ESC Congress 2024 Hot Line Presentation

Finerenone in Heart Failure and

Chronic Kidney Disease with Type 2
Diabetes: the FINE-HEART Pooled
Analysis of Cardiovascular, Kidney,
and Mortality Outcomes
Muthiah Vaduganathan on behalf of
Gerasimos Filippatos; Brian Claggett; Akshay Desai;
Pardeep Jhund; Alasdair Henderson; Meike Brinker; Peter
Kolkhof; Patrick Schloemer; James Lay-Flurrie; Prabhakar
Viswanathan; Carolyn Lam; Michele Senni; Sanjiv Shah;
Adriaan A. Voors; Faiez Zannad; Peter Rossing; Luis
Ruilope; Stefan Anker; Bertram Pitt; Rajiv Agarwal;
John McMurray; Scott Solomon

PROSPERO CRD42024570467
Month Date, Year 2
Strong Epidemiological Overlap of Cardiovascular, Kidney, and
Metabolic Disorders

US NHANES survey cycles 1999–2020 US NHANES survey cycles 2011–2020

CKM stage
0 1 2 3 4
T2D 60

6.8%
(16.9 million) 50

CKM stage prevalence, %

40
3.2%
1.7%
(4.1 million)
(8.1 million)
CKD 30
1.5%
(3.8 million)
20
CVD 3.0% 1.6% 7.5%
(9.5 million) (4.1 million) 10
(18.5 million)

0
2011–2012 2013–2014 2015–2016 2017–2020
NHANES survey years

US NHANES Survey Cycles 1999-2020 US NHANES Survey Cycles 2011-2020

Ostrominski J…Vaduganathan M. JAMA Cardiology 2023 Aggarwal R…Vaduganathan M. JAMA 2024
 Could the Non-Steroidal MRA, Finerenone, Modify Risk across
the Cardio-Kidney-Metabolic Spectrum?

• Finerenone is a non-steroidal MRA

that has been studied in RCTs of
patients with T2D and CKD and
separately in patients with HF
(with and without T2D).

• However, none of these trials were

individually powered to evaluate
treatment effects on mortality
outcomes or effects in key
subgroups.
Design of FINE-HEART Umbrella Program

Prospectively Registered:
PROSPERO CRD42024570467

(n=18,991 Participants) Prespecified in Dedicated

Statistical Analysis Plans

Pooling data in the FINE-HEART program increased precision to

robustly assess the efficacy and safety of the non-steroidal MRA
finerenone on important cardio-kidney outcomes and is enriched for
participants with a high burden of CKM multimorbidity.
 Study Designs of the Individual Trials
FINEARTS-HF FIDELIO-DKD and FIGARO-DKD
Validly Randomized 6,001 12,990
Countries 37 48
Patient population HFmrEF or HFpEF CKD and T2D
Inclusion criteria  Adults (≥40 years)  Adults (≥18 years old)
 Symptomatic HF  T2D
 LVEF ≥40%  UACR ≥ 30 mg/g
 Elevation natriuretic peptides  Maximally tolerated RASi
 Structural heart disease
 Recent diuretic use
Exclusion criteria Potassium >5.0 mmol/L Potassium >4.8 mmol/L
Dosage and titration eGFR ≤60: 10 up to 20 mg eGFR <60: 10 up to 20 mg
eGFR >60: 20 up to 40 mg eGFR ≥60: 20 mg
(potentially down to 10 mg) (potentially down to 10 mg)
Median follow-up 2.6 years 2.6 years (FIDELIO-DKD)
3.4 years (FIGARO-DKD)
Baseline Characteristics of FINE-HEART Integrated Population
Finerenone Placebo Finerenone Placebo
(n=9,501) (n=9,490) (n=9,501) (n=9,490)
Age 67±10 67±10 HbA1c (%) 7.3±1.4 7.3±1.4
Women 36% 35% HF 37% 37%
White Race 72% 72% Diabetes 81% 81%
BMI (kg/m2) 31±6 31±6 CKD 84% 84%
Systolic BP (mmHg) 135±15 134±15 AF 15% 15%
Potassium (mmol/L) 4.4±0.5 4.4±0.5 Diuretics 66% 67%
eGFR ACEi/ARB/ARNI 93% 93%
59±21 59±21 Statins 70% 71%
(mL/min/1.73m2)
<25 1% 1% SGLT2i 9% 9%
25 to <45 29% 29% GLP-1RA 6% 6%
45 to <60 27% 26%
≥60 44% 44%
283 293
UACR (mg/g)
[IQR 46-836] [IQR 47-855]
<30 20% 20%
30 to <300 31% 31%
≥300 49% 50%
High Burden of Cardio-Kidney-Metabolic Disease Overlap
Cardio-Kidney-Metabolic Overlap in FINE-HEART
Primary Endpoint: CV Death
CV Death CV Death (including Undetermined Death)
10 HR 0.89; 95% CI 0.78-1.01; P=0.076 10 HR 0.88; 95% CI 0.79-0.98; P=0.025

