Future insights of empagliflozin in routine clinical care setting

The EMPagliflozin compaRative effectIveness and SafEty

(EMPRISE) study programme: Design and exposure accrual for an evaluation of empagliflozin in
routine clinical care

1
Real world data (RWD) in medicine is data derived from
a number of sources that are associated with outcomes
in a heterogeneous patient population in real-world
settings, including but not limited to 
electronic health records, health insurance claims and
patient surveys.

While no universal definition of real world data exists,

researchers typically understand RWD as distinct from
data sourced from randomized clinical trials.

Real-world data refer to observational data as opposed

to data gathered in an experimental setting such as a 
randomized controlled trial (RCT). They are derived from 
electronic health records (EHRs), claims and billing
activities, product and disease registries,
 The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE).

 programme of studies aims to assess the comparative effectiveness,safety and impact on healthcare
utilization of empagliflozin,based on real-world data from two commercial and Medicare databases in
the United States.

 The study will collect accumulating data on empagliflozin for a period of five years following the date
of approval in the United States, 1 August 2014 through 30 September 2019.

Background: EMPRISE is a study programme on the effectiveness,

safety and healthcare utilization of empagliflozin in routine care, leveraging
real-world data from two commercial and one federal US data sources from 2014 to 2019.
 2 | METHODS
 2.1 | Data sources

 This study includes data from two commercial US health insurance.

“ data sets (Optum Clinformatics and IBM MarketScan) with nationwide commercial coverage including
some Medicare Advantage plans”.

 As a third data source, we included fee-for-service Medicare, a US federal health insurance programme
which provides health care.

 2.2 | Study design

 EMPRISE is a sequentially built new-user active-comparator cohort study that includes
 four planned interim analyses and one final analysis,
 using data from August 2014 to September 2019
EMPRISE patient population (2014–2016)
347,031 patients aged >18 years initiating
empagliflozin or a DPP-4i,
with 12 months of continuous enrollment prior to cohort
entry

Exclusion criteria 40,044 patients

excluded
306,987 patients with T2D aged ≥18 years
initiating empagliflozin or a DPP-4i

1:1 PS matching
(based on >140 baseline covariates)

PS matching

17,539 new users of 17,539 new users of

empagliflozin DPP-4i
 Objectives and trial info
• To assess effectiveness, safety, healthcare resource
utilisation and costs of care of empagliflozin versus
DPP-4i in patients with T2D

• First 5 years of empagliflozin use: 2014−2019 3 large USA databases

• Over 200,000 patients projected to be included by
study completion
– 116,000 empagliflozin : 116,000 DPP-4

Research initiated and currently led by Professors Elisabetta Patorno and Sebastian Schneeweiss from the
Division of Pharmacoepidemiology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA

Built upon an academic collaboration between Brigham and Women's Hospital and Boehringer Ingelheim
Eligibility criteria
Key inclusion criteria1
• Adults aged ≥18 years
• Initiation* of empagliflozin or a DPP-4i between August 2014 and August 2019
• Patients with T2D (claims in the 12 months prior to entry)

Key exclusion criteria1,2

• Concomitant SGLT2i and DPP-4i at treatment initiation
• Use of either SGLT2i or DPP-4i class in the 12 months preceding cohort entry
(switchers)
• Patients with <12 months of continuous database registration prior to drug initiation
Further criteria also apply
 Baseline characteristics for EMPRISE
DPP-4i Empagliflozin Standardised
(n=17,539) (n=17,539) differences
Age, years, mean (SD) 58.75 (9.01) 58.71 (8.97) 0.00
Female 8,137 (46.4%) 8,118 (46.3%) 0.00
History of CVD* 4,333 (24.7%) 4,299 (24.5%) 0.00
Old MI 417 (2.4%) 411 (2.3%) 0.00
History of stroke 940 (5.4%) 938 (5.3%) 0.00
Ischaemic heart disease or coronary procedure 3,174 (18.1%) 3,142 (17.9%) 0.00
Peripheral arterial disease or surgery 921 (5.3%) 907 (5.2%) 0.00
HF 879 (5.0%) 868 (4.9%) 0.00
Hypertension 13,327 (76.0%) 13,375 (76.3%) 0.00
Hyperlipidemia* 14,085 (80.3%) 14,028 (80.0%) 0.00
CKD 1,250 (7.1%) 1,211 (6.9%) 0.00
 Baseline characteristics for EMPRISE
DPP-4i Empagliflozin Standardised
(n=17,539) (n=17,539) differences
Antihypertensive therapy

