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Macrovascular Residual Risk Studies

13 April 2023
EMPA-KIDNEY trial (Study of Heart and Kidney Protection with Empagliflozin): Empagliflozin shows renal and cardiovascular benefit in patients with chronic kidney disease
In patients with chronic kidney disease (CKD) who were at risk for disease progression, treatment with empagliflozin was associated with lower risk of progression of kidney disease or death from cardiovascular causes than placebo.
The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2022; doi: 10.1056/NEJMoa2204233.
STUDY SUMMARY
Objective To investigate the effect of once daily empagliflozin treatment on the progression of kidney disease and cardiovascular disease in patients with CKD
Study design EMPA-KIDNEY was an international, randomized, parallel-group, double-blind, placebo-controlled, clinical trial.
Study population Adults (with or without diabetes) with a race-adjusted estimated glomerular filtration rate (eGFR, calculated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula), at least 20 and <45 mL/min/1.73 m2 regardless of the level of albuminuria; or with an eGFR at least 45 and <90 mL/min/1.73 m2 with a urinary albumin to creatinine ratio ≥200 at screening. Patients were required to be on a clinically appropriate dose of a single-agent renin angiotensin system (RAS) inhibitor but could have been included if an investigator judged that a RAS inhibitor was not indicated or would not be tolerated. Major exclusion criteria were polycystic kidney disease or kidney transplant.
Main study variables • Primary outcome: first occurrence of progression of kidney disease or death from cardiovascular causes. Progression of kidney disease was defined as end-stage kidney disease (the initiation of maintenance dialysis or receipt of a kidney transplant), a sustained decrease in the eGFR to less than 10 mL/min/ 1.73 m2, a sustained decrease from baseline in the eGFR ≥40%, or death from renal causes.
• Prespecified key secondary outcomes: a composite of hospitalization for heart failure or death from cardiovascular causes, hospitalization for any cause, and death from any cause.
Methods Eligible patients who completed at least 6 weeks of the run-in phase (placebo) were randomized to treatment with empagliflozin (10 mg once daily) or matching placebo. Patients were assessed at follow-up visits for kidney status (dialysis treatment or receipt of a kidney transplant), adherence to the assigned trial regimen, concomitant medication, vital signs, laboratory safety and adverse events.
Results

Of 8184 patients enrolled in the run-in phase, 6609 were subsequently randomized to treatment with empagliflozin (n= 3304) or placebo (n=3305). The two groups were similar in baseline characteristics (mean age 63.8 years, 33% women and 46% with diabetes) and broadly representative of patients with CKD at risk for disease progression. Overall, over one-third (34.5%) had an eGFR <30 mL/min/ 1.73 m2.

 

The study was stopped on March 7, 2022, based on fulfilling the prespecified rules (see above) and follow-up completed on July 5. Overall, the mean duration of treatment was 2.0 years (interquartile range, 1.5 to 2.4 years).  

 

Treatment with empagliflozin was associated with significant 28% lower risk of progression of kidney disease or death from cardiovascular causes versus placebo. Hospitalization for any cause was also significantly lower in the empagliflozin group than in the placebo

group (by 14%, p = 0.003) (Table 1). Subgroup analyses showed that the effect of empagliflozin treatment was consistent irrespective of the presence of diabetes or eGFR at randomization.

 

Table 1. Effect of empagliflozin on primary and prespecified key secondary outcomes

Outcome, n (%)

Empagliflozin

Placebo

Hazard ratio (95% CI)

p-value

Primary

432 (13.1)

558 (16.9)

0.72 (0.64–0.82)

<0.001

Key secondary

 

 

 

 

  Hospitalization for heart failure or death from cardiovascular causes

131 (4.0)

152 (4.6)

0.84 (0.67–1.07)

0.15

  Hospitalization for any cause

-

-

0.86 (0.78–0.95)

0.003

  Death from any cause

148 (4.5)

167 (5.1)

0.87 (0.70–1.08)

0.21
Author conclusion Among a wide range of patients with CKD who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo.

COMMENT

The EMPA-KIDNEY trial adds to evidence for renal and cardiovascular benefits of sodium glucose co-transporter-2 (SGLT2) inhibitors in patients with CKD with and without diabetes. The study included a wide range of patients, 54% without diabetes, 28% with an eGFR <30ml/min/1.73m2, and 48% with a urinary albumin-to-creatinine ratio <300mg/g. Thus, the patient population in this trial fills important gaps in evidence from both Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) and Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trials.

Despite a lower than anticipated rate of cardiovascular events (59 and 69 cardiovascular deaths in the active and placebo groups) due to early stopping of the trial based on pre-specified and appropriate rules, the trial still showed a 16% reduction in cardiovascular death. Indeed, hazard ratios for cardiovascular outcomes were consistent with the totality of the evidence to date reported in a recent meta-analysis (3). Safety data show that empagliflozin was well tolerated in this patient population, with no increase in hyperkalemia, serious urinary tract infections, or acute kidney injury.
The robustness of the study findings is strengthened by the large study sample, broad eligibility criteria and high adherence to study treatment. Taken together, the three studies encompass the spectrum of CKD seen in clinical practice, down to an eGFR of 20ml/min/1.73m2. Together, the totality of evidence reinforces guideline recommendations for the use of SGLT2 inhibitors as a foundational therapy to reduce cardiovascular outcomes and the risk of kidney disease progression in patients with CKD irrespective of diabetes status or the level of kidney function.

References 1. Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.
2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46.
3. The Nuffield Department of Population Health Renal Studies Group and the SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022; 400:1788-801.
Key words chronic kidney disease; kidney disease progression; cardiovascular death; sodium glucose co-transporter-2 inhibitors; empagliflozin

 

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