EMPA-REG OUTCOME (ESRD)

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Wanner C, et al. "Empagliflozin and progression of kidney disease in type 2 diabetes". The New England Journal of Medicine. 2016. 375(4):323-334.
PubMed

Clinical Question

In patients with type 2 diabetes and an estimated GFR of at least 30 at high cardiovascular risk, does empagliflozin slow the development of nephropathy, reduce initiation of renal-replacement therapy, or reduce mortality from renal disease when compared to placebo?

Bottom Line

Patients who are treated with empagliflozin 10 mg or 25 mg are associated with lower rates of worsening nephropathy, progression to macroalbuminuria, initiation of renal replacement therapy and mortality over median treatment duration of 2.6 years compared to placebo.

Major Points

Prior to this industry-sponsored trial, evidence demonstrating decreased significant renal events and mortality related to renal events in patients with type-2 diabetes was limited. The secondary outcome of the EMPA-REG study (EMPA-REG OUTCOMES) was a composite outcome of worsening nephropathy.


There was significant relative risk reduction in the composite secondary outcome in patients assigned to the empagliflozin group. For every 20 patients treated with empagliflozin, it prevented one patient progressing to macroalbuminuria. For doubling of serum creatinine and GFR<45, one in every 91 patients were saved from this outcome. Empagliflozin prevented one additional patient (per 333) from requiring initiation of renal-replacement therapy. There was no significant difference in the rate of incident albuminuria between the two groups. Equivalent results were seen across the two doses of empagliflozin.


Genital infections were reported in a higher percentage of patients in the empagliflozin group than in the placebo group, with NNH of 14 and 26 for females and males, respectively. There were no other clinically significant adverse effects across the treatment groups.


In practice, empagliflozin should be considered in patients with type 2 diabetes with high risk for cardiovascular events who have a eGFR greater than 30 mL/min/1.73m2. However, the renal effects of empagliflozin cannot necessarily be generalized to patients with type 2 diabetes at lower cardiovascular risk. Treatment with empagliflozin can cause an initial decrease in renal function, which resolves within approximately 4 weeks.

Guidelines

  • Target HbA1c ﹤7%
  • First line therapy: lifestyle modifications
  • Second line therapy: metformin
  • Third line therapy: addition of second oral glycemic agent, GLP-1 antagonist, or insulin

Design

Population

Inclusion Criteria

  • Adults ≥ 18 years of age
  • BMI of 45 or less
  • Estimated eGFR ≥ 30 mL/min/1.73m2
  • Type 2 diabetes
  • Established cardiovascular disease
  • Not received any glucose-lowering agents for at least 12 weeks before randomization
  • Hgb A1c between 7.0% and 9.0%

Exclusion Criteria

  • Uncontrolled hyperglycemia with fasting glucose >240 mg/dL
  • Liver disease, AST/ALT or alkaline phosphatase above 3 x upper limit of normal
  • Planned cardiac surgery or angioplasty within 3 months
  • Estimated GFR < 30mL/min/1.73m2
  • Bariatric surgery within past 2 years or other surgery that induces malabsorption
  • Blood dyscrasias
  • History of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
  • Contraindications to background therapy
  • Treatment with anti-obesity drugs 3 months prior
  • Treatment with systemic steroids or change in dosage of thyroid hormones within 6 weeks prior to treatment initiation
  • Uncontrolled endocrine disorder except type 2 diabetes
  • Pre-menopausal women who were nursing, pregnant, or of childbearing potential and were not practicing an acceptable form of birth control
  • Alcohol or drug abuse within 3 months of treatment
  • Intake of an investigational drug in another trial within 30 days prior to treatment
  • Acute coronary syndrome, stroke, or TIA within 2 months prior to treatment

Baseline Characteristics

From the pooled empagliflozin-based treatment arms. There was not a significant difference between demographics between treatment and placebo groups.

