Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Two contrasting magmatic types coexist after the cessation of back-arc spreading

Amongst island arcs, Izu–Bonin is remarkable as it has widespread, voluminous and long-lived volcanism behind the volcanic front. In the central part of the arc this volcanism is represented by a series of seamount chains which extend nearly 300 km into the back-arc from the volcanic front. These back-arc seamount chains were active between 17 and 3 Ma, which is the period between the cessation of spreading in the Shikoku Basin and the initiation of currently active rifting just behind the Quaternary volcanic front. In this paper we present new age, chemical and isotopic data from the hitherto unexplored seamounts which formed furthest from the active volcanic front. Some of the samples come from volcanoes at the western limit of the back-arc seamount chains. Others are collected from seamounts of various sizes which lie on the Shikoku Basin crust (East Shikoku Basin seamounts). The westernmost magmatism we have sampled is manifested as a series of volcanic edifices that trace the extinct spreading centre of the Shikoku Basin known as the Kinan Seamount Chain (KSC).Chemically, enrichment in fluid-mobile elements and depletion in HFSE relative to MORB indicates that the back-arc seamount chains and the East Shikoku Basin seamounts have a significant contribution of slab-derived material. In this context these volcanoes can be regarded as a manifestation of arc magmatism and distinct from the MORB-like lavas of the Shikoku back-arc basin. 40Ar/39Ar ages range from 15.7 to 9.6 Ma for the East Shikoku Basin seamounts, indicating this arc magmatism started immediately after the Shikoku Basin stopped spreading.Although the KSC volcanoes are found to be contemporaneous with the seamount chains and East Shikoku Basin seamounts, their chemical characteristics are very different. Unlike the calc-alkaline seamount chains, the KSC lavas range from medium-K to shoshonitic alkaline basalt. Their trace element characteristics indicate the absence of a subduction influence and their radiogenic isotope systematics reflect a mantle source combining a Philippine Sea MORB composition and an enriched mantle component (EM-1). One of the most remarkable features of the KSC is that their geochemistry has a distinct temporal variation. Element ratios such as Nb/Zr and concentrations of incompatible elements such as K2O increase with decreasing age and reach a maximum at ca. 7 Ma when the KSC ceased activity.<br/