Loop diuretics 1,614 (9.2%) 1,675 (9.6%) 0.00

ACE inhibitors/ARBs 12,607 (71.9%) 12,725 (72.6%) 0.00
Beta-blockers 5,691 (32.4%) 5,720 (32.6%) 0.00
Lipid lowering therapy

Statins* 11,636 (66.3%) 11,716 (66.8%) 0.00

Glucose-lowering therapy
Metformin 13,740 (78.3%) 13,844 (78.9%) 0.00
Sulphonylureas 6,262 (35.7%) 6,513 (37.1%) 0.00
Thiazolidinediones 1,662 (9.5%) 1,640 (9.4%) 0.00
GLP-1 RAs 3,371 (19.2%) 3,319 (18.9%) 0.00
Insulin 4,768 (27.2%) 4,701 (26.8%) 0.00
Comprehensive clinical picture of Empagliflozin
Primary outcomes Secondary outcomes
Hospital admission for MI* All-cause mortality* ESRD

Hospital admission for stroke* HHF* Treatment for retinopathy

Effectiveness1
CV mortality 3P-MACE Coronary revascularisation procedure

Secondary outcomes
Bone fracture Lower-limb amputation DKA “Diabetic ketoacidosis”
Safety1 Urinary tract cancers† Severe hypoglycaemia‡ AKI requiring dialysis

Inpatients HCRU Outpatients Costs

All-cause and CV hospitalisation All-cause ED visits Total cost of care Inpatient costs

Length of hospital stay

Office visits Outpatient costs Pharmacy costs
Healthcare Pharmacy
resource utilisation
Medications filled Other outpatient services Emergency care costs
and costs2

3P-MACE : 3 points major cardiovascular event, ESRD end stage renal disease, AKI Acute Kidney injury, DKA
Diabetic Ketoacidosis, ED Emergency department.
 Cumulative incidence of HHF-specific since treatment initiation

53 %
Reduction
Of
HHF

Compared to DPP-4i, the initiation of empagliflozin 10mg and 25mg dose decreased the risk of
HHF-specific by 53% with consistent results in patients with and without baseline CV disease
 Cumulative incidence of HHF-broad since treatment initiation

44 %
Reduction
Of
HHF

Compared to DPP-4i, the initiation of empagliflozin 10mg and 25mg dose decreased the risk of HHF-broad by
44% [0.56 (0.43-0.73)] with consistent results in patients with and without baseline CV disease
 RWE results complement EMPA-REG OUTCOME and indicate the HHF findings translate into routine
clinical practice
EMPRISE1 EMPA-REG OUTCOME®2
DPP-4i Empagliflozin (EMPRISE) Placebo Empagliflozin (EMPA-REG OUTCOME®)

Patients with event (%)

0.05 7
HR 0.56 HR 0.65
(95% CI 0.43, 0.73)† 6
(95% CI 0.50, 0.85)
Cumulative incidence

0.04
p<0.0001 5 p=0.002
0.03
4

0.02 3

2
0.01
1

0 0
0 3 6 9 12 15 18 21 24 0 6 12 18 24 30 36 42 48
Month Month

50 % 35 %
Reduction Of Reduction Of
HHF HHF
Empagliflozin Sitagliptin Empagliflozin Vs Placebo
 The effect of empagliflozin on HHF was consistent between
both doses of empagliflozin
Empagliflozin Comparator

n event/ n event/
Study N analysed (%) N analysed (%) HR (95% CI)

EMPA-REG OUTCOME®1 (empagliflozin vs placebo)

EMPA 10 mg 60/2345 (2.6) 95/2333 (4.1) 0.62 (0.45, 0.86)

EMPA 25 mg 66/2342 (2.8) 95/2333 (4.1) 0.68 (0.50, 0.93)

EMPRISE2 (empagliflozin vs DPP-4i)

