Summary
Background
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.
Discussion
Our analyses showed that, in this cohort of patients with chronic kidney disease at risk of progression, allocation to empagliflozin caused a small dip in kidney function of approximately 2 mL/min per 1·73 m2 (or 6%) and then halved the subsequent rate of long-term loss of kidney function. This overall result complements the 29% (95% CI 19–38) reduction in risk of kidney disease progression when assessed with the categorical composite outcome of end-stage kidney disease, a sustained decrease from baseline in eGFR of at least 40% or to less than 10 mL/min per 1·73 m2, or death from kidney failure. The beneficial effects of empagliflozin on the progression of chronic kidney disease varied by diabetes status and eGFR, but most prominently by albuminuria, where relative benefits might in fact be larger among participants with lower albuminuria. These findings are consistent with observations in other trials of SGLT2 inhibitors in chronic kidney disease, although these trials focused on patients with diabetes, significant levels of albuminuria, or both.
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The broad range of patients included in the large EMPA-KIDNEY trial has allowed this to be explored in a more diverse population than those included in other large trials of SGLT2 inhibition in chronic kidney disease; in particular, EMPA-KIDNEY included participants with an eGFR of less than 25 mL/min per 1·73 m2 and with a uACR of less than 200 mg/g who were excluded from these previous trials.
The acute dip in eGFR when empagliflozin was initiated in EMPA-KIDNEY was modest (in all participant subgroups; it was on average ❤ mL/min per 1·73 m2 or <10% of baseline eGFR) and was largely reversible when treatment was discontinued. The acute effect was larger among participants with diabetes than in those without (on both absolute and relative scales), which might reflect the greater prevalence and degree of hyperfiltration in this group. The acute effect of SGLT2 inhibition on kidney function was recognised early in the development of this drug class (although not in all studies
) and is believed to be due to the acute reduction in intraglomerular pressure caused by afferent arteriolar vasoconstriction stimulated by increased sodium delivery to the macula densa.
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The associated rapid reduction in albuminuria supports this hypothesis,
and this reduction in intraglomerular pressure is one of the postulated mechanisms of the beneficial effects of SGLT2 inhibition on kidney function.
Our exploratory analyses suggest that the reduction in albuminuria might be the most important measured determinant of the benefits observed in EMPA-KIDNEY, explaining a fifth of the effect on chronic slopes and two-fifths of the effect on the primary composite outcome of kidney disease progression, consistent with analyses from other trials in chronic kidney disease.
These analyses need to be interpreted with some caution because they could have been subject to bias due to measurement error and residual mediator–outcome confounding. Whether this association is due to avoidance of direct toxic effects of albumin on tubular function, a reduction in intraglomerular pressure, or another unmeasured correlate of urinary albumin is not clear. However, these analyses also suggest that other mechanisms unrelated to albuminuria, blood pressure, or glycaemic control contribute to the benefit of SGTL2 inhibition on kidney function.
Our analyses focused on chronic slopes. Although effects on total slope correlate strongly with effects on clinical outcomes over short (2–3-year) follow-up periods,
the chronic slope is likely to be more informative for longer time periods. When the magnitude of the acute dip correlates with the relative reduction in the chronic slope (which is plausible because they share causal mechanisms, such as reduced intraglomerular pressure), this reduces variation between subgroups in total slope when measured over 2–3 years. However, this would not be the case with longer follow-up (see appendix p 29 for an explanatory example). Clinicians seeking to delay or avoid kidney failure would usually consider such longer time periods for which the chronic slope is most relevant. Furthermore, the limited variation in total slopes between patient subgroups reduces the ability to explore any such differences in treatment effect that might exist between those subgroups. This is shown by the apparent consistency of treatment effect on total slope in EMPA-KIDNEY versus the evidence of effect modification when using chronic slopes.
When comparing chronic slopes, we have reported both the absolute and relative differences but have emphasised the latter. Absolute differences are determined by both the background annual rate of change in eGFR and the relative effect of treatment, so any heterogeneity observed could be due to either of these components. This is demonstrated in the analysis by baseline uACR: the absolute difference in the chronic slope among participants with a uACR of 2000 mg/g or higher was 1·82 mL/min per 1·73 m2 per year, whereas the background chronic slope among participants with a uACR of less than 30 mg/g was 0·88 mL/min per 1·73 m2 per year, so it was impossible for the absolute difference in the latter subgroup to be similar to that observed in the highest uACR subgroup. Indeed, the absolute difference in the chronic slope was positively associated with baseline uACR; however, the relative difference was inversely associated such that participants with the lowest baseline uACR had the largest relative reduction (86% [95% CI 36–136] in those with uACR <30 mg/g vs 29% [19–38] in those with uACR ≥2000 mg/g). There was no strong evidence that this association was importantly modified by the presence or absence of diabetes. Contrary to some international guidelines that only suggest (rather than recommend) using SGLT2 inhibitors in patients without diabetes and without significant albuminuria (uACR <200 mg/g),
these analyses suggest that patients with low albuminuria (with or without diabetes) are likely to gain substantial benefit in terms of preservation of kidney function from SGLT2 inhibition, in addition to the other benefits of reductions in risk of acute kidney injury and cardiovascular disease.
Given the short follow-up in EMPA-KIDNEY (median 2 years) it would be expected that a treatment that causes a 2 mL/min per 1·73 m2 acute dip in eGFR in the subgroup of patients with uACR <30 mg/g (progressing at only 1 mL/min per 1·73 m2 per year) would not demonstrate definitive benefits on the categorical outcome (by contrast with subgroups with higher uACR progressing faster than 2 mL/min per 1·73 m2 per year). These analyses of the chronic slope suggest that important benefits would likely emerge with longer treatment (see appendix p 29 for an example).
These analyses are limited by the characteristics of patients included in EMPA-KIDNEY.
Few patients with type 1 diabetes were included, and patients with autosomal dominant polycystic kidney disease or with a kidney transplant were not eligible for the trial. In a companion paper, we assess whether the effects of allocation empagliflozin vary in different types of kidney disease.
The trial deliberately excluded patients at low risk of chronic kidney disease progression (ie, those with an eGFR of ≥45 mL/min per 1·73 m2 and uACR <200 mg/g), but demonstrated that the relative benefit on the chronic slope was inversely proportional to predicted risk of kidney failure. Participants only received study treatment for 2 years on average because the trial was stopped earlier than planned owing to clear evidence of benefit. A further 2 years of off-treatment follow-up is underway to assess the longer-term effects of an average of 2 years of treatment.
In summary, in EMPA-KIDNEY, allocation to empagliflozin compared with placebo caused a modest acute dip in eGFR, and then substantially slowed the longer-term progression of chronic kidney disease. The longer-term benefits varied by diabetes status, eGFR, and most prominently uACR (and related characteristics such as predicted risk of kidney failure). Although the trial stopped early because of clear benefits emerging based on results in patients at highest risk, these analyses show that patients at lower risk such as those with lower levels of albuminuria—many of whom in their lifetime would otherwise develop kidney failure—could benefit in terms of preservation of kidney function, in addition to other proven cardiovascular and mortality benefits.
If widely implemented, use of SGLT2 inhibitors could have a substantial effect on the public health impacts of chronic kidney disease.
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