Ambulatory Care Clinical Pharmacy - Articles of Interest

Title
Empaglifozin in Patients with Chronic Kidney Disease
Objective (s)
Both the CREDENCE and DAPA-CKD were double-blind, placebo-controlled, multicenter, randomized control trials that
investigated SGLT2 inhibitors, canagliflozin and dapaglifozin, and renal outcomes. At the time of the trial’s design, the
results of the previous trials were not known yet. EMPA-KIDNEY’s trial rationale was based on the findings of the
subgroup analysis in the EMPA-REG OUTCOME trial.
The objective of this trial was to assess another SGLT2 inhibitor, empagliflozin, in patients with chronic kidney disease
who are at risk for progression to ESKD, with or without albuminuria and with or without albuminuria.
Study Design
Design:
 International, randomized, parallel-group, double-blind, placebo-controlled trial
 Conducted at 241 centers in 8 counties in Europe, North America and East Asia

Funding:
 Boehringer Ingelheim
 Eli Lilly through a grant given to the University of Oxford
 United Kingdom Medical Research Council (MRC)
 The British Heart Foundation
 National Institute for Health and Care Research Biomedical Research Council
 Heath Data Research UK

Inclusion Criteria:
 > 18 years old
 eGFR > 20 but < 45 mL/min/1.73m 2
 eGFR > 45 but < 90 mL/min/1.73m 2 with a urinary albumin-to-creatinine ratio of at least 200
 Prescribed single-agent RAAS inhibitor unless not tolerated or indicated

Exclusion Criteria:
 Type 2 diabetes mellitus with prior atherosclerotic CVD with eGFR > 60 mL/min/1.73m 2
 Polycystic kidney disease
 History of functioning or scheduled kidney transplant
 Ketoacidosis in the past 5 years
 Symptomatic hypotension, or systolic BP < 90 or > 180 mmHg
 Pregnant and lactating women, and women of child-bearing potential unless on highly effective contraception

Run-in Phase:
 All eligible patients entered a pre-randomization run-in phase
 15 weeks of once daily placebo
 Local investigators reviewed screening data, RAAS inhibitor use and approved for later randomization
 After > 6 weeks of run-in completed, intervention randomization occurred

Intervention:
 Empagliflozin 10 mg by mouth daily versus matching placebo

Primary Composite Endpoint:

Secondary Endpoints:
 First occurrence of hospitalization for heart failure or cardiovascular death
 All-Cause Hospitalization
 Death from any cause
 Composite of cardiovascular death or ESKD
 Components of the primary outcome tested separately

Statistical Analysis
 Driven to continue until > 1070 patients experienced primary outcome
 Early stopping for benefit was pre-specified
- HR for primary outcome <0.78 with two-sided p-value < 0.002 AND
- HR < 0.78 and two-sided p-value <0.05 for secondary outcome of death from CV causes or ESKD
 Cox proportional-hazards regression model with pre-specified baseline adjustments for time-to event analysis
Results
Follow-Up Visits
 2 months, 6 months, and every 6 months thereafter until end of the trial
 Kidney status updated
 Adherence to assigned trial regimen assessed
 Details of other medications patients used
 Inquired about serious adverse effects
 Clinical assessment of BP, weight, blood samples, and urine specimens

Participants and Baseline characteristics:

Baseline Demographics
Empagliflozin (n=3304) Placebo (n=3305)
Age, years 63.9 + 13.9 63.8+13.9
Female sex – no. (%) 1097 (33.2) 1095 (33.1)
Race – no (%)
White 1939 (58.7) 1920 (58.1)
Black 128 (3.9) 134 (4.1)
Asian 1194 (36.1) 1199 (36.3)
Multiple 14 (0.4) 7 (0.2)
Other 29 (0.9) 45 (1.4)
History of Diabetes – no (%)
Yes 1525 (46.2) 1515 (45.8)
History of CVD – no (%)
Yes 861 (26.1) 904 (27.4)
BMI 29 28.4
Estimated GFR
Mean 37.4+14.5 37.7+14.4
Distribution – no (%)
<30 1131 (34.2) 1151 (34.8)
>30 to <45 1467 (44.4) 1461 (44.2)
>45 706 (21.4) 693 (21)
 Ambulatory Care Clinical Pharmacy - Articles of Interest
Urinary albumin-to-
creatinine ration
Median (IQR) 331 (46-1061) 327 (54-1074)
Distribution – no (%)
< 30 665 (20.1) 663 (20.1)
>30 to <300 927 (28.1) 937 (28.4)
>300 1712 (51.8) 1705 (51.6)

Primary Outcome:

Secondary and Safety Outcomes:

Primary Outcome – Primary Outcome

Personal Conclusion
The use of empagliflozin in patients with chronic kidney disease was statistically significant in regards to the primary
composite outcome which included progression of kidney disease and death from cardiovascular causes. This trial
supports the use of empagliflozin in non-diabetic patients with CKD (45.8% of the population randomized). It also
supports the use of empagliflozin down to an eGRF of 20 mL/min/1.73m 2. This was done without a significant increase
in adverse effects.
However, due to stopping the trial early, there were fewer events in the subgroups such as urinary albumin-to-
creatinine ratio. The subgroup analysis, if the trial continued, could have shown different results in either a beneficial
or non-beneficial direction.
Impact to Practice
This trial helped re-establish a potential role for SGLT2 inhibitors, specifically empagliflozin, in patients with chronic
kidney disease. Empagliflozin can be used as an option for CKD in patients with a GFR of > 20 mL/min/1.73m 2 and can
be considered in patients who do not have diabetes.

Pharmacist: Rachel Thomas

Abbreviations:
CKD = Chronic Kidney Disease
CVD = cardiovascular disease
eGFR = estimated glomerular filtration rate
ESKD = End stage kidney disease
HR = Hazard Ratio
RAAS = renin-angiotensin-aldosterone system
SGLT2 inhibitor = sodium glucose co-transporter 2 inhibitors