EMPA 10 mg 46/10,059 (0.5) 95/10,059 (0.9) 0.53 (0.37, 0.76)†

EMPA 25 mg 34/7433 (0.5) 75/7433 (1.0) 0.46 (0.31, 0.69)†

0.125 1.25

Favours Favours
empagliflozin comparator
HF
EMPEROR-REDUCED
 BACKGROUND
• Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization
for heart failure in patients regardless of the presence or absence of diabetes.
• More evidence is needed regarding the effects of these drugs in patients across the
broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

METHODS
 Study Design and Oversight
• Randomized, Double-Blind, Parallel-group, Placebo-controlled, event-driven trial.
• The trial was performed at 520 centers in 20 countries, (North America, Latin America, Europe, Asia, or other).
• Enrolled pts: 3730 patients.
• With HF Class II, III, or IV heart failure and ejection fraction of 40% or less.
• 1863 Pts Received Empagliflozin (10 mg once daily).
• 1867 Pts Received placebo, in addition to recommended therapy.
• During a median of 16 months, From April 2017 through November 2019
 Trial Inclusion and Exclusion Criteria
Inclusion criteria1,2 Exclusion criteria1,2
Age ≥18 years.
MI, coronary artery bypass graft surgery or other major CV
Diabetic or Non- Diabetic surgery, stroke or TIA ≤90 days before Visit 1

Chronic HF NYHA class II−IV

HFrEF (LVEF ≤40%) and elevated NT-proBNP Heart transplant recipient, or listed for heart transplant

Symptomatic hypotension and/or a SBP <100 mmHg

Patients with HF & at high risk for a serious HF event.
Patients with ejection fraction > 30% requiring a history of
HHF or a high level of N-terminal prohormone of brain
natriuretic peptide within the previous 12 months eGFR <20 ml/min/1.73 m2 or requiring dialysis

Dose of medical therapy for HF that is consistent with

CV guidelines stable for ≥1 week prior to screening
and throughout screening period Further exclusion criteria apply
Diuretics + ARBs / ACIs + ARNI + BB &
When indicated cardiac device

*The cutoff for patients with AF is doubled in EMPEROR-Reduced See slides notes for abbreviations
New York Heart Association (NYHA) Classification 1. ClinicalTrials.gov. NCT03057977 (accessed Aug 2020); 2. Zannad F et al. ESC-HF 2018; poster P1755
EMPEROR-REDUCED Outcomes.

Primary Outcomes Secondary Outcomes Additional Pre-specified

Efficacy Outcomes

CV Death

 a composite renal outcome.

COMPOSITE PRIMARY ENDPOINT SECONDARY ENDPOINTS  Total hospitalizations for any reason.
 Quality of life.
 Time to first event of adjudicated CV  The first secondary outcome  Safety analyses.
death or adjudicated HHF First and recurrent adjudicated HHF events

 The second secondary outcome

Slope of change in eGFR (CKD-EPI) from
baseline

24
 • 1863 Pts Received Empagliflozin (10 mg once daily).
EMPEROR-Reduced • 1867 Pts Received placebo

Randomised Double-Blind Placebo-Controlled Trial

Aim: To investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical
therapy in patients with HF with reduced ejection fraction
Population: T2D and non-T2D, aged ≥18 years, chronic HF (NYHA class II–IV)

Study design1-3 Confirmatory endpoints1,2

COMPOSITE PRIMARY ENDPOINT
1863 Pts Time to first event of adjudicated CV death or
Empagliflozin 10 mg qd + SOC* adjudicated HHF
EMPEROR-Reduced
LVEF ≤40%
1867 Pts SECONDARY ENDPOINTS
3730 patients Placebo qd + SOC* • First and recurrent adjudicated HHF events
• Slope of change in eGFR (CKD-EPI) from
Median follow-up = 16 months baseline

*Guideline-directed medical therapy

CV, cardiovascular; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; HF, heart failure; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction; NYHA,
New York Heart Association; qd, once daily; SOC, standard of care; T2D, type 2 diabetes
1. ClinicalTrials.gov. NCT03057977 (accessed Aug 2020); 2. Packer M et al. Eur J Heart Fail 2019;21:1270; 3. Data on file
 Main results
(hazard
ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated
glomerular filtration rate was slower in the empagliflozin group than in
the placebo group (–0.55 vs. –2.28 ml per minute per 1.73 m 2 of body-surface area
per year, P<0.001),

28
Primary endpoint: First adjudicated CV death or HHF
Empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the
placebo group, regardless of the presence or absence of diabetes.

