Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial

doi:10.1016/S2213-8587(21)00243-6

The Lancet Diabetes & Endocrinology

Volume 9, Issue 11, November 2021, Pages 755-766

https://doi.org/10.1016/S2213-8587(21)00243-6 Get rights and content

Summary

Background

Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.

Methods

DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m² and 75 mL/min per 1·73 m² and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150.

Findings

Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI –33·1 to –25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of −35·1% (95% CI −39·4 to −30·6; p<0·0001) in patients with type 2 diabetes and −14·8% (−22·9 to −5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (p_interaction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change –3·06, 95% CI –5·20 to –0·90; p=0·0056).

Interpretation

In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria.

Funding

AstraZeneca.

Introduction

Albuminuria is a well established risk marker for kidney failure and cardiovascular events in patients with chronic kidney disease.1, 2 Various pharmacological interventions, including renin–angiotensin system inhibitors, SGLT2 inhibitors, and glucagon-like peptide 1 receptor agonists, reduce albuminuria.3, 4 Meta-analyses of clinical trials showed that an early reduction in albuminuria is associated with a lower risk of kidney failure, supporting the use of albuminuria as a surrogate for kidney failure.⁵

SGLT2 inhibitors slow progression and reduce the risk of kidney failure in patients with and without chronic kidney disease. SGLT2 inhibitors were initially developed as oral glucose-lowering drugs for patients with type 2 diabetes and were not recommended for patients with chronic kidney disease because of lower glycaemic efficacy in patients with lower estimated glomerular filtration rate (eGFR). However, clinical trials showed that SGLT2 inhibitors reduce albuminuria in patients with type 2 diabetes and chronic kidney disease.6, 7 These findings raised interest in studying the effect of SGLT2 inhibitors on long-term kidney outcomes. The CREDENCE trial⁸ showed that canagliflozin reduced the risk of clinically important kidney and cardiovascular endpoints in patients with type 2 diabetes and chronic kidney disease.⁸ The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial extended these findings to patients with chronic kidney disease with and without type 2 diabetes, showing significantly lower rates of progressive chronic kidney disease, cardiovascular death or heart failure hospitalisation, and all-cause mortality.⁹ In this prespecified analysis of the DAPA-CKD trial, we assessed the effects of dapagliflozin on albuminuria, investigated the consistency of these effects in patients with and without type 2 diabetes, and explored the association between early changes in albuminuria and subsequent longer-term changes in kidney function.

Research in context

Evidence before this study

We searched PubMed between Jan 1, 2000, and April 2, 2021, for trials published in English, using the search terms “SGLT2”, “SGLT2 inhibitor”, “chronic kidney disease”, “albuminuria”, “UACR”, and “randomised controlled clinical trial’. Albuminuria is an established risk marker for progression of chronic kidney disease. Previous clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce albuminuria in patients with type 2 diabetes and chronic kidney disease. For example, in the DELIGHT study, the SGLT2 inhibitor dapagliflozin reduced the urinary albumin-to-creatinine ratio (UACR) by 28% at 4 weeks compared with placebo in patients with chronic kidney disease and type 2 diabetes. Two small clinical studies in patients with chronic kidney disease without diabetes reported that the albuminuria-lowering effect of dapagliflozin was diminished compared with patients with diabetes. Because these studies were relatively small and of short duration, no definitive conclusions could be drawn over whether the different effects of dapagliflozin on albuminuria between patients with and without diabetes were an actual or chance finding.The DAPA-CKD trial was a large international clinical trial to assess the effects of dapagliflozin on clinical outcomes in patients with chronic kidney disease with and without type 2 diabetes. The results of the trial showed that dapagliflozin compared with placebo significantly decreased the relative risks of kidney failure, cardiovascular death or heart failure hospitalisation, and all-cause mortality. In this prespecified analyses of the DAPA-CKD trial, we assessed the effect of dapagliflozin on albuminuria, investigated the consistency of these effects in patients with and without type 2 diabetes, and explored the association between early changes in albuminuria and subsequent longer-term changes in kidney function.

Added value of this study

The acute decline in estimated glomerular filtration rate (eGFR) after 2 weeks treatment with dapagliflozin correlated with the reduction in UACR at week 2. This association was present in patients with and without type 2 diabetes. The reduction in UACR after 2 weeks was associated with a lower rate of decline in eGFR during the trial both in patients with and without type 2 diabetes.

Implications of all the available evidence

In this prespecified analysis of the DAPA-CKD trial, we showed that dapagliflozin reduced albuminuria in patients with chronic kidney disease with and without type 2 diabetes, with a larger reduction in patients with type 2 diabetes. These data, in combination with the available evidence that dapagliflozin consistently reduces the risk of clinical outcomes in patients with and without type 2 diabetes, suggest that the protective effects of dapagliflozin in patients with chronic kidney disease are likely to be mediated in part through pathways related, and in part through pathways unrelated, to reduction in albuminuria. The association between an early reduction in albuminuria with attenuated longer-term eGFR decline highlights the importance of monitoring albuminuria as a marker to guide patient management.

