arterioles and glomeruli.Am J Physiol. 1992; 262: F367-F372PubMed Google Scholar Beyond physiological interest in how SGLT2 inhibitors regulate acute eGFR and the dip that is commonly associated with initiation, the impact of SGLT2 inhibitors on kidney function is also essential to understand from a clinical perspective, especially to interpret eGFR changes over time, also known as eGFR slope. Change in eGFR slope is an accepted surrogate outcome for kidney disease progression with a preservation of eGFR of ≥0.75 ml/min per 1.73 m2 per year considered highly favorable and sufficient for regulatory agencies to recognize as a pathway for new drug indications.12Cherney D.Z.I. Cosentino F. Dagogo-Jack S. et al.Ertugliflozin and slope of chronic eGFR: prespecified analyses from the randomized VERTIS CV trial.Clin J Am Soc Nephrol. 2021; 16: 1345-1354Crossref PubMed Scopus (0) Google Scholar Recent data from DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) and EMPA-Kidney (The Study of Heart and Kidney Protection With Empagliflozin) demonstrate benefits of SGLT2 inhibitors in individuals with or without diabetes, including those without albuminuria. In EMPA-Kidney, although subgroup analyses suggested that the benefit on delaying progression of kidney disease was attenuated in the subgroup of urine albumin-to-creatinine ratio <300 mg/g, prespecified analyses still supported the use of SGLT2 inhibitors in those with lower levels of albuminuria (A1 and A2 urine albumin-to-creatinine ratio levels) based on eGFR slope as the difference in mean annual eGFR change was still statistically significant and clinically meaningful in those using empagliflozin.3Herrington W.G. Staplin N. Wanner C. et al.Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127Crossref PubMed Scopus (631) Google Scholar Although the initial eGFR dip associated with SGLT2 inhibitor treatment may raise concern among clinicians, analyses from SGLT2 inhibitor trials have consistently demonstrated that the dip is reversible and not harmful, and conversely portends long-term kidney benefit on eGFR trajectory (Figure 1). What constitutes significant eGFR dipping? In the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, 6668 participants were categorized as an "eGFR dipper" if they had >10% acute decline in eGFR, "intermediate" for up to a 10% decrease, whereas the remainder were considered nondippers at 4 weeks from baseline. A >10% dip was observed in 28% of empagliflozin users versus 13% receiving placebo. The use of a diuretic or more advanced CKD was associated with a higher likelihood of an eGFR dip. In this analysis, eGFR nondippers had an annual slope of –1.60 (95% confidence interval [CI], –2.08 to –1.12) ml/min per 1.73 m2, –1.28 (95% CI, –1.75 to –0.80) ml/min per 1.73 m2 in the "eGFR intermediate dip" group, and –0.72 (95% CI, –1.71 to 0.28) ml/min per 1.73 m2 in "eGFR dippers," suggesting a numerically smaller slope in patients with eGFR dipping.13Kraus B.J. Weir M.R. Bakris G.L. et al.Characterization and implications of the initial estimated glomerular filtration rate "dip" upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.Kidney Int. 2021; 99: 750-762Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Similarly in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial, which had a primary kidney composite end point, long-term eGFR trajectory analyses of 4289 participants was similarly divided into "dipper" categories 3 weeks from baseline. Large declines in eGFR were uncommon, with a >30% eGFR decrease occurring in 4% of canagliflozin users. Kidney safety outcomes were similar at 42 months in those regardless of eGFR dipping. However, in the "on-treatment" analysis, those who had an acute dip >10% had a slower rate of eGFR rate of decline from month 3 in comparison to those who had an acute eGFR increase (P = 0.037).14Oshima M. Jardine M.J. Agarwal R. et al.Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice.Kidney Int. 2021; 99: 999-1009Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Similar to the on-treatment analysis in CREDENCE, in VERTIS-CV (eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes), where ertugliflozin-treated patients were categorized into tertiles based on acute eGFR change at 6 weeks, chronic eGFR slopes were −0.76, −0.29, and −0.05 ml/min per 1.73 m2 in the respective tertiles, with the largest eGFR dippers experiencing the slowest rate of chronic eGFR decline (P < 0.001).12Cherney D.Z.I. Cosentino F. Dagogo-Jack S. et al.Ertugliflozin and slope of chronic eGFR: prespecified analyses from the randomized VERTIS CV trial.Clin J Am Soc Nephrol. 