25 %
RRR
Estimated cumulative incidence
function (%)

Days After Randomisation

The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence
of diabetes.
Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment
CV, cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; ARR, absolute risk reduction; RRR, relative risk reduction. NNT: Number needed to treat
Data on file
 Key secondary: Adjudicated total HHF (first and recurrent)
Mean Number of Events per Patient

30 %
RRR

900

Days After Randomisation

Analysis of first and recurrent HHF accounting for CV death as terminal event using a joint frailty model. Model includes covariates age, baseline eGFR, treatment, region, baseline diabetes status, sex, and baseline LVEF, estimated dependence between
adjudicated HHF and adjudicated CV death, and variance of frailty. CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction
The annual rate of decline in the eGFR was slower in the empagliflozin group than in placebo
 Composite renal endpoint (end-stage kidney disease or sustained profound decrease in eGFR)

Estimated cumulative incidence

6 HR 0.50 (95% CI 0.32, 0.77)

P=0.0019
function (%)

Placebo
RRR ARR
4
50% 1.5%

Empagliflozin

0 90 180 270 360 450 540 630 720 810

Days after randomisation

Empagliflozin-treated patients had a lower risk of serious renal outcomes.

Composite renal endpoint is defined as chronic dialysis, renal transplant, sustained reduction of ≥40% eGFR or sustained eGFR <15 ml/min/1.73 m2 for patients with eGFR ≥30 ml/min/1.73 m2 at baseline (<10 ml/min/1.73 m2 for patients with eGFR <30
ml/min/1.73 m2 at baseline). Dialysis is regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days. Cox regression model including covariates age, baseline eGFR (CKD-EPI), region, baseline diabetes status, sex, and
baseline LVEF. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PY, patient years. ARR, absolute risk reduction; RRR, relative risk reduction
 Overview of results from EMPEROR-Reduced 1
Primary outcome Secondary outcomes Exploratory outcomes

Composite
HHF or kidney KCCQ clinical
CV death Total HHF* eGFR slope† outcome‡ summary score

↓ ↓
↓ ↓
↓ 25% RRR ↓ 30% RRR +1.73 HR 0.50 1.75 rate ratio
p<0.001 p<0.001 difference (95% CI 0.32, 0.77) p=0.0058
p<0.001 NA

The rates of AEs were similar between empagliflozin and placebo 1

*Analysis of first and recurrent HHF accounting for CV death as terminal event using a joint frailty model. Model includes covariates age, baseline eGFR, treatment, region, baseline diabetes status, sex, and baseline LVEF, estimated dependence between
adjudicated HHF and adjudicated CV death, and variance of frailty; †eGFR slope is analysed based on on-treatment data using a random coefficient model including age and baseline eGFR as linear covariates and sex, region, baseline LVEF, baseline diabetes
status, and baseline by time and treatment by time interactions as fixed effects; the model allows for randomly varying slope and intercept between patients ; ‡Composite renal endpoint is defined as chronic dialysis, renal transplant, sustained reduction of ≥40%
eGFR or sustained eGFR <15 ml/min/1.73 m2 for patients with eGFR ≥30 ml/min/1.73 m 2 at baseline (<10 ml/min/1.73 m 2 for patients with eGFR <30 ml/min/1.73 m 2 at baseline); NA denotes not applicable because p-values for efficacy outcomes are reported
only for outcomes that were included in the hierarchical testing strategy
CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HHF, hospitalisation for heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; NA, not applicable
1. Packer M et al. N Engl J Med. 2020;383(15):1413 33
 Serious adverse events and prespecified
adverse events of interest
Empagliflozin (n=1863) – N (%) Placebo (n=1863) – N (%)
Patients with any AEs 1420 (76.2) 1463 (78.5)
Serious AEs 772 (41.4) 896 (48.1)
Serious AEs of special interest
Volume depletion 197 (10.6) 184 (9.9)
Hypotension 176 (9.4) 163 (8.7)
Symptomatic hypotension 106 (5.7) 103 (5.5)
Ketoacidosis 0 (0.0) 0 (0.0)
Confirmed severe hypoglycaemic events‡ 27 (1.4) 28 (1.5)
In patients with type 2 diabetes 20 (2.2) 22 (2.4)
In patients without type 2 diabetes 7 (0.7) 6 (0.6)
Urinary tract infections 91 (4.9) 83 (4.5)
Complicated urinary tract infections 19 (1.0) 15 (0.8)
Genital tract infections 31 (1.7) 12 (0.6)
Complicated genital tract infections 6 (0.3) 5 (0.3)
Bone fractures 45 (2.4) 42 (2.3)
Events leading to lower limb amputation 13 (0.7) 10 (0.5)

