Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial

Cherney, David Z.I.; Dekkers, Claire C J; Barbour, Sean J.; Cattran, Daniel C.; Gafor, Abdul Halim Abdul; Greasley, Peter J.; Laverman, Gozewijn D.; Lim, Soo Kun; Tanna, Gian Luca Di; Reich, Heather N.; Vervloet, Marc G.; Wong, Muh Geot; Gansevoort, Ron T.; Heerspink, Hiddo J L; investigators, Diamond

doi:10.1016/s2213-8587(20)30162-5

Cited by 185 publications

(178 citation statements)

References 28 publications

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“…In conclusion, the DAPA-CKD trial has enrolled a group of participants with a variety of kidney diseases and will allow assessment of SGLT2 inhibition in a broad cohort of patients with proteinuric kidney disease. While small mechanistic studies have demonstrated that SGLT2 inhibitors exert physiological effects in people with non-DKD, including a characteristic haemodynamic ‘dip’ in GFR [ 9 ], the DAPA-CKD trial is the first to capture the effects on clinical kidney outcomes. In the context of other trials in this field, the DAPA-CKD trial will provide unique insights into how to treat patients with kidney disease due to diverse aetiologies.…”

Section: Discussionmentioning

confidence: 99%

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Wheeler

Stefánsson

Батюшин

et al. 2020

Nephrology Dialysis Transplantation

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Background The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D.

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Section: Discussionmentioning

confidence: 99%

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Wheeler

Stefánsson

Батюшин

et al. 2020

Nephrology Dialysis Transplantation

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136

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“…Currently, several clinical studies to elucidate the reno-protective on CKD are going on, but it is still controversial [ 17 ]. In addition to ours, several studies have shown its effectiveness [ 14 , 18 ], but no effect was observed in other kinds of CKD models.…”

Section: Discussionmentioning

confidence: 99%

Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes

et al. 2020

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Background Sodium–glucose co-transporter 2 (SGLT2) inhibitor, a new class of glucose lowering agents, has been shown to be reno-protective in diabetes. Objective We aimed to explore whether SGLT2 inhibitor ipragliflozin has a direct reno-protective effect on non-diabetic chronic kidney disease (CKD) in mice. Methods CKD mice was induced by feeding of 0.25% w/w adenine containing diet. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) was orally administered to CKD mice for 4 weeks, concomitantly with adenine containing diet. Results CKD mice exhibited increases in kidney weight/body weight ratio, plasma creatinine levels, urinary fatty acid binding protein 1 excretion and plasma interleukin-6 levels, and a decrease in hematocrit, accompanied by morphological changes such as crystal deposits in the tubules, tubular dilatation, interstitial fibrosis, and increased 8-hydroxy-2′-deoxyguanosine staining. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) did not affect either plasma glucose levels or urinary glucose excretion, while it improved levels in plasma creatinine (P < 0.05 for 0.03 mg/kg/day, P < 0.001 for 0.1 mg/kg/day), interleukin-6 (P < 0.05 for 0.1 mg/kg/day) and hematocrit (P < 0.05 for 0.1 mg/kg/day), and morphological changes dose-dependently except crystal deposit formation in the CKD mice. Conclusions Low-dose ipragliflozin has a reno-protective effect in non-diabetic adenine-induced CKD mice, independently of plasma glucose levels and urinary glucose excretion. Low dose SGLT2 inhibitor may be a useful therapeutic option for non-diabetic CKD with the advantage of fewer adverse effects.

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“…The EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial tested empagliflozin in patients with HF [ 15 ], while the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA-CKD) tested dapagliflozin in patients with CKD [ 16 ]. In addition, a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials has been published [ 17 ], as well as a small crossover RCT of dapagliflozin in non-diabetic CKD (DIAMOND) [ 18 ].…”

Section: Sglt2 Inhibitors Improve Kidney Outcomes In Non-diabetic Patmentioning

confidence: 99%

“…An interesting piece of information is provided by the DIAMOND trial, although it had a small sample size and short follow-up [ 18 ]. In this crossover trial, 53 non-diabetic proteinuric (500–3500 mg/24 h) CKD patients with a mean eGFR of 58 ± 23 mL/min/1.73 m 2 were randomly assigned to dapagliflozin–placebo or placebo–dapagliflozin.…”

Section: Sglt2 Inhibitors Additionally Improve Kidney and CV Outcomesmentioning

confidence: 99%

SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia

Fernández-Fernández

Sarafidis

Kanbay

et al. 2020

Clinical Kidney Journal

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Sodium–glucose co-transporter-2 (SGLT2) inhibitors decreased cardiovascular (CV) events and improved renal outcomes in CV safety studies in type 2 diabetes melitus (T2DM) patients at high CV risk. Canagliflozin also improved kidney outcomes in diabetic kidney disease in the Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluationtrial. More recently, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed that dapagliflozin improved CV outcomes in patients with HF with or without diabetes. Protection from HF in non-diabetics was confirmed for empagliflozin in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. A meta-analysis of DAPA-HF and EMPEROR-Reduced confirmed reductions in all-cause and CV death and the combined risk of CV death or worsening HF, as well as in the composite renal endpoint {hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.43–0.90]} without differences based on the presence of diabetes or baseline estimated glomerular filtration rate (eGFR). Moreover, the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA-CKD) showed that dapagliflozin as an add-on over renin–angiotensin system blockade in patients with chronic kidney disease (CKD; with or without T2DM) reduced the HR for the primary endpoint (time to the first occurrence of ≥50% eGFR decline, end-stage kidney disease or renal or CV death) to 0.61 (95% CI 0.51–0.72) and for the secondary endpoints of worsening renal function or death from kidney failure [HR 0.56 (95% CI 0.45–0.68)], hospitalization for HF or CV death [HR 0.71 (95% CI 0.55–0.92)] and all-cause mortality [HR 0.69 (95% CI 0.53–0.88)]. These beneficial effects were consistent in patients with and without T2DM. In conclusion, SGLT2 inhibitors offer CV and kidney protection in both diabetic and non-diabetic CKD and, additionally, improve glycaemic control in T2DM, making them first-line therapy for CKD independent from diabetic status.

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Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial

Cited by 185 publications

References 28 publications

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes

SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia

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