2021; 16: 1345-1354Crossref PubMed Scopus (0) Google Scholar A prespecified analysis of DAPA-CKD also examined the long-term eGFR slope in dippers at 2 weeks. In dapagliflozin users, dippers experienced an annual eGFR decline of −1.58, versus −2.44 and −2.48 ml/min per 1.73 m2 in intermediate or nondippers, respectively. In the DAPA-HF (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) trial, individuals with heart failure and reduced ejection fraction using dapagliflozin who experienced >10% acute eGFR decline at 2 weeks from baseline had a reduction in the primary outcome of worsening heart failure or cardiovascular death (hazard ratio, 0.73; 95% CI, 0.5-0.91). Recapitulating the results of VERTIS-CV and DAPA-CKD, long-term favorable effects on annual eGFR slope were observed in dapagliflozin users with a >10% dip (–0.7 ml/min per 1.73 m2) versus –1.7 ml/min per 1.73 m2 in those with <10% eGFR decline, and –2.3 ml/min per 1.73 m2 in nondippers. Together, these findings suggest that long-term eGFR trajectory is more favorable in eGFR dippers, which appears to correspond to reduction in glomerular hypertension.15Jongs N. Chertow G.M. Greene T. et al.Correlates and consequences of an acute change in eGFR in response to the SGLT2 inhibitor dapagliflozin in patients with CKD.J Am Soc Nephrol. 2022; 33: 2094-2107Crossref PubMed Scopus (0) Google Scholar This is analogous to evidence from trials of RAS blockade, where the magnitude of reduction in eGFR in patients with T2D treated with losartan has been associated with long-term eGFR preservation, underscoring the potential clinical benefit of attenuating glomerular hyperfiltration. Although it remains challenging to predict who will experience an acute eGFR dip, analyses of EMPA-REG OUTCOME and DAPA-HF have suggested that older age, diabetes, higher left ventricular ejection fraction, poor systolic blood pressure control, and lower eGFR are associated with eGFR dipping following SGLT2 inhibitor initiation. However, the association between lower eGFR and dipping is likely confounded by the lower absolute decrease in eGFR required to obtain a 10% dip in advanced CKD.13Kraus B.J. Weir M.R. Bakris G.L. et al.Characterization and implications of the initial estimated glomerular filtration rate "dip" upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.Kidney Int. 2021; 99: 750-762Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,16Adamson C. Docherty K.F. Heerspink H.J.L. et al.Initial decline (dip) in estimated glomerular filtration rate after initiation of dapagliflozin in patients with heart failure and reduced ejection fraction: insights from DAPA-HF.Circulation. 2022; 146: 438-449Crossref PubMed Scopus (59) Google Scholar Furthermore, in EMPA-REG OUTCOME, background RAS blockade in combination with empagliflozin was found to elicit a greater acute eGFR dip than in those taking empagliflozin alone.17Mayer G.J. Wanner C. Weir M.R. et al.Analysis from the EMPA-REG OUTCOME.Kidney Int. 2019; 96: 489-504Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This suggests an interaction between RAS blockade and SGLT2 inhibitors on hemodynamic effects in the glomerular microcirculation. Acting together, the combination of SGLT2 inhibitors and RAS inhibitors is likely to attenuate glomerular hypertension, explaining the broad benefit observed across the spectrum of CKD. Therefore, following SGLT2 inhibitor initiation, the acute eGFR dip that rarely exceeds 30% is likely reflective of its protective mechanistic effect, and thus routine bloodwork monitoring is not indicated following initiation in most individuals. However, by nature of the initial decrease in eGFR, acute dippers generally had a lower absolute eGFR than nondippers for the duration of SGLT2 inhibitor trials, which ranged from 144 to 260 weeks. As a final piece of evidence underscoring the role of the dip in eGFR with SGLT2 inhibitors, early in the clinical development of these therapies, acute hemodynamic effects of SGLT2 inhibitors initially led to concern that these agents could increase the risk for acute kidney injury. However, a meta-analysis combining 90,351 trial participants provides high-quality evidence to suggest the opposite: a lower risk of acute kidney injury (hazard ratio, 0.77; 95% CI, 0.70-0.84) with SGLT2 inhibitor use, which may reflect a variety of favorable hemodynamic changes, including a reduction in kidney hypoxia because of lower kidney work load, which corresponds to whole-kidney oxygen consumption.1Nuffield Department of Population Health Renal Studies GroupSGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.Lancet. 