Shown are adverse events up to 7 days following discontinuation of study medication, but lower limb amputations were shown up to the end of the trial
*Includes all cardiac AEs (inclusive but not restricted to heart failure AEs); †Based on reported preferred terms of acute kidney injury, prerenal failure, renal failure, azotemia, toxic nephropathy, oliguria, and renal impairment;
‡
Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. Data on file
EMPEROR-PRESERVED
EMPEROR-Preserved study design
Phase III trial* in patients with HFpEF

Aim: To investigate the safety and efficacy of empagliflozin versus placebo in patients with HF with preserved
ejection fraction
Population: T2D and non-T2D, aged ≥18 years, chronic HF (NYHA class II–IV)

COMPOSITE PRIMARY ENDPOINT

Empagliflozin 10 mg OD • Time to first event of adjudicated CV death or
adjudicated HHF
EMPEROR-Preserved
LVEF >40% CONFIRMATORY KEY SECONDARY
Placebo ENDPOINTS
5988 patients
• First and recurrent adjudicated HHF
Median follow-up 26.2 months • Slope of change in eGFR (CKD-EPI) from baseline

36
 EMPEROR-Preserved:
Characteristics of patients at baseline (1 of 4)
Empagliflozin Placebo
(n=2997) (n=2991)
Age, years (mean±SD) 71.8±9.3 71.9±9.6
Women, n (%) 1338 (44.6) 1338 (44.7)
Race, n (%)
White 2286 (76.3) 2256 (75.4)
Black 133 (4.4) 125 (4.2)
Asian 413 (13.8) 411 (13.7)
Other or missing 165 (5.5) 199 (6.7)
Region, n (%)
North America 360 (12.0) 359 (12.0)
Latin America 758 (25.3) 757 (25.3)
Europe 1346 (44.9) 1343 (44.9)
Asia 343 (11.4) 343 (11.5)
Other 190 (6.3) 189 (6.3)

SD, standard deviation

Anker S et al. N Engl J Med. 2021;XX:XXX.

37
 EMPEROR-Preserved:
Characteristics of patients at baseline (2 of 4) Empagliflozin Placebo
(n=2997) (n=2991)
NYHA functional class, n (%)
Class I 3 (0.1) 1 (<0.1)
Class II 2432 (81.1) 2451 (81.9)
Class III 552 (18.4) 531 (17.8)
Class IV 10 (0.3) 8 (0.3)
BMI, kg/m2
EMPEROR-Preserved
29.77±5.8
reflects the HFmrEF and HFpEF
29.90±5.9
Heart rate, bpm
population that is seen in clinical practice
70.4±12.0 70.3±11.8
Systolic BP, mmHg 131.8±15.6 131.9±15.7
LVEF, % 54.3±8.8 54.3±8.8
>40 to <50%, n (%) 995 (33.2) 988 (33.0)
≥50 to <60%, n (%) 1028 (34.3) 1030 (34.4)
≥60%, n (%) 974 (32.5) 973 (32.5)

Values are mean ± standard deviation unless stated otherwise.

BMI, body mass index; BP, blood pressure; bpm, beats per minute; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
Anker S et al. N Engl J Med. 2021;XX:XXX, Fonarow GC et al. J Am Coll Cardiol 2007;50:768.

38
Empagliflozin demonstrated a clinically meaningful 21% RRR in the
composite primary endpoint of CV death or HHF
Estimated cumulative incidence (%) 25

20
RRR ARR
21% 3.3% NNT*=31
Placebo
15

10 Empagliflozin HR: 0.79

(95% CI: 0.69, 0.90)
p<0.001
5

0 Empagliflozin:
0 3 6 9 12 15 18 21 24 27 30 33 36 415 (13.8%) patients with event
Months since randomization Rate: 6.9/100 patient-years
Patients at risk Placebo:
Placebo 2991 2888 2786 2706 2627 2424 2066 1821 1534 1278 961 681 400 511 (17.1%) patients with event
Empagliflozin 2997 2928 2843 2780 2708 2491 2134 1858 1578 1332 1005 709 402 Rate: 8.7/100 patient-years
*During a median trial period of 26 months. ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; NNT, number needed to treat; RRR, relative risk reduction. Anker S et al. N Engl J Med.
2021;XX:XXX.
39
 EMPEROR-Preserved is the first and only study to demonstrate a consistent, clinically
meaningful benefit across all prespecified subgroups (2/3)
Empagliflozin Placebo
n with event/N analysed HR (95% CI)

Overall 415/2997 511/2991 0.79 (0.69, 0.90)

Baseline LVEF
<50% 145/995 193/988 0.71 (0.57, 0.88)
≥50% to <60% 138/1028 173/1030 0.80 (0.64, 0.99)
≥60% 132/974 145/973 0.87 (0.69, 1.10)
Baseline diabetes status
Diabetes 239/1466 291/1472 0.79 (0.67, 0.94)
No diabetes 176/1531 220/1519 0.78 (0.64, 0.95)
Baseline eGFR (CKD-EPI)
≥60 mL/min/1.73 m² 152/1493 189/1505 0.81 (0.65, 1.00)
<60 mL/min/1.73 m² 263/1504 321/1484 0.78 (0.66, 0.91)
Baseline NYHA class
II 275/2435 361/2452 0.75 (0.64, 0.87)
III/IV 140/562 150/539 0.86 (0.68, 1.09)
HF hospitalization in ≤12 months
No 258/2298 319/2321 0.81 (0.68, 0.95)
Yes 157/699 192/670 0.73 (0.59, 0.90)
Cause of HF
Ischaemic 157/1079 177/1038 0.85 (0.69, 1.06)
Non-ischaemic 258/1917 334/1953 0.75 (0.64, 0.89)

0.25
Anker S et al. N Engl J Med. 2021;XX:XXX.
Empagliflozin better Placebo better
40
 EMPEROR-Preserved is the first and only study to demonstrate a consistent, clinically
meaningful benefit across all prespecified subgroups (3/3)
Empagliflozin Placebo
n with event/N analysed HR (95% CI)

Overall 415/2997 511/2991 0.79 (0.69, 0.90)

Baseline use of ACE inhibitor, ARB or ARNI
No 90/569 121/587 0.75 (0.57, 0.99)
Yes 325/2428 390/2404 0.80 (0.69, 0.93)
Baseline use of MRA
No 233/1878 306/1866 0.73 (0.62, 0.87)
Yes 182/1119 205/1125 0.87 (0.71, 1.06)
Baseline NT-proBNP (calculated by AF/flutter status)
<Median 126/1477 168/1508 0.76 (0.61, 0.96)
≥Median 288/1516 341/1476 0.78 (0.67, 0.91)
Baseline body mass index
<30 kg/m2 223/1654 292/1642 0.74 (0.62, 0.88)
≥30 kg/m 2
192/1343 219/1349 0.85 (0.70, 1.03)
Baseline systolic blood pressure
<Median 200/1496 249/1474 0.76 (0.63, 0.91)
≥Median 215/1501 262/1517 0.82 (0.68, 0.98)
History of AF or atrial flutter
No 170/1417 219/1427 0.78 (0.64, 0.95)
Yes 244/1576 292/1559 0.78 (0.66, 0.93)

0.25
See slide notes for abbreviations.
Anker S et al. N Engl J Med. 2021;XX:XXX.
Empagliflozin better Placebo better
41
 Empagliflozin reduced first and recurrent HHF by 27% in a
confirmatory
0.25 secondary endpoint
Mean number of events per patient

0.20 RRR
27%

0.15
Placebo

0.10 HR: 0.73

(95% CI: 0.61, 0.88)
Empagliflozin
p<0.001
0.05

0 Empagliflozin:
0 3 6 9 12 15 18 21 24 27 30 33 36 407 patients with
event
Months since randomization
Patients at risk Placebo:
Placebo 2991 2945 2901 2855 2816 2618 2258 1998 1695 1414 1061 747 448 541 patients with
Empagliflozin 2997 2962 2913 2869 2817 2604 2247 1977 1684 1429 1081 765 446 event
Anker S et al. N Engl J Med. 2021;XX:XXX.

