Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration

Škrtić, Marko; Yang, Gary K.; Perkins, Bruce A.; Soleymanlou, Nima; Lytvyn, Yuliya; Eynatten, Maximilian von; Woerle, Hans J.; Johansen, Odd Erik; Broedl, Uli C.; Hach, Thomas; Silverman, Melvin; Cherney, David Z.I.

doi:10.1007/s00125-014-3396-4

Cited by 141 publications

(91 citation statements)

References 10 publications

(12 reference statements)

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“…As the effects of SGLT2 inhibition on UACR occur in conjunction with small declines in eGFR over the initial 3-4 weeks in patients with type 2 diabetes, it is possible that the UACR-lowering effects of these agents are due to reduced intraglomerular pressure. Consistent with this hypothesis is the preliminary observation that SGLT2 inhibition with empagliflozin reduces calculated afferent arteriolar tone and reduces calculated glomerular capillary pressure in patients with type 1 diabetes [12]. Furthermore, in the present pooled analysis, the effect of empagliflozin on UACR remained significant and of a clinically relevant magnitude (20-40% reduction) after controlling for on-treatment changes in BP, weight and HbA 1c .…”

Section: Discussionsupporting

confidence: 88%

“…The albuminuria-lowering effect of SGLT2 inhibition may be due to several mechanisms. First, SGLT2 inhibition achieved through either pharmacological blockade or genetic knockout models reduces renal hyperfiltration, which is considered to be a surrogate marker for intraglomerular pressure in humans [11,12,19,26]. Such a mechanism would be expected to reduce albuminuria independent of changes in systemic BP, similar to the effects of RAAS blockade, but through afferent vasoconstrictive effects rather than efferent vasodilatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…Empagliflozin has been shown to decrease renal hyperfiltration in patients with type 1 diabetes [11]. This renal physiological characteristic has been linked to the development of nephropathy in type 1 and type 2 diabetes [12][13][14]. Furthermore, SGLT2 inhibition may improve this early glomerular haemodynamic abnormality through inhibition of sodium-glucose reabsorption at the proximal tubule [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…This renal physiological characteristic has been linked to the development of nephropathy in type 1 and type 2 diabetes [12][13][14]. Furthermore, SGLT2 inhibition may improve this early glomerular haemodynamic abnormality through inhibition of sodium-glucose reabsorption at the proximal tubule [12][13][14]. Such a natriuretic effect increases sodium delivery to the distal tubule, thereby stimulating tubuloglomerular feedback, ultimately causing afferent renal arteriolar vasoconstriction and a reduction in intraglomerular pressure [11,12].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, SGLT2 inhibition may improve this early glomerular haemodynamic abnormality through inhibition of sodium-glucose reabsorption at the proximal tubule [12][13][14]. Such a natriuretic effect increases sodium delivery to the distal tubule, thereby stimulating tubuloglomerular feedback, ultimately causing afferent renal arteriolar vasoconstriction and a reduction in intraglomerular pressure [11,12]. Based on available data in healthy humans and in patients with type 1 diabetes, the renal haemodynamic effects of SGLT2 inhibition appear to be RAAS independent, as plasma and urinary levels of RAAS mediators increase modestly, rather than decline, in response to the intervention [11,13,14].…”

Section: Introductionmentioning

confidence: 99%

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The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA 1c , systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA 1c , SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 3 0 -3 0 0 m g / g ; n = 6 3 6 ) o r m a c r o a l b u m i n u r i a (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA 1c , SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (−32% vs placebo; p < 0.001) or macroalbuminuria (−41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA 1c , SBP or weight. Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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Extra‐glycaemic properties of empagliflozin

Solini

2015

Diabetes Metabolism Res

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Type 2 diabetes is a complex and multifaceted disease requiring an individualized approach. A special attention, in treating the patients, should be devoted to the presence of comorbidities like overweight or obesity and arterial hypertension. Among the available anti-hyperglycaemic agents, several are associated with side effects like hypoglycaemia and weight gain. An increasing interest is reported in sodium-glucose co-transporter-2 inhibitors, a relatively novel class of glucose-lowering drugs that act independently of insulin, provide benefits beyond glucose-lowering actions and show a better tolerability compared with traditional medications for type 2 diabetes. This review tries to offer a balanced view on the main extra-glycaemic effects of empagliflozin, also mentioning clinical data obtained with other sodium-glucose co-transporter-2 inhibitors; the role of the proximal tubule in the pathophysiology of diabetic nephropathy and the potential nehroprotection exerted by this compound are also briefly discussed.

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SGLT2 inhibition to address the unmet needs in diabetic nephropathy

Barutta

Bernardi

Gargiulo

et al. 2019

Diabetes Metabolism Res

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Summary Current treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an “ideal” new drug should include primary prevention of microalbuminuria, additive/synergistic anti‐proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end‐stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium‐glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.

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Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration

Cited by 141 publications

References 10 publications

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

Extra‐glycaemic properties of empagliflozin

SGLT2 inhibition to address the unmet needs in diabetic nephropathy

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