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Effects of Empagliflozin on the Progression of Chronic Kidney Disease
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This prespecified analysis from the EMPA-KIDNEY trial assessed the effects of empagliflozin on the progression of chronic kidney disease (CKD). Empagliflozin caused a 6% reduction in eGFR in the first 2 months and thereafter halved the chronic slope per year. There was a significant decrease in the rate of progression of CKD among patients with a baseline urinary albumin-to-creatinine ratio less than 30 mg/g, although the absolute difference in chronic slopes was lower in those with a lower baseline urinary albumin-to-creatinine ratio. However, the relative difference of the chronic slope in this group was significant.
- Empagliflozin is associated with a slower rate of progression of CKD among patients with and without albuminuria. SGLT2 inhibitors may be used in patients without albuminuria to slow the progression of CKD.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.
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), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 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. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.
FINDINGS
Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001).
INTERPRETATION
Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.
FUNDING
Boehringer Ingelheim and Eli Lilly.
Additional Info
Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial
Lancet Diabetes Endocrinol 2023 Dec 04;[EPub Ahead of Print], The EMPA-KIDNEY Collaborative GroupFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Prior outcome trials that assessed the impact of SGLT2 inhibitors on CKD progression have provided limited insights about the benefit of these agents in renal outcomes in patients with lower risk for CKD progression as well as those with more advanced stages of CKD. The current study from the EMPA-KIDNEY collaborative group is a post hoc analysis of data from the EMPA-KIDNEY trial that compares the eGFR slope among various subgroups. The goal of this study is to expand our understanding of the magnitude of benefit from empagliflozin treatment in these different subgroups. The investigators report both an acute eGFR slope, defined as baseline to 2 months, and a chronic eGFR slope, defined as 2 months to the final follow-up visit.
Regarding the acute slope, a modest dip in eGFR of −2.12 mL per min per 1.73 m2 (relative change of −6%) was seen during the first 2 months of therapy with empagliflozin. In a subset of patients with 4-week post follow-up data, this dip was found to be reversible after discontinuation of therapy.
Regarding the chronic slope, empagliflozin reduced the rate of eGFR decline by 50% in all participants (−1.37 mL/min/1.73 m2/year in empagliflozin group vs −2.73 mL/min/1.73 m2/year in placebo group). A notable finding in this study was the −18% per year relative difference in the chronic slope for empagliflozin versus placebo in individuals with an eGFR <20 mL/min/1.73 m2. Although the magnitude of this effect is less than what was observed in higher eGFRs, it is still remarkable to see the renoprotective benefit of slowing CKD progression extend into lower eGFRs. This has clinical implications such that empagliflozin may delay the time until starting dialysis in people with advanced CKD, allowing more time for dialysis planning or a preemptive transplant.
Another notable finding was the benefit seen in individuals without albuminuria. While the absolute difference in yearly chronic slope reduction in those with uACR <30 mg/g treated with empagliflozin was lower compared with groups with elevated albuminuria, this was likely due to an overall low rate of decline in eGFR in individuals without albuminuria. In this scenario one can be misled without considering the relative difference, as opposed to the absolute difference, in the yearly chronic slope reduction. In fact, in those with a uACR <30 mg/g, the relative difference in the yearly chronic slope reduction was notably higher than in those with more elevated uACR levels (−86% for uACR, <30 mg/g; −71% for uACR, 30–300 mg/g; −49% for uACR, >300 to <1000 mg/g; −47% for uACR, 1000 to <2000 mg/g; −29% for uACR, >2000 mg/g). This finding supports the long-term benefit of delaying CKD progression in people without elevated albuminuria and argues for this to be reflected in guidelines.
In summary, this study expands our understanding of who benefits from treatment with empagliflozin, which includes patients with less disease severity based on the absence of albuminuria as well as those with more disease severity based on having a lower eGFR, and it supports the broad use of empagliflozin for the treatment of CKD.