Section snippets

Study design and participants

DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries (Argentina, Brazil, Canada, China, Denmark, Germany, Hungary, India, Japan, Mexico, Peru, Philippines, Poland, Russia, South Korea, Spain, Sweden, UK, Ukraine, USA, and Vietnam). The trial protocol, statistical analysis plan, and study design have been published previously.9, 10 The trial protocol was approved by a central or local ethics committee at each trial site. In brief, the

Results

In the DAPA-CKD trial, between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). These participants were followed up for a median of 2·4 years (IQR 2·0–2·7). Overall, participants had a median UACR of 949 mg/g (IQR 477–1885; 107 mg/mmol, IQR 53·9–213) at baseline. Median UACR at baseline was 965 mg/g (472–1903) in the dapagliflozin group and 934 mg/g (482–1868) in the placebo group. 2079 (48%) of 4304

Discussion

SGLT-2 inhibitors reduce albuminuria in patients with type 2 diabetes.¹¹ Herein, we extend these findings by showing that dapagliflozin reduced albuminuria in patients with chronic kidney disease with and without type 2 diabetes, with a larger reduction in patients with type 2 diabetes. Consistent with these findings, dapagliflozin significantly increased the likelihood of regression to normoalbuminuria or microalbuminuria and reduced the likelihood of progression to more severe degrees of

Data sharing

Data underlying the findings described in this Article can be obtained in accordance with AstraZeneca's data sharing policy, described online.

Declaration of interests

TG has received grants for statistical consulting from AstraZeneca, CSL Pharma, and Boehringer-Ingelheim, and has received personal fees from Janssen Pharmaceuticals, DURECT Corporation and Pfizer for statistical consulting. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from the US National Institute of Diabetes and Digestive and Kidney Diseases, and Amgen, is on the board of directors for Satellite Healthcare, has received fees for advisory

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Cited by (91)

