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N Engl J Med 2022 Nov 4. doi: 10.1056/NEJMoa2204233. Online ahead of print.
Empagliflozin in Patients with Chronic Kidney Disease
EMPA-KIDNEY Collaborative Group; William G Herrington , Natalie Staplin , Christoph Wanner , Jennifer B Green , Sibylle J Hauske , Jonathan R Emberson, David Preiss , Parminder Judge , Kaitlin J Mayne , Sarah Y A Ng , Emily Sammons , Doreen Zhu , Michael Hill , Will Stevens , Karl Wallendszus , Susanne Brenner , Alfred K Cheung , Zhi-Hong Liu, Jing Li , Lai Seong Hooi , Wen Liu , Takashi Kadowaki , Masaomi Nangaku Adeera Levin, David Cherney , Aldo P Maggioni Roberto Pontremoli , Rajat Deo , Shinya Goto , Xavier Rossello , Katherine R Tuttle1, Dominik Steubl , Michaela Petrini , Dan Massey , Jens Eilbracht , Martina Brueckmann , Martin J Landray, Colin Baigent, Richard Haynes
PMID: 36331190
Also read: Meta-analysis of all major Flozin RCTs in the Lancet
Introduction
Are SGLT2 inhibitors the next greatest thing to have been discovered from the apple tree after gravity? Benjamin Franklin once said, “in this world, nothing is certain except death and taxes”. For a nephrologist, trials demonstrating kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors can be added to the list of certainties. The SGLT2 inhibitors (aka flozins) have demonstrated improved outcomes in:
Diabetes with high cardiovascular risk - EMPA-REG OUTCOME (Zinman et al, NEJM 2015), CANVAS (Neal et al, NEJM 2017)), SCORED (Bhatt et al, NEJM 2021), VERTIS CV (Cosentino et al, Circulation 2020) and DECLARE-TIMI 58 (Wiviott et al, NEJM 2019)
Diabetes and chronic kidney disease (CKD) - CREDENCE (Perkovic et al, NEJM 2019)
Proteinuric CKD with or without diabetes down to eGFR 25ml/min/1.73m2 - DAPA-CKD (Heerspink et al, NEJM 2020)
Heart Failure with reduced ejection fraction - DAPA-HF (McMurray et al, NEJM 2019) and EMPEROR-Reduced (Packer et al, NEJM 2020)
Heart Failure with preserved ejection fraction - DELIVER (Solomon et al, NEJM 2022) and EMPEROR-Preserved (Anker et al, NEJM 2021)
Indeed, Dr. Eugene Braunwald called these agents ‘the statins of the 21st century’ (Braunwald E, Eur Heart J, 2022). So why did we need another flozin in CKD trial?
At the time of inception of the EMPA-KIDNEY trial in 2018, the results of CREDENCE and DAPA-CKD were not known. The rationale for EMPA-KIDNEY was based on the findings of the EMPA-REG OUTCOME trial (Herrington et al, CKJ 2018). While the glucose lowering effect of flozins wane at lower GFRs due to reduction in the filtered glucose load, the cardioprotective effects are sustained. This was shown in a subgroup analysis of EMPA-REG OUTCOME in patients with diabetes and established CVD with eGFR 30-60 ml/min/1.73m2 (Wanner et al, Circulation 2018). Non-glycemic actions of SGLT2i contributing to improvement in CV outcomes include natriuresis, diuresis, and improvement in BP (Griffin et al, Circulation 2020, NephJC summary). While diabetes is the most common cause of CKD in most regions worldwide, nearly 50-70% of patients with CKD do not have diabetes (Jha et al, Lancet 2013). Now, DAPA-CKD did include patients without diabetes, but they did need to have albuminuria (uACR 200-5000 mg/g, equivalent to uACR 23-565 mg/mmol). So we do not have any data on whether flozins provide benefit to those with CKD but without DM and without albuminuria. Lastly, the inclusion eGFR lower limits for CREDENCE and DAPA-CKD were 30 and 25 ml/min/1.73m2, respectively. In DAPA-CKD, only about 15% (~600/4000) of participants had a GFR < 30. When is it too late to start an SGLT2i? Do we have a floor for flozination? This is what EMPA-KIDNEY set to help establish - and why the trial was continued even after the unequivocal results from CREDENCE and DAPA-CKD were published.
EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) was designed to assess the effect of empagliflozin in a wide variety of CKD patients who were at risk of progression to end stage kidney disease (ESKD), with or without diabetes and with or without albuminuria. It is also the largest IgA nephropathy trial yet conducted, but more on that later.
