SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

Wheeler, David C.; James, June; Patel, Dipesh; Viljoen, Adie; Amar, Ali; Evans, Marc; Fernando, Kevin; Hicks, Debbie; Milne, Nicola; Newland‐Jones, Philip; Wilding, John

doi:10.1007/s13300-020-00930-x

Cited by 25 publications

(29 citation statements)

References 38 publications

(168 reference statements)

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“…There have been multiple reviews trying to explain these benefits which do not seem to relate to the blood glucose lowering effect [ 39 , 40 ]. Suggested mechanisms include weight loss, reduction in the systemic or intraglomerular pressure, lowering of uric acid, decreased inflammation, as well as changes in cell metabolism [ 41 , 42 ]. Recently, increasing focus has been on a unifying mechanism related to the potential impact on hypoxia as demonstrated experimentally and reviewed by Packer [10] .…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…3 SGLT2 inhibitors have emerged as a new therapeutic option that not only improves the metabolic profile in patients who are diabetic, but also conveys strong renoprotective effects. 3,27 Intriguingly, SGLT2 inhibition reduces ER stress in renal tubular cells. 28 In this study, we show the reverse also holds true: inhibition of CHOP reduces SGLT2 expression.…”

Section: Discussionmentioning

confidence: 99%

“…3 However, their long-term efficacy and safety profile remain to be established. 3 Hence, there remains an unmet need for new therapies to treat DKD.…”

mentioning

confidence: 99%

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease

Shahzad

Fatima

Al‐Dabet

et al. 2021

JASN

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Background: Maladaptive ER stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental DKD. Methods: Following an in vivo dose-escalation study, we determined the efficacy of CHOPASO in the early and later stages of experimental DKD (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results: CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented cell death of human kidney cells in vitro. Conclusions: The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

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“…In the last years, SGLT2 inhibitors have shown an important efficacy in the prevention of progressive DKD [89]. During hyperglycemia, there is an increase in glucose delivery to the proximal convoluted tubule (PCT), which results in increased tubular glucose uptake and increased sodium reabsorption, through the sodium-glucose cotransporter-2 (SGLT2).…”

Section: Drug Therapies Evaluationmentioning

confidence: 99%

Perspectives on the Role of Magnetic Resonance Imaging (MRI) for Noninvasive Evaluation of Diabetic Kidney Disease

Mora-Gutiérrez

Fernández‐Seara

Echeverria‐Chasco

et al. 2021

JCM

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Renal magnetic resonance imaging (MRI) techniques are currently in vogue, as they provide in vivo information on renal volume, function, metabolism, perfusion, oxygenation, and microstructural alterations, without the need for exogenous contrast media. New imaging biomarkers can be identified using these tools, which represent a major advance in the understanding and study of the different pathologies affecting the kidney. Diabetic kidney disease (DKD) is one of the most important diseases worldwide due to its high prevalence and impact on public health. However, its multifactorial etiology poses a challenge for both basic and clinical research. Therefore, the use of novel renal MRI techniques is an attractive step forward in the comprehension of DKD, both in its pathogenesis and in its detection and surveillance in the clinical practice. This review article outlines the most promising MRI techniques in the study of DKD, with the purpose of stimulating their clinical translation as possible tools for the diagnosis, follow-up, and monitoring of the clinical impacts of new DKD treatments.

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SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

Cited by 25 publications

References 38 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

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease

Perspectives on the Role of Magnetic Resonance Imaging (MRI) for Noninvasive Evaluation of Diabetic Kidney Disease

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