The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes

Raalte, Daniël H. van; Bjornstad, Petter; Persson, Frederik; Powell, David R.; Castro, Rita; Wang, Ping Stella; Liu, Minzhi; Heerspink, Hiddo J.L.; Cherney, David Z.I.

doi:10.2337/dc19-0937

Cited by 50 publications

(32 citation statements)

References 43 publications

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“…The main reason is the risk of diabetic ketoacidosis [45]. However, preliminary post hoc analyses from the studies in type 1 diabetes do support kidney benefits [46] and our results might contribute additionally to the debate on the potential risks and benefits with SGLT2 inhibition in type 1 diabetes [45].…”

Section: Article In Pressmentioning

confidence: 54%

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

et al. 2021

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Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R 2 * (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three-and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019À004,557À92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21À58] mg/g and an eGFR of 73 (32) ml/min/1¢73m 2 . The mean changes in renal cortical R 2 * from baseline to six hours were for dapagliflozin -1¢1 (SD 0¢7) s À1 and for placebo +1¢3 (0¢7) s À1 , resulting in a difference between interventions of -2¢3 s À1 [95% CI -4¢0 to -0¢6]; p = 0¢012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R 2 * without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

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Section: Article In Pressmentioning

confidence: 54%

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

et al. 2021

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“…Furthermore, as discussed in detail in other sections of this supplement, in the only dedicated renal endpoint trial that has been published to date—CREDENCE—in patients with eGFR between 30 and 90 mL/min/1.73 m 2 and albuminuria, canagliflozin significantly reduced the composite primary endpoint by 30%, including the risks of ESKD and dialysis, regardless of background clinical characteristics . In people with type 1 diabetes, a great deal of data has been generated around HbA1c lowering, weight reduction, blood pressure lowering and changes in eGFR and hyperfiltration, with many of the changes mirroring those observed in the setting of T2D, albeit with the additional safety concern around DKA . Unfortunately, the effectiveness of these agents in reducing cardiorenal risk has yet to be clarified in people with type 1 diabetes, and even less is known in other relevant clinical situations such as in children and/or adolescents with early DKD, people with T1D, kidney transplant patients, and non‐DKD .…”

Section: Conclusion and Considerations For Future Directionsmentioning

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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“…This marks another important difference between SGLT2i and other diuretics: the latter are responsible for RAAS hyperactivation, uric acid blood levels increase, electrolytes loss and, above all, metabolic disorders. In fact, SGLT2i do not increase uric blood levels [56] and, although they stimulate tubule-glomerular feedback and induce plasma volume depletion, they determine small variation of serum magnesium, calcium, potassium, and phosphate values and no effects on serum sodium [57]. Moreover, stimulating magnesium blood level increase, SGLT2i have an anti-arrhythmic and cardioprotective effect [58,59].…”

Section: The Pleiotropic Effects Of Sodium-glucose Cotransporter 2 Inhibitors: Molecular and Pathophysiological Insightsmentioning

confidence: 99%

“…SGLT2i-related urinary volume increase may induce hemoconcentration, hematocrit, as well as serum albumin increase [56,61]. SGLT2i can restore a better heart oxygenation through hematocrit and hemoglobin levels increase, stopping the vicious cardio-renal involvement, seen in HF [62].…”

Section: The Pleiotropic Effects Of Sodium-glucose Cotransporter 2 Inhibitors: Molecular and Pathophysiological Insightsmentioning

confidence: 99%

Sodium-glucose cotransporter 2 inhibitors and heart failure: the best timing for the right patient

et al. 2021

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially born as anti-diabetic drugs, have shown many beneficial effects on the cardiovascular system, in particular against heart failure (HF). HF is a complex and multifaceted disease that requires a comprehensive approach. It should not be considered as a simplistic cardiac disease, but a systemic disease that leads to multisystemic organ failure and death. Exploiting their pleiotropic effects, SGLT2i are a very valid tool for HF treatment. Beyond the indication to reduce HF hospitalization and death risk, in patients with diabetes mellitus at high cardiovascular risk or with established cardiovascular event, SGLT2i administration reported beneficial effects regarding the wide spectrum of HF manifestations and stages, independently by diabetes mellitus presence. Recent evidence focuses on HF rehospitalization, cardiac and all-cause death reduction, as well as symptoms and quality of life improvement, in patients with chronic HF or with a recent HF decompensation episode. Given the recent finding about the SGLT2i usefulness in HF patients, further studies are needed to define the best administration timing to maximize the SGLT2i-derived beneficial effects.

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The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes

Cited by 50 publications

References 43 publications

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

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

Sodium-glucose cotransporter 2 inhibitors and heart failure: the best timing for the right patient

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