Populations in the SGLT2i trials according to KDIGO CKD classification. Figure modified from Heerspink et al, NDT 2020
The Study
Methods
EMPA-KIDNEY is a multinational, randomized, parallel-group, double-blind, placebo-controlled trial of the SGLT2 inhibitor empagliflozin. This trial was conducted in 241 centers in 8 countries in Europe, North America and East Asia.
Study population
Inclusion criteria
Adults ≥ 18 years of age
CKD at risk of progressive disease - as defined by laboratory samples taken ≥3 months before and at the time of the screening visit:
eGFR (by CKD-EPI) ≥ 20-45 ml/min/1.73m2 (no uACR cutoff) or
eGFR (by CKD-EPI) ≥ 45-90ml/min/1.73m2 and uACR ≥ 200mg/g (≥22.6mg/mmol)
Prescribed a clinically appropriate dose of single-agent RAAS inhibitor, unless such treatment was either not tolerated or not indicated (as judged by a local investigator)
People with or without DM were eligible, although it was pre-specified that the trial should recruit at least one-third of its sample from each patient group.
Exclusion criteria
Type 2 DM and prior atherosclerotic CVD with eGFR >60ml/min/1.73m2 at screening
Functioning transplant or scheduled live donor transplant
Polycystic kidney disease (the only primary renal diagnosis which was excluded)
Ketoacidosis in past 5 years
Symptomatic hypotension, or systolic BP <90 or >180 mm Hg
AST or ALT >3x the upper limit of normal
On intravenous immunosuppression within 3 months, or prednisolone >45mg/day
Pregnant and lactating women, and women of child-bearing potential unless on highly effective contraception
Type 1 diabetes (introduced in the exclusion criteria later)
Patients were excluded at the randomization visit if they did not adhere to the run-in treatment or experienced ketoacidosis, heart attack, stroke, hospitalization for heart failure, UTI or AKI during the “placebo” run-in period.
Intervention
After screening for eligibility, participants underwent a run-in phase of 8-12 weeks during which they were given a 15 week supply of single blind placebo. The main objective of this phase was to exclude those who were unlikely to have long-term compliance for the study. Cardiovascular risk factors and RAS inhibitors were optimized. Patients were randomly assigned to receive empagliflozin 10 mg once daily or a matching placebo. They were followed up at 2 months and 6 months, and 6 monthly thereafter till the end of the trial.
Study design of EMPA KIDNEY trial
Trial endpoints
Primary outcome
The primary outcome was the first occurrence of a composite of
Kidney disease progression - defined by
ESKD (start of maintenance dialysis or receipt of transplant)
Sustained decrease in eGFR to <10 ml/min/1.73m2 (not <15 as is common, possibly as inclusion was down to 20)
Sustained decline of ≥40% in eGFR from the time of randomization
‘Sustained’ = Measured on 2 consecutive follow-up visits at least 30 days apart or at last scheduled follow-up visit in the study or at the last scheduled visit before death, withdrawal of consent or loss to follow-up
Death due to renal causes
Death due to cardiovascular causes
Secondary outcomes
First occurrence of hospitalization for heart failure or cardiovascular death
All-cause hospitalization
Death from any cause
Composite of first cardiovascular death or ESKD
The components of the primary outcome tested separately
There were also several prespecified subgroups (discussed in results).
Statistical analysis
EMPA-KIDNEY was an event driven study with plan to continue the study till at least 1070 patients had experienced the primary outcome
It was estimated that occurrence of primary outcome in 1070 patients would provide 90% power at a two-sided P-value of 0.05 to detect relative risk reduction of 18% for this primary outcome in the empagliflozin group compared to placebo
An interim analysis for efficacy was planned when 150 patients had first occurrence of ESKD. At this interim analysis, it was expected that 60% of the primary outcome events (642 events) would have occurred. Early stopping for benefit was pre-specified if
Hazard ratio for the primary outcome was <0.78 with two-sided p-value <0.002 and
Hazard ratio of < 0.78 and two-sided p-value <0.05 for the secondary outcome of death from cardiovascular causes or ESKD
All analyses were done on intention-to-treat basis
A Cox proportional-hazards regression model with adjustment of pre-specified baseline variables (age, sex, history of diabetes, eGFR, urinary albumin-to-creatinine ratio, and geographic region) was used to determine the hazard ratio and 95% confidence interval for empagliflozin vs placebo for a time-to-event analysis
Funding
EMPA-KIDNEY was sponsored by Boehringer Ingelheim, the manufacturer of empagliflozin, and Eli Lilly through a grant provided to the University of Oxford. It was also supported by funding from the United Kingdom Medical Research Council (MRC) , the British Heart Foundation, National Institute for Health and Care Research Biomedical Research Council, and Health Data Research UK.
Results
Study population:
A total of 8544 participants attended a screening visit between February 2019 and April 2021 → 8184 (95.8%) entered the run-in phase → 6609 were randomized. The CONSORT flow diagram is given in the Supplementary appendix of the study.
CONSORT flow diagram of EMPA-KIDNEY trial. From Supplementary Figure S1, EMPA-KIDNEY, NEJM 2022
The randomized participants had a mean age of 63 years and 33% were women. Fifty-four percent had no history of diabetes. They had a mean eGFR of 37ml/min/1.73m2, with 35% having an eGFR <30 ml/min/1.73m2. The median uACR was 329 mg/g (37 mg/mmol). The trial population was representative of the spectrum of CKD at risk of progression to ESKD, as shown in the figure below.
Distribution of study population by eGFR and uACR. Adapted from Supplementary Table S2, EMPA-KIDNEY, NEJM 2022
The baseline characteristics of the study population are given in the table below. Sixty-nine percent had kidney disease due to a cause other than diabetic kidney disease, with glomerular diseases making up a quarter of the study cohort.
Table 1: Baseline characteristics. EMPA-KIDNEY, NEJM 2022
Interim analysis
The trial was stopped early due to meeting efficacy outcomes at interim analysis, based on the prespecified criteria described above. 624 primary outcome events were reported on March 7, 2022, with follow-up completed by July 5, 2022. Mean follow-up duration was 2 years (Interquartile range, IQR = 1.5-2.4 years). 6552 (99.1%) patients completed follow-up or died during this period. 0.3% had missing data and 0.6% withdrew consent. Finally, there were 990 primary outcomes.
Primary outcome
The primary outcome of kidney disease progression or cardiovascular death occurred in 432/3304 (13.1%) patients in the empagliflozin group vs 558/3305 (16.9%) patients in the placebo group (HR = 0.72, 95% CI = 0.64 to 0.82, P<0.001); a 28% risk reduction with empagliflozin. This was greater than the 18% which had been required for the power calculations. On evaluating the event rate, there were 42 fewer primary outcome events/1000 patients with the study arm compared to placebo over the median follow-up period.
Figure 1: Primary outcome of kidney disease progression and cardiovascular death. EMPA-KIDNEY, NEJM 2022
Secondary outcomes
Hospitalization due to any cause was significantly lower in the empagliflozin group occurring at a rate of 24.8/100 patient-years vs 29.2 hospitalisations/100 patient-years in the placebo arm (HR = 0.86, 95% CI = 0.78 to 0.95, P=0.003), indicating a 14% relative risk reduction. The difference in the secondary outcomes of composite of heart failure hospitalization and cardiovascular death as well as death due to any cause was not significantly different.
Table 2: Primary and secondary outcomes. EMPA-KIDNEY, NEJM 2022
When the components of the primary outcome were analyzed separately, there was significant reduction in the rates of kidney disease progression with relative risk reduction of 29%. There were numerically fewer events of cardiovascular deaths in the empagliflozin arm. The event rate for this outcome was relatively less at 0.91 and 1.06 events/100 patient-years in the empagliflozin and placebo arms respectively.
Supplementary figure S2, EMPA-KIDNEY, NEJM 2022
Subgroup analyses
The effect of empagliflozin across the prespecified subgroups (DM, GFR and uACR) was mostly consistent as can be seen below. The number of events with uACR < 300 mg/g are quite low, and it seems to suggest a greater benefit in those with uACR > 300, but more on that below.
Figure 2 and Supplementary figure S5: Subgroup analysis for primary outcome, and then for key secondary outcome of kidney disease progression. EMPA-KIDNEY, NEJM 2022
Many other subgroups were also examined with quite consistent results.
Supplementary figure S4: Subgroup analyses of primary outcome. EMPA-KIDNEY, NEJM 2022
Slope of eGFR
Despite the initial decline in eGFR in the first 2 months of randomization, the annual rate of eGFR decline was slower in the empagliflozin arm by 0.75ml/min/1.73m2.
Figure 3: Slope of decline of eGFR. EMPA-KIDNEY, NEJM 2022
This slowing of eGFR decline was preserved in the key subgroups, including those with uACR < 300 mg/g, as seen in supplementary figure 7 below.
Supplementary figure 7: Subgroup analysis of slope of eGFR decline, EMPA-KIDNEY, NEJM 2022
Safety outcomes
There was no significant increase in certain adverse events in the empagliflozin arm such as hyperkalemia, serious urinary tract infections, or AKI (table 3, below). The event rate of lower limb amputations and ketoacidosis were numerically higher in the empagliflozin arm vs the placebo arm. The amputations were mostly toe or forefoot amputations (supplemental table S7, not included here).
