Molecular regulation of the renin–angiotensin system by sodium–glucose cotransporter 2 inhibition in type 1 diabetes mellitus

Kopecky, Chantal; Domenig, Oliver; Antlanger, Marlies; Kovarík, J; Kaltenecker, Christopher C.; Poglitsch, Marko; Perkins, Bruce A.; Rye, Kerry‐Anne; Cherney, David Z.I.; Säemann, Marcus D.

doi:10.1007/s00125-019-4871-8

Cited by 22 publications

(21 citation statements)

References 9 publications

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“…This is in contrast to previous literature in which it has been proposed that SGLT-2 inhibition with concomitant RASi may synergistically boost the alternative RAS axis, leading to upregulation of angiotensin (1)(2)(3)(4)(5)(6)(7). 37 In our analysis, we did not find modulation by RASi or any indication of a possible synergistic effect, thus the effect of RASi is probably smaller. This would also explain why the magnitude of UACR reduction in our analysis was comparable in patients with and without RASi at baseline.…”

Section: Discussioncontrasting

confidence: 99%

“…Our analysis also showed that the magnitude of UACR reduction was similar in patients treated with and without RASi at baseline. This is in contrast to previous literature in which it has been proposed that SGLT‐2 inhibition with concomitant RASi may synergistically boost the alternative RAS axis, leading to upregulation of angiotensin (1–7) . In our analysis, we did not find modulation by RASi or any indication of a possible synergistic effect, thus the effect of RASi is probably smaller.…”

Section: Discussioncontrasting

confidence: 99%

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The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

Scholtes

Raalte

Correa‐Rotter

et al. 2019

Diabetes Obesity Metabolism

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Aims Renin‐angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium‐glucose co‐transporter‐2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo‐controlled studies in patients with T2D with a urinary albumin‐to‐creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo‐adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

Scholtes

Raalte

Correa‐Rotter

et al. 2019

Diabetes Obesity Metabolism

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show abstract

“…In T1D, empagliflozin was recently shown to cause an increase in the favorable alternative RAS component angiotensin(1-7) in combination with RAS blockade. 21 However, angiotensin(1-7) is presumed to cause preglomerular vasodilation, indicating that the interaction between RAS, SGLT2is, and renal hemodynamics is likely to be complex. We observed a clear effect of the clamps on renal hemodynamic function: GFR, ERPF, and renal blood flow were reduced, while RVR and FF were increased.…”

Section: Discussionmentioning

confidence: 99%

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

Bommel

Muskiet

Baar

et al. 2020

Kidney International

241

207

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“…This sequence of events has been demonstrated in the setting of diabetes‐related renal hyperfiltration . Importantly, tubuloglomerular feedback mechanisms related to SGLT2 inhibition have not yet been studied in patients with lower kidney function (especially CKD stages 3 and 4), and other autoregulatory factors, including efferent arteriolar changes, may be important in individuals with T2D, especially in the absence of hyperfiltration; (2) Suppression of pro‐inflammatory and pro‐fibrotic factors in the kidney, possibly via reducing hyperglycaemia, suppressing the renin angiotensin aldosterone system (RAAS) and also by reducing glomerular hypertension; and (3) Reducing renal ischemia via multiple pathways, thereby reducing kidney injury . While it is not known which of these hypotheses is most closely related to kidney protection, the largest body of experimental and human trial evidence exists for changes in glomerular hypertension, which could also explain the rapid anti‐proteinuric effect achieved with these agents and the rapid, reversible “dip” in eGFR seen with these agents .…”

Section: Mechanisms For Renal Protection With Sglt2 Inhibitionmentioning

confidence: 99%

What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?

Sridhar

Rahman

Cherney

2020

Diabetes Obesity Metabolism

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Over the past 5 years, sodium-glucose cotransport 2 (SGLT2) inhibitors have been increasingly regarded as glycaemic agents with cardiovascular (CV) and renal protective effects. The CV benefits of SGLT2 inhibitors have been well established in patients with type 2 diabetes (T2D) and a range of CV comorbidities at baseline. Subsequently, the renal benefits of SGLT2 inhibitors were established in the CREDENCE trial, a dedicated renal outcome trial where canagliflozin reduced the primary composite renal outcome by 30%. In light of these trials, clinical practice guidelines have rapidly evolved, recommending the use of SGLT2 inhibitors as renal and cardioprotective agents in appropriate patient populations. Accordingly, it is important to have an in-depth understanding of the evidence underlying the use of SGLT2 inhibitors in patients with T2D based on published clinical trials and real-world evidence (RWE) studies, as well as information related to potential safety concerns. To accomplish this, we reviewed the evidence for renal protection and safety with SGLT2 inhibitors in the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 CV safety trials, and in the growing body of evidence emerging from real-world studies. This body of work has shown that SGLT2 inhibitors reduce the risk of surrogate renal endpoints such as albuminuria and mitigate the risk of hard renal endpoints including doubling of serum creatinine and end-stage kidney disease in patients with T2D. K E Y W O R D S diabetic nephropathy, SGLT2 inhibitor 1 | INTRODUCTION Sodium-glucose cotransport-2 (SGLT2) inhibitors have been in clinical use for >5 years and were originally developed and prescribed to achieve additional glucose lowering by inducing glycosuria. As part of Food and Drug Administration (FDA) mandated requirements put in place in 2008, as a novel glucose lowering therapy, SGLT2 inhibitors underwent extensive safety evaluation in cardiovascular outcome trials (CVOTs). Accordingly, over the past 5 years, a large body of evidence has emerged from these CVOTs, and from observational realworld evidence (RWE) studies, as discussed and reviewed elsewhere. 1In stark contrast with other anti-hyperglycaemic agents assessed in CVOTs up to that time, SGLT2 inhibitors were shown to have substantial cardiovascular (CV) and renal protective effects across each medication in the class, and across all subgroups analysed to date.These CVOT results have transformed the way that SGLT2 inhibitors are thought about as therapies for patients with type 2 diabetes (T2D). In perhaps, the same way that ACE inhibitors and ARBs were Vikas S. Sridhar and Habib U. Rahman are the co-first authors.

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Molecular regulation of the renin–angiotensin system by sodium–glucose cotransporter 2 inhibition in type 1 diabetes mellitus

Cited by 22 publications

References 9 publications

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

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

What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?

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