Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

DeFronzo, Ralph A.; Reeves, W. Brian; Awad, Alaa S.

doi:10.1038/s41581-021-00393-8

Cited by 314 publications

(352 citation statements)

References 241 publications

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“…By inhibiting sodium absorption in the proximal tubule, SGLT2is increase distal delivery of sodium chloride to the macula densa, activating tubulo-glomerular feedback and ameliorating glomerular hypertension and hyperfiltration through reversal of both afferent arteriole vasodilation and efferent arteriole vasoconstriction typically observed in diabetes [ 5 , 6 , 7 ]. Moreover, NaCl delivery to the distal nephron reduces the glomerular filtration rate (GFR) by increasing hydrostatic pressure in Bowman’s space [ 6 ].…”

Section: Mechanisms Of Renal Protection With Sglt2mentioning

confidence: 99%

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

Leoncini

Russo

Bussalino

et al. 2021

IJMS

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In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.

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Section: Mechanisms Of Renal Protection With Sglt2mentioning

confidence: 99%

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

Leoncini

Russo

Bussalino

et al. 2021

IJMS

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“…DKD diagnosis has traditionally been based on microalbuminuria; however, renal structural damage might precede albumin excretion, as suggested by the number of diabetic patients (about 20%) that develop DKD in the absence of albuminuria [ 6 ], limiting the accuracy of its diagnosis in a significant part of DM population. The lack of sensitivity and specificity of albumin for the early identification of high-risk patients has prompted the search for novel noninvasive alternatives to cover this clinical need.…”

Section: Urinary Extracellular Vesicles (Uevs) As Potential Biomarkers In Diabetic Kidney Diseasementioning

confidence: 99%

“…The pathogenesis of DKD is multifactorial and contributes to the progressive decline in the glomerular filtration rate, affecting tubuloglomerular feedback and inducing tubule hypertrophy, podocyte injury, albuminuria, inflammation, endothelial dysfunction, fibrosis, etc. [ 6 ]. As a consequence, hormonal and hemodynamic changes (including microcirculation impairments) are produced, and circulating levels of advanced glycation end products (AGEs), inflammatory mediators and/or growth factors increase [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Intensive glycemic control reduces the incidence of albuminuria by 50% and normotensive patients with advanced DKD show slower progression of kidney disease than do patients with hypertension. Accordingly, the primary strategy for preventing the development of DKD should aim at maintaining HbA1c <6.5% and blood pressure <140/80 mmHg [ 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…The problem remains on those patients with DKD with high levels of albuminuria, where the normalization of the blood glucose might not completely halt the progression of the pathology. Moreover, almost 20% of patients with diabetes develop DKD in the absence of albuminuria [ 6 ], and in many others the coexistence of T2DM and nephropathy at the time of diagnosis can go unrecognized for years due to the complex natural history of T2DM [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Saenz-Pipaon

Echeverria

Orbe

et al. 2021

JCM

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Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

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Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinopathy in Patients With Type 2 Diabetes

Yen,

Wei,

et al. 2023

JAMA Netw Open

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ImportanceDiabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy.ObjectiveTo compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D).Design, Setting, and ParticipantsThis cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023.ExposuresTreatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016.Main Outcomes and MeasuresThe main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups.ResultsA total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P &lt; .001), pioglitazone (4.32 vs 5.76; P &lt; .001), and sulfonylureas (2.94 vs 4.67; P &lt; .001).Conclusions and RelevanceThis cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.

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Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

Cited by 314 publications

References 241 publications

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinopathy in Patients With Type 2 Diabetes

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