8 8
Cumulative Incidence (%)

Cumulative Incidence (%)

6 6

4 4

2 2
Placebo Placebo
0
Finerenone 0
Finerenone

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months Months

Primary Analysis: Prespecified Sensitivity Analysis:

CV Death Excluding Undetermined Deaths CV Deaths Including Undetermined Deaths
Finerenone 421 (4.4%) vs. Placebo 471 (5.0%) Finerenone 627 (6.6%) vs. Placebo 703 (7.4%)
Secondary Endpoint: All-Cause Mortality
20

18 All-Cause Mortality
HR 0.91; 95% CI 0.84-0.99
16
Cumulative Incidence (%)

P=0.027
14

12

10

2 Placebo
Finerenone
0

0 6 12 18 24 30 36 42 48
Months
Secondary Endpoint: HF Hospitalization
20

18
HF Hospitalization
HR 0.83; 95% CI 0.75-0.92
16 P<0.001
Cumulative Incidence (%)

14

12

10

2
Placebo
Finerenone
0

0 6 12 18 24 30 36 42 48
Months
Secondary Endpoint: Kidney Composite Endpoint
sustained eGFR decline of ≥50%, kidney failure*, or death due to kidney failure
20
Kidney Composite Endpoint
18
HR 0.80; 95% CI 0.72-0.90
16
Cumulative Incidence (%)

P<0.001
14

12

10

2
Placebo
0 Finerenone

0 6 12 18 24 30 36 42 48
Months
*sustained eGFR < 15 ml/min/1.73m2, chronic dialysis, or kidney transplantion
 Summary of Prespecified Efficacy Endpoints
Outcome HR (95% CI) P-value
Primary Endpoint

CV death (excluding undetermined death) 0.89 (0.78–1.01) 0.076

Prespecified sensitivity analysis:

0.88 (0.79–0.98) 0.025
CV death (including undetermined death)
Secondary Endpoints
Kidney Composite Endpoint 0.80 (0.72–0.90) <0.001
HF Hospitalization 0.83 (0.75–0.92) <0.001
CV Death or HF Hospitalization 0.85 (0.78–0.93) <0.001
New-onset Atrial Fibrillation 0.83 (0.71–0.97) 0.018
Major Adverse Cardiovascular Events* 0.91 (0.85–0.98) 0.010
All-cause Death 0.91 (0.84–0.99) 0.027
All-cause Hospitalization 0.95 (0.91–0.99) 0.025
All-cause Death or All-cause Hospitalization 0.94 (0.91–0.98) 0.007