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria
2024, American Heart Journal
Sodium–glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes.
A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m² and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome.
Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP.
In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.
Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial
2024, Kidney Medicine
Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a “rapid decliner” phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m².
This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m².
Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available.
Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care.
Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups.
Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m²/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001).
This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established.
Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug.
The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.
clinicaltrials.gov ID: NCT01131676
In most people with type 2 diabetes, their kidney function starts to decline over time. However, in some people, this can happen more rapidly, which can increase their risk of kidney or cardiovascular disease. A major study, EMPA-REG OUTCOME, has shown that empagliflozin, which helps to control blood sugar in people with type 2 diabetes, also reduced the risk of cardiovascular disease events and slowed the progression of kidney disease, when compared with people in the study who received placebo. In this new research from the same major study empagliflozin, compared with a placebo, was shown to reduce the risk of people having a rapid decline in their kidney function over the 3 years of the study.
Cost-effectiveness of home-based screening of the general population for albuminuria to prevent progression of cardiovascular and kidney disease
2024, eClinicalMedicine
Chronic kidney disease (CKD) is often detected late, leading to substantial health loss and high treatment costs. Screening the general population for albuminuria identifies individuals at high risk of kidney events and cardiovascular disease (CVD) who may benefit from early start of preventive interventions. Previous studies on the cost-effectiveness of albuminuria population screening were inconclusive, but were based on survey or cohort data rather than an implementation study, modelled screening as performed by general practitioners rather than home-based screening, and often included only benefits with respect to kidney events. We evaluated the cost-effectiveness of home-based general population screening for increased albuminuria based on real-world data obtained from a prospective implementation study taking into account prevention of CKD as well as CVD events.
We developed an individual-level simulation model to compare home-based screening using a urine collection device with usual care (no home-based screening) in individuals of the general population aged 45–80, based on the THOMAS study (Towards HOMe-based Albuminuria Screening). Cost-effectiveness was assessed from the Dutch healthcare perspective with a lifetime horizon. The costs of the screening process and benefits of preventing CKD progression (dialysis and kidney transplantation) and CVD events (non-fatal myocardial infarction, non-fatal stroke, fatal CVD event) were reflected. Albuminuria detection led to treatment of identified risk factors. The model subsequently simulated CKD progression, the occurrence of CVD events, and death. The risks of experiencing CVD events were calculated using the SCORE2 CKD risk prediction model and individual-level data from the THOMAS study. Relative treatment effectiveness, quality of life scores, resource use, and cost inputs were obtained from literature. Model outcomes were the number of CKD and CVD-related events, total costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) per QALY gained by screening versus usual care. All results were obtained through probabilistic analysis.
The absolute difference between screening versus usual care in lifetime probability of dialysis, kidney transplantation, non-fatal myocardial infarction, non-fatal stroke, and fatal CVD events were 0.2%, 0.05%, 0.6%, 0.6%, and 0.2%, respectively. This led to relative decreases compared to usual care in lifetime incidence of these events of 10.7%, 11.1%, 5.1%, 4.1%, and 1.6%, respectively. The incremental costs and QALYs of screening were €1607 and 0.17 QALY, respectively, which led to a corresponding ICER of €9225/QALY. The probability of screening being cost-effective for the Dutch willingness-to-pay threshold for preventive population screening of €20,000/QALY was 95.0%. Implementing the screening in the subgroup of 45–64 years old reduced the ICER (€7946/QALY), whereas implementing screening in the subgroup of 65–80 years old increased the ICER (€10,310/QALY). A scenario analysis assuming treatment optimization in all individuals with newly diagnosed risk factors or known risk factors not within target range reduced the ICER to €7083/QALY, resulting from the incremental costs and QALY gain of €2145 and 0.30, respectively.
Home-based screening for increased albuminuria to prevent CVD and CKD events is likely cost-effective. More health benefits can be obtained by screening younger individuals and better optimization of care in individuals identified with newly diagnosed or known risk factors outside target range.
Dutch Kidney Foundation, Top Sector Life Sciences & Health of the Dutch Ministry of Economic Affairs.
Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial
2024, The Lancet
Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection.
This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m², a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed.
Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m² (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was –3% (95% CI –19 to 17) with placebo, –22% (–36 to –7) with BI 690517 3 mg, –39% (–50 to –26) with BI 690517 10 mg, and –37% (–49 to –22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study.
BI 690517 dose-dependently reduced albuminuria with concurrent renin–angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals.
Boehringer Ingelheim.
Urine Albumin-Creatinine Ratio Variability in People With Type 2 Diabetes: Clinical and Research Implications
2024, American Journal of Kidney Diseases
Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring.
Descriptive cross-sectional analysis.
People with type 2 diabetes (n = 826, 67.1 [IQR, 60.3-72.4] years, 64.9% male) participating in the Progression of Diabetic Complications (PREDICT) cohort study.
Four spot urine collections for measurement of urinary albumin-creatinine ratio (UACR) within 4 weeks.
Variability of UACR.
We characterized within-individual variability (coefficient of variation [CV], 95% limits of random variation, intraclass correlation coefficient), developed a calculator displaying probabilities that any observed difference between a pair of UACR values truly exceeded a 30% difference, and estimated the ranges of diagnostic uncertainty to inform a need for additional UACR collections to exclude or confirm albuminuria. Multiple linear regression examined factors influencing UACR variability.
We observed high within-individual variability (CV 48.8%; 95% limits of random variation showed a repeated UACR to be as high/low as 3.78/0.26 times the first). If a single-collection UACR increased from 2 to 5 mg/mmol, the probability that UACR actually increased by at least 30% was only 50%, rising to 97% when 2 collections were obtained at each time point. The ranges of diagnostic uncertainty were 2.0-4.0 mg/mmol after an initial UACR test, narrowing to 2.4-3.2 and 2.7-2.9 mg/mmol for the mean of 2 and 3 collections, respectively. Some factors correlated with higher (female sex; moderately increased albuminuria) or lower (reduced estimated glomerular filtration rate and sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment) within-individual UACR variability.
Reliance on the mean of 4 UACR collections as the reference standard for albuminuria.
UACR demonstrates a high degree of within-individual variability among individuals with type 2 diabetes. Multiple urine collections for UACR may improve capacity to monitor changes over time in clinical and research settings but may not be necessary for the diagnosis of albuminuria.
Albuminuria (albumin in urine) is a diagnostic and prognostic marker of diabetic chronic kidney disease. However, albuminuria can vary within an individual from day to day. We compared 4 random spot urinary albumin-creatinine ratio (UACR) samples from 826 participants. We found that a second UACR collection may be as small as a fourth or as large as almost 4 times the first sample’s UACR level. This high degree of variability presents a challenge to our ability to interpret changes in albuminuria. Multiple collections have been suggested as a solution. We have constructed tools that may aid clinicians in deciding how many urine collections are required to monitor and diagnose albuminuria. Multiple urine collections may be required for individual monitoring but not necessarily for diagnosis.
Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial
2024, The Lancet Diabetes and Endocrinology
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.
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.
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; p_trend<0·0001).
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.
Boehringer Ingelheim and Eli Lilly.

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ArticlesEffect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Declaration of interests

Lancet

Kidney Int

Lancet Diabetes Endocrinol

Lancet Diabetes Endocrinol

Lancet Diabetes Endocrinol

Lancet Diabetes Endocrinol

Lancet Diabetes Endocrinol

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

The albuminuria-lowering response to dapagliflozin is variable and reproducible among individual patients

Diabetes Obes Metab

The effect of liraglutide on renal function: a randomized clinical trial

Diabetes Obes Metab

Articles
Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial