Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial

Correa‐Rotter, Ricardo; Hou, Fanfan; Lindberg, Magnus; McMurray, John J.V.; Rossing, Peter; Heerspink, Hiddo J L; Wheeler, David C.; Chertow, Glenn M.; Greene, Tom; Hou, F. F.; McMurray, John J.V.; Rossing, Peter; Toto, Roberto D.; Stefánsson, Bergur V.; Langkilde, Anna Maria; Pfeffer, Marc A.; Pocock, Stuart J.; Swedberg, Karl; Rouleau, Jean L.; Chaturvedi, Nishi; Ivanovich, Peter; Levey, Andrew S.; Christ‐Schmidt, Heidi; Mann, Johannes F.E.; Held, Claes; Varenhorst, Christoph; Holmgren, Pernilla; Hallberg, Theresa; Douthat, Walter; Pecoits‐Filho, Roberto; Cherney, David Z.I.; Hou, Fan Fan; Persson, Frederik; Haller, Hermann; Wittmann, István; Tudományegyetem, Pécsi; Khullar, Dinesh; Kashihara, Naoki; Correa-Rotter, R; Escudero, Elizabeth; Isidto, Rey; Iloilo, Healthlink; Nowicki, Michał; Батюшин, М. М.; Kang, Shin‐Wook; Teruel, J.L.; Furuland, Hans; Bilchenko, Oleksandr; Mark, Patrick B.; Dwyer, Jamie P.; Bui, Pham Van

doi:10.1093/ndt/gfz290

Cited by 170 publications

(165 citation statements)

References 13 publications

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“…Due to the proposed mechanism of kidney protection with these agents, both DAPA-CKD and EMPA-KIDNEY may also include participants with and without T2DM. 32,33 Of note, DAPA-CKD has recently been stopped on advice of the data safety monitoring board due to overwhelming efficacy, raising the possibility that this class of drug may also slow the progression of non-diabetic kidney disease.…”

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

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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

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“…Therefore, an interaction between the degree of HbA 1c lowering and kidney protection cannot be ruled out. Based on existing data, it may be speculated that, rather than being based on alterations in body weight, BP or HbA 1c , reductions in albuminuria and eGFR preservation are based primarily on reduced glomerular hypertension or improvements in glomerular membrane barrier function [49]-a hypothesis that is being tested in dedicated kidney outcome studies [50].…”

Section: Discussionmentioning

confidence: 99%

Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials

et al. 2020

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Aims/hypothesis This study aimed to evaluate the effect of ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.gov NCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population. Methods Post hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks. Results Overall, mean (SD) baseline eGFR was 88.2 (18.8) ml min −1 (1.73 m) −2 and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were −2.3, −2.7 and −0.7 ml min −1 (1.73 m) −2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were −0.2, 0.1 and −2.0 ml min −1 (1.73 m) −2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was −29.5% (−44.8, −9.8; p < 0.01) for ertugliflozin 5 mg and −37.6% (−51.8, −19.2; p < 0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA 1c (mmol/mol [95% CI]) at week 104 were similar between treatment groups: −6.84 (−7.64, −6.03), −7.74 (−8.54, −6.94) and −6.84 (−7.65, −6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1 c (% [95% CI]) at week 104 were: −0.63 (−0.70, −0.55), −0.71 (−0.78, −0.64) and −0.63 (−0.70, −0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Conclusions/interpretation Ertugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA 1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria. Trial registration clinicaltrials.gov NCT01999218 and NCT02033889.

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“…The most interesting data relate to DAPA-CKD trial [ 16 , 19 , 20 ]. As in the case of the other large trial with a primary kidney endpoint (CREDENCE) [ 8 ], DAPA-CKD was stopped early for overwhelming efficacy.…”

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.

show abstract

Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial

Cited by 170 publications

References 13 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

Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials

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

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