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, Erik J.M. van; Muskiet, Marcel H.A.; Baar, Michael; Tonneijck, Lennart; Smits, Mark M.; Emanuel, Anna L.; Božović, Andrea; Danser, A.H. Jan; Geurts, Frank; Hoorn, Ewout J.; Touw, Daan; Larsen, Emil List; Poulsen, Henrik Enghusen; Nieuwdorp, Max; Joles, Jaap A.

doi:10.1016/j.kint.2019.09.013

Cited by 232 publications

(198 citation statements)

References 35 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…21,22 More recent data in type 2 diabetes have raised the possibility that efferent arteriolar tone may also be affected. 23 Regardless, reductions in intraglomerular pressure, along with enhanced natriuresis, are likely to play an important role not only in protection against kidney failure but also in reducing the risk of heart failure, especially in patients with CKD where subclinical volume overload is highly prevalent. 24 A number of other potential mechanisms have also been suggested, including protective effects on the vascular endothelium, anti-inflammatory actions, improvements in tubular oxygenation, and other direct cellular and metabolic effects.…”

Section: Discussionmentioning

confidence: 99%

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Neuen

Ohkuma

Neal

et al. 2021

American Journal of Kidney Diseases

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Discussionmentioning

confidence: 99%

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Neuen

Ohkuma

Neal

et al. 2021

American Journal of Kidney Diseases

View full text Add to dashboard Cite

show abstract

“…19 Aldosterone was measured by radioimmunoassay (Demeditec Diagnostics, Kiel, Germany). 20 Brachial BP was measured in supine position with a semiautomatic device (Omron 705 IT, OMRON Healthcare, The Netherlands) after at least 10 min of supine rest in a quiet and temperature-controlled room. We performed five sequential measurements and used the mean of last two readings for analysis.…”

Section: Study Design and Measurementsmentioning

confidence: 99%

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial

Wenstedt

Rorije

Engberink

et al. 2020

BMJ Open Diab Res Care

View full text Add to dashboard Cite

IntroductionPatients with type 1 diabetes are susceptible to hypertension, possibly resulting from increased salt sensitivity and accompanied changes in body fluid composition. We examined the effect of a high-salt diet (HSD) in type 1 diabetes on hemodynamics, including blood pressure (BP) and body fluid composition.Research design and methodsWe studied eight male patients with type 1 diabetes and 12 matched healthy controls with normal BP, body mass index, and renal function. All subjects adhered to a low-salt diet and HSD for eight days in randomized order. On day 8 of each diet, extracellular fluid volume (ECFV) and plasma volume were calculated with the use of iohexol and 125I-albumin distribution. Hemodynamic measurements included BP, cardiac output (CO), and systemic vascular resistance.ResultsAfter HSD, patients with type 1 diabetes showed a BP increase (mean arterial pressure: 85 (5) mm Hg vs 80 (3) mm Hg; p<0.05), while BP in controls did not rise (78 (5) mm Hg vs 78 (5) mm Hg). Plasma volume increased after HSD in patients with type 1 diabetes (p<0.05) and not in controls (p=0.23). There was no significant difference in ECFV between diets, while HSD significantly increased CO, heart rate (HR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in type 1 diabetes but not in controls. There were no significant differences in systemic vascular resistance, although there was a trend towards an HSD-induced decrease in controls (p=0.09).ConclusionsIn the present study, patients with type 1 diabetes show a salt-sensitive BP rise to HSD, which is accompanied by significant increases in plasma volume, CO, HR, and NT-proBNP. Underlying mechanisms for these responses need further research in order to unravel the increased susceptibility to hypertension and cardiovascular disease in diabetes.Trial registration numbersNTR4095 and NTR4788.

show abstract

“…The proposed mechanisms by which SGLT2 inhibition may lower the risk of cardiovascular and kidney outcomes are most likely multifactorial and may include improvements in BP control, reduction in total body sodium and water, and weight loss, all of which are associated with improved outcomes in patients with type 2 diabetes. The restoration of tubuloglomerular feedback is likely to be an important contributor to the mechanism of action of the kidney-protective effect of SGLT2 inhibitors, although this is not yet fully understood (22). Additional kidney mechanisms (e.g., tubular protection, reduced hypoxia and inflammation, and long-term effects of natriuresis) may also contribute to these kidneyprotective effects (23).…”

Section: P-value For Interaction N With Event/n Analyzed (%)mentioning

confidence: 99%

Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories

Levin¹,

Perkovic²,

Wheeler³

et al. 2020

CJASN

View full text Add to dashboard Cite

Background and objectivesIn the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin.Design, setting, participants, & measurementsPatients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc, we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework.ResultsOf 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes (P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes (P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category.ConclusionsThe observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status.Clinical Trial registry name and registration number:EMPA-REG OUTCOME, NCT01131676

show abstract

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

Cited by 232 publications

References 35 publications

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial

Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories

Contact Info

Product

Resources

About