Study of Heart and Kidney Protection With Empagliflozin - EMPA-KIDNEY

Dec 23, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Boehringer Ingelheim
Date Presented:
11/06/2022
Date Published:
11/25/2024
Date Updated:
12/23/2024
Original Posted Date:
11/06/2022
References

Contribution To Literature:

Highlighted text has been updated as of December 20, 2024.

The EMPA-KIDNEY trial showed that empagliflozin has salutary effects on renal function and CV mortality among patients with CKD, with or without DM, who are already on appropriate doses of ACEi/ARB.

Description:

The goal of the trial was to assess the safety and efficacy of empagliflozin in improving cardiac and renal outcomes among patients with chronic kidney disease (CKD).

Study Design

Eligible patients were randomized in a 1:1 fashion to either empagliflozin 10 mg daily (n = 3,304) or placebo (n = 3,305).

  • Total screened: 8,544
  • Total number of enrollees: 6,609
  • Duration of follow-up: 2 years
  • Mean patient age: 64 years
  • Percentage female: 33%

Inclusion criteria:

  • Age ≥18 years or at “full age” as required by local regulation
  • Evidence of CKD at risk of kidney disease progression defined by ≥3 months before and at the time of screening visit:
    • Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) ≥20 to <45 mL/min/1.73 m² or
    • CKD-EPI eGFR ≥45 to <90 mL/min/1.73 m² with urinary albumin:creatinine ratio ≥200 mg/g (or protein:creatinine ratio ≥300 mg/g)
  • Clinically appropriate doses of single agent renin–angiotensin system (RAS) inhibitor with either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) unless such treatment is either not tolerated or not indicated

Exclusion criteria:

  • Currently receiving sodium–glucose cotransporter 2 (SGLT2) or SGLT1/2 inhibitor
  • Diabetes mellitus type 2 (DM2) and prior atherosclerotic cardiovascular disease (CVD) with an eGFR >60 mL/min/1.73 m2 at screening
  • Receiving combined ACEi and ARB treatment
  • Maintenance dialysis, functioning kidney transplant, or scheduled living donor transplant
  • Polycystic kidney disease
  • Previous or scheduled bariatric surgery
  • Ketoacidosis in the past 5 years
  • Symptomatic hypotension, or systolic blood pressure <90 or >180 mm Hg at screening
  • ALT or AST >3x ULN at screening
  • Hypersensitivity to empagliflozin or other SGLT2 inhibitor
  • Any intravenous immunosuppression therapy in last 3 months; or anyone currently on >45 mg prednisolone (or equivalent)
  • Known to be poorly compliant with clinic visits or prescribed medication
  • Medical history that might limit the individual’s ability to take trial treatments for the duration of the study (e.g., severe respiratory disease; history of cancer or evidence of spread within last 4 years, other than nonmelanoma skin cancer; or recent history of alcohol or substance misuse)
  • Current pregnancy, lactation, or women of childbearing potential, unless using highly effective contraception
  • Type 1 DM

Other salient features/characteristics:

  • Mean eGFR: 37 mL/min/1.73 m2
  • DM: 46%
  • CVD: 26%

Principal Findings:

The primary outcome, progression of kidney disease (end-stage kidney disease, a sustained decrease in eGFR to <10 mL/min/1.73 m2, a sustained decrease in eGFR of ≥40%, or death from renal causes) or CV death for empagliflozin vs. placebo, was: 13.1% vs. 16.9% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82, p < 0.001).

Outcomes were similar among patients with or without prior CVD, and with or without known DM.

Secondary outcomes for empagliflozin vs. placebo:

  • All-cause hospitalization (HR 0.86, 95% CI 0.78-0.95, p = 0.003)
  • Hospitalization for heart failure or CV death: 4.0% vs. 4.6% (p > 0.05)
  • All-cause mortality: 4.5% vs. 5.1% (p > 0.05)

Long-term follow-up: At the final follow-up visit of the active trial, no additional supplies of trial empagliflozin or placebo were provided to the patients. Blinding was maintained. During the post-trial period, the use of open-label SGLT2 inhibitors was similar in the two groups (43% and 40%, respectively). A total of 4,891 (74%) patients were followed for an additional median follow-up of 2.0 years. The primary outcome for empagliflozin vs. placebo was: 26.2% vs. 30.3% (HR 0.79, 95% CI 0.72-0.87, p < 0.001). This HR was a combination of the HR for the active-trial period (0.72; 95% CI 0.64-0.82, with 990 outcomes) and the HR for the post-trial period (0.87; 95% CI 0.76-0.99, with 876 additional first primary-outcome events).

  • Kidney disease progression (empagliflozin vs. placebo): 23.5% vs. 27.1% (HR 0.79, 95% CI 0.72-0.87)
  • End-stage renal disease: 9.0% vs. 11.3% (HR 0.74, 95% CI 0.64-0.87)
  • CV death: 3.8% vs. 4.9% (HR 0.75, 95% CI 0.59-0.95)
  • All-cause mortality: 9.1% vs. 10.2% (HR 0.86, 95% CI 0.74-1.01) 

Interpretation:

The results of this trial indicate that empagliflozin has salutary effects on renal function among patients with CKD, with or without DM, who are already on appropriate doses of ACEi/ARB. There were also beneficial effects noted on CV mortality and all-cause hospitalizations but not all-cause mortality at 2 years. In the 2-year post-trial observation period, the original group-assignment blinding was maintained but approximately 50% of patients in both arms received a clinically indicated SGLT2 inhibitors. There were important residual cardiorenal benefits from assignment to the empagliflozin group after the trial drug was discontinued, suggesting a legacy effect; the majority of this benefit was within the first 6 months.

Results are similar to the DAPA-CKD trial, where dapagliflozin was superior to placebo in improving cardiorenal outcomes in a similar patient population (CKD, with or without DM). CREDENCE (canagliflozin) and SCORED (sotagliflozin) trials were conducted among patients with both CKD and DM2. Even though the SGLT-2 inhibitors were introduced as DM2 management drugs, results of these trials suggest a clear benefit in CKD management, and based on EMPA-KIDNEY and DAPA-HF trials, even among patients with CKD without DM. The exact mechanism of benefit is somewhat clear. Irrespective, these drugs will likely change practice and have a prominent role in future CKD management guidelines.

References:

The EMPA-KIDNEY Collaborative Group. Long-Term Effects of Empagliflozin in Patients With Chronic Kidney Disease. N Engl J Med 2024;Oct 25:[Epub ahead of print].

Presented by Dr. David Preiss at the American Heart Association Scientific Sessions, Chicago, IL, November 6, 2022.

The EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients With Chronic Kidney Disease. N Engl J Med 2022;388:117-27.

Editorial: August P. Chronic Kidney Disease — Another Step Forward. N Engl J Med 2023;388:179-80.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: AHA Annual Scientific Sessions, AHA22, Diabetes Mellitus, Type 2, Heart Failure, Kidney Failure, Chronic, Metabolic Syndrome, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors


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