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

Contribution To Literature:

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 (SGLT-2) or SGLT-1/2 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 SGLT-2 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)

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.

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:

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;Nov 4:[Epub ahead of print].

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

Keywords: AHA Annual Scientific Sessions, AHA22, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Creatinine, Diabetes Mellitus, Diabetes Mellitus, Type 2, Disease Progression, Glomerular Filtration Rate, Heart Failure, Kidney Failure, Chronic, Metabolic Syndrome, Renal Insufficiency, Chronic, Renin-Angiotensin System, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors


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