Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial

Abstract

Aims/hypothesis In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories. Methods DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25–75 ml min−1 [1.73 m]−2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200–5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories. Results Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories. Conclusion/interpretations The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity. Trial registration ClinicalTrials.gov NCT03036150. Funding The study was funded by AstraZeneca. Graphical abstract

Cardiorenal effects of sodium glucose cotransporter 2 inhibitors in patients with diabetic and non-diabetic chronic kidney disease: A system review and meta-analysis

“…The results of our analysis indicated that, compared to placebo, SGLT-2 inhibitors could reduce the overall cardiorenal risk by 29%, the risk of kidney disease progression by 31%, and the risk of CV death or hospitalization for HF by 25%. Similar bene ts were found in patients coexisting CKD and T2DM, which was consistent with the results of previous studies conducted on T2DM populations [35][36][37][38]. In addition, our results also suggested that the cardiorenal bene ts of SGLT-2 inhibitors were similar in CKD patients with eGFR 45 mL/min/1.73 m 2 and those with better eGFR levels, although the relative risk reduction was numerically higher in individuals with eGFR ≥ 45 mL/min/1.73 m 2 (38% vs 24%).…”

Impact of baseline kidney function on the effects of sodium‐glucose co‐transporter‐2 inhibitors on kidney and heart failure outcomes: A systematic review and meta‐analysis of randomized controlled trials

“…Nonetheless, the significant renal benefits observed in the smallest eGFR categories show that SGLT2is protect the kidney also through other pathways, which may include enhancement of kidney oxygenation, direct effects on glomerular endothelial function, metabolic and anti‐inflammatory effects 44 . Furthermore, a recent post hoc analysis of the DAPA‐CKD trial, which evaluated the effect of dapagliflozin on a composite renal outcome in subjects with and without T2D with an eGFR of between 25 and 75 ml/min/1.73m 2 and urine albumin‐to creatinine ratio (UACR) of between 20 and 5000 mg/g, showed more pronounced benefits among participants with higher UACR, also suggesting albuminuria‐lowering effects 40 . Conversely, although the fundamental mechanisms responsible for the beneficial cardiac effects of SGLT2is have yet not been clarified, the observed trend towards higher HF benefits with declining eGFR suggests that the pathways through which SGLT2is exert their cardioprotective effects are kidney‐independent and support the existence of different mechanisms of action.…”

Sub-analyses of the DAPA-CKD study: new data on the use of sodium-glucose cotransporter type 2 inhibitor in the treatment of chronic kidney disease

“…Основываясь на том, что у лиц с более выраженными стадиями ХБП выше риск развития терминальной стадии болезни почек, сердечно-сосудистых событий и смертности, S. Waijer и соавт. выполнили post-hoc-анализ результатов исследования DAPA-CKD с целью оценки эффективности и безопасности дапаглифлозина в зависимости от исходной категории риска по широко используемой классификации KDIGO [21]. Более высокий уровень альбуминурии и более низкий показатель рСКФ являются предикторами почечной недостаточности и сердечно-сосудис тых событий и включены в классификационную систему KDIGO по оценке комбинированного сердечно-сосудистого и почечного риска [22].…”

“…Для этого исследователи разделили пациентов на подгруппы, взяв за основу категории комбинированного риска сердечно-сосудистых и почечных событий у пациентов с ХБП в зависимости от категории рСКФ и альбуминурии KDIGO, проведя, однако, их определенную модификацию [21,22]. Необходимость модификации была обусловлена тем, что исходно абсолютное большинство участников исследования DAPA-CKD относились к категории очень высокого риска по KDIGO, в связи с этим создание дополнительной категории «умеренно-высокого риска» позволило сформировать когорты с относительно сопоставимыми размерами для дальнейшей стратификации.…”