2022; 400: 1788-1801Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Although individuals with lower eGFR generally experience lower absolute decreases in eGFR with SGLT2 inhibitor initiation, in DAPA-HF and EMPA-REG OUTCOME, those with a lower eGFR were more likely to have a >10% dip in eGFR, suggesting that the relative eGFR dip is predictive of a protective hemodynamic effect.13Kraus B.J. Weir M.R. Bakris G.L. et al.Characterization and implications of the initial estimated glomerular filtration rate "dip" upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.Kidney Int. 2021; 99: 750-762Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,16Adamson C. Docherty K.F. Heerspink H.J.L. et al.Initial decline (dip) in estimated glomerular filtration rate after initiation of dapagliflozin in patients with heart failure and reduced ejection fraction: insights from DAPA-HF.Circulation. 2022; 146: 438-449Crossref PubMed Scopus (59) Google Scholar However, in individuals with advanced CKD, where minimal eGFR dip may be observed with treatment, additional mechanisms beyond hemodynamic effects may explain the long-term benefit of treatment with SGLT2 inhibitors. In conclusion, mechanistic physiology studies and clinical trials both support glomerular hypertension as a final common pathway for CKD progression, which is directly targeted by SGLT2 inhibitors. This effect may, in part, explain the benefits of SGLT2 inhibitors in kidney disease across diverse CKD causes, including patients with and without diabetes. Rather than inducing anxiety, observation of an eGFR dip should generally reassure clinicians and patients that SGLT2 inhibition is achieving the desired hemodynamic effect and protecting long-term kidney function. KY has received speaking honorarium from GlaxoSmithKline. DZIC has received consulting fees or speaking honorarium or both from Janssen, Bayer, Boehringer Ingelheim, Eli-Lilly, AstraZeneca, Merck & Co Inc., Prometic, and Sanofi; and has received operating funds from Janssen, Boehringer Ingelheim-Eli, Lilly, Sanofi, AstraZeneca, and Merck & Co Inc. DHvR has acted as a consultant and received honoraria from Boehringer Ingelheim, Eli-Lilly, Merck, Bayer, Sanofi, and AstraZeneca; and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca, and Sanofi. All the other authors declared no competing interests. KY is supported by the University of Toronto Department of Medicine Eliot Phillipson Clinician Scientist Training Program, Clarence Henry Trelford Clinician Scientist Award in Diabetes, and a KRESCENT Postdoctoral Fellowship. The KRESCENT program is cosponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institute of Health Research. DZIC is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the Canadian Institutes of Health Research, Diabetes Canada, and the Heart and Stroke Richard Lewar Centre of Excellence. DHvR is supported by a senior fellowship of the Dutch Diabetes Foundation and a PIONEER+ grant of the Dutch Kidney Foundation. KY, BEW, DHvR, and DZIC all contributed to the writing of the manuscript, provided critical edits, and reviewed and approved the final manuscript. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidneyKidney InternationalVol. 105Issue 6PreviewIn the healthy adult kidney, cellular homeostasis is maintained by the balance between nutrient surplus and nutrient deprivation signaling.1 The primary nutrient deprivation signals are sirtuin 1 (SIRT1) and adenosine monophosphate protein kinase (AMPK), which are activated by low intracellular levels of glucose and adenosine triphosphate (ATP) and by the oxidation-reduction state, and function to reduce oxidative stress and proinflammatory signaling, thus promoting cellular survival. The primary nutrient surplus signals are mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α), which are activated by high intracellular levels of glucose to enhance flux through glucose-driven anabolic pathways and to promote maladaptive tubular hypertrophy, oxidative stress, inflammation, fibrosis, and apoptosis. Full-Text PDF SGLT2 inhibitor: 2-way superstar in nephrology?Kidney InternationalVol. 105Issue 6PreviewShohei Ohtani became an amazing 2-way player in a modern-day game of baseball that basically never sees them, and he won his second American League most valuable player award unanimously in 2023. Full-Text PDF