Table 3: Safety outcomes. EMPA-KIDNEY, NEJM 2022
Discontinuation of the trial regimen
>80% of the study medications were taken in 89.6% of patients in the empagliflozin arm compared to 90.3% in the placebo arm by 12 months of follow-up. Discontinuation at follow-up was seen in 16.9% and 19.4% of the participants respectively.
Other clinical and laboratory measures
The empagliflozin arm was associated with mean difference in body weight of −0.9 ± 0.1 kg, systolic BP of −2.6 ± 0.3 mm Hg, and HbA1c of −0.39 mmol/mol. The geometric mean uCAR was 19% lower in the empagliflozin group (95% CI 15 to 23).
Discussion
What did this study show?
This looks like yet another flozin win. There was significant benefit in terms of the primary outcome with empagliflozin, with good safety and tolerability. The benefits extend into non-diabetic populations (confirming DAPA-CKD), and down to a GFR of 20.
Limitations
This is a clean, well done trial with few limitations. It was stopped early, based on pre-specified and appropriate rules - but that did mean that not many events had accrued in certain subgroups, such as uACR < 300 mg/g.
Were the results comparable with the other two CKD trials of SGLT2i?
The renal outcomes were consistent with those seen with the CREDENCE and DAPA-CKD trials, as can be seen in this graphic below. This emphasizes that the benefits of flozins span a wide GFR range, regardless of diabetic status.
Comparison of SGLT2i RCTs in CKD from Priti Meena
How do the results from the CKD trials of SGLT2i stack up together?
The outcomes from SGLT2i trials were studied in this meta-analysis where the primary outcome specified was CKD progression (Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Lancet. 2022). It included these 3 trials, along with the SCORED trial, and reported a 38% RRR in the risk of kidney disease progression.
Risk of kidney disease progression in the CKD trials. From Lancet 2022
The CV outcomes are quite consistent. Note the small total number of CV events in the non-diabetic subgroups of the CKD trials (~ 50 to 100), which may contribute to the apparent lack of benefit seen.
Risk of cardiovascular outcomes in SGLT2i trials. From Lancet 2022
How was EMPA-KIDNEY different from CREDENCE and DAPA-CKD?
As stated earlier, CREDENCE only included patients with type 2 diabetes with moderately increased albuminuria, and patients with eGFR<30ml/min/1.73m2 were excluded. As evidence for the benefit in patients without diabetes began to grow, the DAPA-CKD trial was done with a third of its cohort (~ 1398 participants) not having diabetes. It had an eGFR criteria of 25-75ml/min/1.73m2 and required albuminuria of at least 200mg/g. 624 of the DAPA-CKD participants had eGFR <30ml/min/1.73m2, and so the eGFR cutoff for initiation of SGLT2is was lowered to 25ml/min/1.73m2. The EMPA-KIDNEY trial has further expanded on the results of DAPA-CKD with inclusion of 3569 patients without diabetes, representing 54% of the study population. 2282 patients in the study had an eGFR <30ml/min/1.73m2. The distinct feature of EMPA-KIDNEY was the inclusion of 3192 patients (48%) with uACR <300mg/g (<34mg/mmol), with 1328 being normoalbuminuric. Together, these 3 studies cover the spectrum of CKD down to an eGFR of 20ml/min/1.73m2 and wide ranges of albuminuria.
Proportion of patients in trials with eGFR <60ml/min/1.73m2 and uACR >300. Modified from Heerspink et al, NDT 2020
So what were the results in these unique subgroups?
The key outcomes were in favour of flozins in both the subgroups with and without diabetes. This study also showed that use of empagliflozin can be extended to eGFRs down to 20ml/min/1.73m2, although starting flozinating at higher eGFRs may result in greater accrual of the beneficial effects.
In patients with CKD but without albuminuria, questions still persist. Event rates were lower in the groups with uACR<300mg/g (as would be expected), and this may be related to the lack of significant benefit in this subgroup. Would the signal for benefit in this subgroup be clearer if the trial had not been stopped early? Among patients with diabetes who do not have albuminuria, we do know flozins have CV benefits based on the cardiovascular outcome trials in diabetes (e.g. EMPAREG, CANVAS, DECLARE, etc). However, should non-diabetic patients who do not have significant albuminuria also be given flozins? In the low albuminuria groups (uACR < 30 or 30-300, including DM and non DM), though the primary outcome benefit was not impressive, the slope of GFR was slower. Is that enough to start prescribing flozins to all patients with CKD regardless of diabetes or albuminuria?