  • Demographics: Age 63 years, Male sex 71%
    • Race: White 72%, Asian 21%, Black 5%
    • Ethnicity: Hispanic or Latino 18%
    • Geographic region: Europe 41%, North America 20%, Asia 19%, Latin America 15%, Africa 4%
  • Health measurements: BMI 31 kg/m2, BP 135/77 mmHg
  • Laboratory
    • eGFR:
      • eGFR ≥ 90 : 22%
      • eGFR 60 -90: 52%
      • eGFR < 60 : 26%
  • Urine albumin:creatinine:
    • <30 mg/g: 59%
    • 30-300 mg/g: 28%
    • > 300 mg/g: 11%
  • PMH/PSH:
    • DM: Time since diagnosis
      • <1 yr: 2%
      • 1-5 yr: 15%
      • 5-10 yr: 25%
      • >10 yr: 57%
  • Glucose-related medications:
    • Monotherapy: 30%
    • Dual therapy: 48%
    • Other medications: ACE/ARB 81%, Beta-blocker 65%, diuretics 43%, CCB 33%, mineralocorticoid antagonist 6%, renin inhibitor 1%, other 8%

Interventions

  • Randomization in a 1:1:1 ratio between groups with stratification by A1c, BMI, renal function, and geographic region:
    • Empagliflozin 10 mg
    • Empagliflozin 25 mg
    • Placebo
  • All doses taken daily after a 2 week open-label placebo run-in period. Other CV risk factors were treated at the discretion of investigators based on local guidelines.

Outcomes

Comparisons are empagliflozin vs placebo

Primary Outcomes

  • This report focuses on the secondary outcomes of this trial. Primary outcomes can be found in the main publication, EMPA-REG OUTCOME.

Secondary Outcomes

  • Renal Outcome Measures Indicating Worsening Nephropathy
    • Incident worsening nephropathy or cardiovascular death
      • 16.2% vs 23.6% (HR 0.61; CI 0.55-0.69; P<0.001; NNT 14)
    • Incident or worsening nephropathy
      • 12.7% vs 18.8% (HR 0.61; CI 0.53- 0.70; P<0.001; NNT 16)
    • Progression to macroalbuminuria
      • 11.2% vs 16.2% (HR 0.62; CI 0.54 - 0.72; P<0.001; NNT 20)
    • Doubling of serum creatinine level accompanied by eGFR≤ 45 mL/min/1.73m2
      • 1.5% vs 2.6% (HR 0.56; CI 0.39-0.79; P<0.001; NNT 91)
    • Composite of doubling of serum creatinine level accompanied by eGFR of ≤ 45 mL/min/1.73m2, initiation of renal-replacement therapy, or death from renal disease
      • 1.7% vs 3.1% (HR 0.54; CI 0.40-0.75; P<0.001; NNT 71)
    • Initiation of renal-replacement therapy
      • 0.6% vs 0.3% (HR 0.45, CI 0.21-0.97; P=0.04; NNT 333)

Adverse Events

Reported as empagliflozin vs placebo

  • Any: 90.2% vs 91.7% (P<0.001)
  • Severe: 23.5% vs 25.4% (P < 0.05)
  • Death: 3.8% vs 5.1% (P<0.01)
  • Leading to discontinuation: 17.3% vs 19.4% (P<0.01)
  • Hypoglycemia requiring assistance: 1.3% vs 1.5% (NS)
  • UTI: 18.0% vs 18.1% (NS)
  • Complicated UTI (pyelonephritis, sepsis, or UTI-related serious event): 1.7% vs 1.8% (NS)
  • Genital infection: 6.4% 1.8% (P<0.001, NNH 26 male, 14 female)
  • Volume depletion: 5.1% vs 4.9% (NS)
  • Acute renal failure: 5.2% vs 6.6% (P<0.01)
  • Acute kidney injury: 1.0% vs 1.6% (P<0.05)
  • Diabetic ketoacidosis: 0.1% vs <0.1% (NS)
  • Thromboembolic events: 0.6% vs 0.9% (NS)
  • Bone fracture: 3.8% vs 3.9% (NS)

Criticisms

  • No additional studies have been shown to demonstrate similar statistical significant outcomes for empagliflozin or any other SGLT-2 inhibitors
  • The renal effects of empagliflozin cannot necessarily be generalized to patient with type 2 diabetes at lower cardiovascular risk
  • Generalizations to black patients has limitations due to small sample size

Funding

  • Boehringer Ingelheim, Eli Lilly and Company Diabetes Alliance funded all research, including consultation and data monitoring

Further Reading

1. Wanner, C, et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes”. New England Journal of Medicine N Engl J Med. 2016;374(11):1092–4.

2.Oral E. “Closing the knowledge gap on cardiovascular disease in type 2 diabetes: the EMPA-REG OUTCOME trial and beyond”. Drugs in Context DIC. 2016Feb;5:1–10.

3.Pham, David et al.Impact of empagliflozin in patients with diabetes and heart failure.Trends in Cardiovascular Medicine , Volume 0 , Issue 0