0.5 1 2
* CV death or non-fatal CV event
(MI, stroke, or HF hospitalization) Favors Finerenone Favors Placebo
 Broad Consistency Across 17 Prespecified Subgroups for the
Primary Endpoint (CV Death)
Finerenone Placebo HR (95% CI) Finerenone Placebo HR (95% CI)
(n=9501) (n=9490) (n=9501) (n=9490)
Category Category
n/N n/N n/N n/N
Age KDIGO Risk Categories
≤ Median 149/5071 179/5053 0.84 (0.68–1.05) Low risk 48/1052 50/1034 0.94 (0.63–1.39)
>Median 272/4430 292/4437 0.91 (0.77–1.07) Moderately increased risk 84/1545 88/1455 0.89 (0.66–1.20)
Sex High risk 1203/3184 161/3318 0.78 (0.61–0.98)
Male 265/6111 298/6216 0.87 (0.74–1.03) Very high risk 157/3616 161/3577 0.96 (0.77–1.20)
Female 156/3390 173/3274 0.89 (0.72–1.11) History of HF
Race Present 273/3488 299/3520 0.92 (0.78–1.08)
Asian 56/1910 57/1946 0.98 (0.68–1.42) Absent 148/6013 172/5970 0.85 (0.68–1.06)
Black 7/300 11/308 0.58 (0.22–1.53) History of Diabetes Mellitus
Other 15/476 19/447 0.72 (0.37–1.44) Present 294/7715 343/7714 0.85 (0.73–1.00)
White 343/6815 384/6789 0.89 (0.77–1.03) Absent 127/1786 128/1776 0.98 (0.77–1.25)
Region History of CKD
Asia 56/1808 55/1815 0.99 (0.68–1.44) Present 330/7949 363/7929 0.90 (0.77–1.04)
Eastern Europe 176/3001 187/2941 0.93 (0.76–1.14) Absent 91/1552 108/1561 0.84 (0.64–1.11)
Latin America 40/1041 69/1034 0.58 (0.39–0.85) Cardio-Kidney-Metabolic Conditions
North America 43/1259 50/1261 0.85 (0.57–1.28) 1 Condition 58/996 61/978 0.93 (0.65–1.33)
Western Europe, Oceania, Others 107/2392 110/2439 0.98 (0.75–1.28) 2 Conditions 250/7359 286/7351 0.87 (0.74–1.03)
Baseline BMI (kg/m2) 3 Conditions 113/1146 124/1161 0.91 (0.71–1.18)
<30 210/4591 237/4616 0.87 (0.73–1.05) GLP-1RA at Baseline
≥30 210/4880 234/4856 0.89 (0.74–1.07) No 403/8925 453/8956 0.88 (0.77–1.01)
Baseline Systolic Blood Pressure (mmHg)
Yes 18/576 18/534 1.05 (0.54–2.07)
≤ Median 254/4790 257/4786 1.00 (0.84–1.19)
SGLT2i at Baseline
>Median 1664/4707 214/4701 0.76 (0.62–0.93)
No 375/8672 422/8629 0.88 (0.76–1.01)
Baseline Serum Potassium (mmol/L)
Yes 46/829 49/861 0.96 (0.64–1.44)
≤4.5 284/6746 308/6419 0.91 (0.77–1.06)
0.25 0.5 1 2 4
>4.5 137/3024 163/3068 0.86 (0.69–1.08)
0.25 0.5 1 2 4 Favors Finerenone Favors Placebo

Favors Finerenone Favors Placebo

 Safety Outcomes

Finerenone Placebo
n=9,482 n=9,467
Any serious adverse event 35% 37%
Any potassium >5.5 mmol/L 17% 8%
Any potassium >6.0 mmol/L 3% 1%
Any potassium <3.5 mmol/L 5% 10%
Hyperkalemia 13% 6%
Hyperkalemia leading to hospitalization 0.8% 0.2%
Hyperkalemia leading to death 0% 0%
Acute kidney injury 4% 3%
Acute kidney injury leading to hospitalization 2% 1%
Systolic blood pressure<100mmHg 11% 7%
Gynecomastia or breast hyperplasia 0.2% 0.2%

Treatment-emergent adverse events are defined as any adverse event occurring in any patient who has received at
least one dose of study drug and within 3 days of permanent discontinuation. This safety table includes 1 patient
who was randomized to placebo but who actually received finerenone.
 Conclusions
• The FINE-HEART participant-level pooled analysis represents the largest analysis of
the effects of the non-steroidal MRA finerenone across the CKM spectrum.
• While in this pooled analysis the reduction in cardiovascular death was not
statistically significant, finerenone reduced deaths of any cause, cardiovascular
events, and kidney outcomes.
• Treatment effects were consistent across all tested clinical subgroups including those
with multiple intersecting CKM conditions and on background SGLT2i or GLP-1RA.
• No new or unexpected safety signals were uncovered in this pooled analysis.

The totality of the evidence supports the disease-modifying

potential of finerenone in broad, high-risk patient populations
encompassing cardiovascular, kidney, and metabolic diseases.
Full Details Available Online in Nature Medicine

Finerenone in Heart Failure and Chronic Kidney Disease

with Type 2 Diabetes: the FINE-HEART Pooled Analysis of
Cardiovascular, Kidney, and Mortality Outcomes

Muthiah Vaduganathan, Gerasimos Filippatos; Brian Claggett;

Akshay Desai; Pardeep Jhund; Alasdair Henderson; Meike
Brinker; Peter Kolkhof; Patrick Schloemer; James Lay-Flurrie;
Prabhakar Viswanathan; Carolyn Lam; Michele Senni; Sanjiv
Shah; Adriaan A. Voors; Faiez Zannad; Peter Rossing; Luis
Ruilope; Stefan Anker; Bertram Pitt; Rajiv Agarwal; John
McMurray; Scott Solomon
https://doi.org/10.1038/s41591-024-03264-4
In Memory of the Late Dr. George Bakris (1952-2024)

A pioneer in cardio-kidney-metabolic research,

physician, leader, colleague, and dear friend