What about IgA nephropathy?
What was also interesting in this trial was that, while the original article mentioned the inclusion of 1669 patients with glomerular diseases, there was no outcome data for this subgroup. However, the data was included in the supplement of the Lancet meta-analysis, and showed that EMPA-KIDNEY had in fact included the largest cohort of IgA nephropathy of any RCT of any intervention, with over 800 patients. Combining the results of DAPA-CKD and EMPA-KIDNEY showed a halving of the risk of kidney disease progression with SGLT2i.
Effect of SGLT2i on kidney disease progression by glomerular diseases. From Webfigure 5, Lancet 2022
Are these drugs safe and tolerable?
Let us examine the safety again from the Lancet meta-analysis. Putting together data from all the SGLT2i trials, there is a signal for higher RR for ketoacidosis in patients with diabetes. There was only 1 case of ketoacidosis reported among the population without diabetes (out of 15592 participants).
Effect of SGLT2i on ketoacidosis. From Webfigure 8, Lancet 2022
CANVAS was the first trial to show the higher incidence of amputations in the SGLT2i-treated population, with nearly doubling of risk over placebo. Combining data from all trials including CANVAS, there was a 15% greater risk of lower limb amputations with SGLT2i. This risk was, however, not significant in the population without diabetes.
Effect of SGLT2i on lower limb amputations. From Webfigure 9, Lancet 2022
There was a significant increase in other adverse events such as UTIs (small increase, and not serious UTIs), and also a larger increase seen for genital mycotic infections in the meta-analysis.
Effect of SGLT2i on other safety outcomes. From Webfigure 10, Lancet 2022
The picture below from the meta-analysis depicts the risks versus benefits of SGLT2 inhibitors for different subgroups. For example, for every 1000 patients of CKD with diabetes treated for a year with flozins, there would be 11 fewer episodes of kidney disease progression and 11 fewer episodes of CV death or HF hospitalization, but with at least 1 each of lower limb amputation and development of ketoacidosis. The side effects of flozins and possible mitigating actions have been presented in this article on the renal fellow network.
Absolute benefits and harms of SGLT2i per 1000 patient-years. From figure 5, Lancet 2022
What do we need to know further?
As the benefit of SGLT2i in diabetic CKD and albuminuric CKD has been shown in several trials, RCTs with these groups would no longer be ethical. The benefit, especially for cardiovascular outcomes, of this class of drugs in non-diabetic, non-albuminuric CKD is to be established further. As the indications for this class of drugs expand, some questions remain to be answered. Can the needle be moved further below the threshold eGFR of 20ml/min/1.73m2 for flozination? What about the role of SGLT2i in patients on dialysis and transplant? Ongoing trials include:
RENAL LIFECYCLES, which aims to recruit 1500 participants with advanced CKD (eGFR < 25 ml/min/1.73 m2), on dialysis or transplant recipients, to study renal and cardiovascular outcomes with dapagliflozin
DAPA-HD, with an estimated enrollment of 108 participants, aims to study change in left ventricular mass indexed to body surface area (measured by cMRI) in patients on maintenance HD
PRESERVE trial, with an estimated enrollment of 52 patients on stable peritoneal dialysis, aims to study the effect of dapagliflozin on peritoneal glucose uptake and ultrafiltration
INFINITI2019 trial, which will study the efficacy and safety of SGLT2i in an estimated 52 transplant recipients with type 2 diabetes or post-transplant diabetes mellitus
CONFIDENCE trial, will study renal outcomes in about 807 patients with diabetes and CKD in 3 arms of finerenone-empagliflozin combination, finerenone only or empagliflozin only
What we do also need are studies of implementation - how can we accelerate flozination and reduce the ‘knowledge generation to change in practice’ gap?
Conclusion
EMPA-KIDNEY showed that empagliflozin significantly reduces the risk of progression of kidney disease and cardiovascular death, without a significant increase in adverse events. It’s beneficial effect was preserved across different eGFRs among patients with and without diabetes, and was greater amongst those with moderately increased albuminuria. SGLT2 inhibitors have made a long journey in the last 150 years from the bark of the apple tree to patients with CKD stage 4, and we look forward to trials which can further expand the evidence base for this class of drugs.
Summary prepared by
Faculty, Department of Nephrology,
Sri Ramachandra Institute of Higher Education and Research,
Chennai, India
NSMC Intern, Class of 2022-23
Reviewed by
Jamie Willows, Jade Teakell, Raad Chowdhury and Swapnil Hiremath
Putting the mellitus back into diabetes. Is inducing glycusuria the key to diabetic nephropathy? EMPA-REG renal outcomes.