42
 Empagliflozin protected the kidney by significantly slowing
the decline in kidney function
0 The rate of eGFR decline in patients
Early difference between empagliflozin and placebo due to the
Change from baseline eGFR (mL/min/1.73 m2)

well-known initial drop with empagliflozin treated with empagliflozin was half
that of patients treated with placebo
-2

1.36 mL/min/1.73 m2/year

-4 difference in eGFR slope (95%
CI: 1.06, 1.66; p<0.001)

-6 Empagliflozin Placebo
−1.25
-8 (±0.11)
Placebo (MMRM Model)
-10 Empagliflozin (MMRM Model) −2.62
Placebo (Random Intercept Random Slope Model) (±0.11)
Empagliflozin (Random Intercept Random Slope Model)
-12 mean (±SE)
4 12 32 52 76 100 124 148 172 196 mL/min/1.73 m2/year
Baseline Weeks

eGFR slope = rate of decline (and is a measure for long-term renal function). eGFR slope is analysed based on on-treatment data using a random coefficient model including age, baseline eGFR and baseline LVEF as linear
covariates and sex, region, baseline diabetes status, and baseline by time and treatment by time interactions as fixed effects; the model allows for randomly varying slope and intercept between patients.
eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; SE, standard error.
Developed from data reported in Anker S et al. N Engl J Med. 2021;XX:XXX.

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EMPEROR-Preserved:
Specific endpoints for hierarchical testing

EMPEROR-Preserved

Primary endpoint: HR: 0.79

Adjudicated CV death or Confirmatory* (95% CI: 0.69, 0.90)
HHF p<0.001

Key secondary endpoint: HR: 0.73

Adjudicated first and recurrent Confirmatory †
(95% CI: 0.61, 0.88)
HHF p<0.001

Key secondary endpoint: +1.36

Confirmatory ‡
mL/min/1.73 m2 per year
eGFR slope p<0.001

*Cox regression with a=0.0497. †Joint frailty model that included CV death as source of information censoring. ‡Random coefficient model. See slide notes for more information.
Anker S et al. N Engl J Med. 2021;XX:XXX.

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EMPEROR-Preserved: Selected adverse events of interest
85.9%
Any AE
86.5%
Placebo Empagliflozin
(n=2989) (n=2996)
47.9%
Serious AE
51.6%

10.4%
Hypotension 8.6%
12.1%
Acute renal failure 12.8%
0.1%
Ketoacidosis† 0.2%

2.4%
Hypoglycaemic events‡ 2.6%
9.9%
UTI 8.1%
2.2%
Genital infections 0.7%

4.5%
Bone fractures 4.2%
Events leading to 0.5%
lower limb amputation* 0.8%
3.8%
Hepatic injury 5.2%
*Investigator-defined events. †All events occurred in patients with diabetes mellitus at baseline. ‡Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that
required assistance. AE, adverse event; UTI, urinary tract infection. Anker S et al. N Engl J Med. 2021;XX:XXX.

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 Key takeaways
There remains a need for treatments that improve outcomes for patients with heart failure 1 REMEMBER: We still have
a residual risk.

+ Based on recent HF trials, SGLT2 inhibitors have been shown to improve outcomes in patients with both
HFrEF & HFpEF, and may add to the effects of mainstay heart failure medications 2–4

Results of trials of SGLT2 inhibitors in both HFrEF & HFpEF show a consistent safety profile, similar to that seen in
T2D, with no increase in hypovolaemia, hypotension or hypoglycaemic events 2,3,5

Empagliflozin is now considered a class I recommendations for treating HFrEF patients according to the ESC 2021
HF guidelines.

CV, cardiovascular; CVOT, cardiovascular outcomes trial; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes
1. Heart Disease and stroke statistics – 2019 update. A report from the American Heart Association. Circulation 2019;139:e56; 2. Packer M et al. N Engl J Med. 2020;383(15):1413;
3. McMurray J et al. N Engl J Med 2019;381:1995; 4. Farkouh ME & Verma S. J Am Coll Cardiol 2018;71:2507; 5. Zinman B et al. N Engl J Med 2015;373:2117

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