Cardiorenal Benefits of SGLT2 Inhibitors in Heart Failure

여수제일병원
심장내과
이 우 석
2023.4.25 세르비에 심포지엄

국내 사망 원인 2위 심부전

CV-DEATH residual risk despite quadruple therapy

GDMT in Heart Failure
Bozkurt B. JACC: Heart Failure 2022;10:992

Common side effects of guideline-directed medical therapy
Rosano GMC, et al. Eur J Heart Fail 2021;23:872
The Barrier of the treatment implementation/Tolerability issues
Low blood pressure/Heart rate/Impaired renal function/Hyperkalemia

Patients profiling in heart failure for tailoring medical therapy

Personalized approach
“Guideline-directed medical therapy (GDMT) has a major impact on mortality and
morbidity of heart failure (HF) patients.” However, despite guideline recommendations
and available evidence majority of patients are not treated optimally.
“A personalized patient approach, adjusting GDMT to the patient’s hemodynamic
profile (blood pressure, heart rate and kidney function), may allow to achieve a better
therapy for each individual patient better than the more traditional hierarchical, step
by step, standardized forced titration of each drug class before initiating treatment
with the next, in a misguided ‘one size fits all’ approach.”

Patient profiling in heart failure for tailoring medical therapy

 Why is Heart Rate so important?
 Why do we use Ivabradine Earlier ?
OVERVIEW

평균 혈압 30 mmHg, 심박수 6회/분

Are you running out of heartbeats?
Every living creature has a limited number of heartbeats or breaths (basal metabolic rate).
Poiríer P. Circulation 2014;129:2085

Resting heart rate in general population:
Copenhagen male study
Jensen MT, et al. Heart 2013;99:882
63 yo

Resting heart rate in HF patients:
Analysis from SHIFT trial
Böhm M et al. Lancet 2010;376:886

Resting heart rate in CAD patients with LVD:
BEAUTIFUL trial (sub-analysis of the placebo group)
Fox K, et al. Lancet 2008;372:817, Fox K, et al. J Am Coll Cardiol 2007;50:823

HR control from the time of HF diagnosis and across
follow-up is crucial
Kurgansky KE, et al. BMC Cardiovasc Disord 2020;20:92

Relationship between mean change in HR and mean change in
mortality in studies of patients with chronic HF
Fox K, et al. J Am Coll Cardiol 2007;50:823

HR reduction and clinical outcome in patients with systolic CHF receiving beta-
blockers: 35 trials with 22,926 patients with a mean follow-up duration 9.6 months
Flannery G, et al. Am J Cardiol 2008;101:865

The Slower, The Better?
Reil JC, et al. Lancet 2008;372:779

Resting heart rate reduction in HF patients
‘F’Channel
Heart rate Reduction  Event?
Inhibition by Ivabradine

The Systolic Heart failure treatment
with the If inhibitor ivabradine Trial
Swedberg K, et al. Lancet 2010;376:875

Ivabradine reduced primary endpoint

Ivabradine reduced PEP across all subgroups
1. Voors AA, et al. Eur J Heart Fail 2014;16:426, 2. Komajda M, et al. Eur J Heart Fail 2014;16:810,
3. Komajda M, et al. Eur J Heart Fail 2015;17:1294, 4. Swedberg K, et al. Lancet 2010;376:875

Ivabradine reduced death from HF

Ivabradine reduced repeated hospitalizations
Borer JS, et al. Eur Heart J 2012;33:2813

Ivabradine prevented early readmission after discharge
Komajda M, et al. Eur J Heart Fail 2016;18:1182

Incremental benefit of drug therapies for chronic HFrEF:
Results of the network meta-analysis: hazard ratios and their 95% credible intervals vs. placebo.
Komajda M, et al. Eur J Heart Failure 2018;20:1315

HR at baseline influences the effect of Ivabradine on CV
outcomes in chronic HF: analysis from the SHIFT study
1. Böhm M, et al. Clin Res Cardiol 2013;102:11, 2. Böhm M, et al. Int J Heart Fail 2020;2:1

Ivabradine improved CV outcomes
1. Böhm M, et al. Clin Res Cardiol 2013;102:11, 2. Böhm M, et al. Int J Heart Fail 2020;2:1

CV outcomes in the Ivabradine group according to
heart rate achieved at 28 days
1. Böhm M, et al. Clin Res Cardiol 2013;102:11

Effect of ivabradine on mortality in patients with
heart failure & reduced left ventricular ejection fraction
not receiving a beta blocker
Cleland JG et al. Eur Heart J. 2017 Aug;38(Suppl_1):ehx501.246
: An analysis from the SHIFT trial
심부전 표준치료(RASI:91%,BB:89%,MRA:60%)로 잘 치료 받고 있던
6,505명의 EF 35% 이하이며 분당 심박수가 70회 이상인 만성수축기 심부전 환자를 대
상으로
사망과 이환에 대한 이바브라딘의 효과를 본 SHIFT 연구에서
베타차단제를 복용하지 못한 환자 (n=685)에 대한 하위 분석 결과
PRO-SEM-22102-K-1.0

Ivabradine reduced mortality in patients who were not
receiving a beta blocker
1. Cleland JG, et al. Eur Heart J 2017;38(Suppl_1):ehx501.246_Graph Adapted from oral session at the ESC congress 2017
2. Swedberg K, et al. J Am Coll Cardiol 2012;59:1938, 3. McDonagh TA, et al. Eur Heart J 2021;42:3599
Main reasons not receiving a beta blocker
in SHIFT trial2
- COPD (34%)
- Hypotension (19%)
- Asthma (11%)
- Cardiac decompensation (8%)
- Fatigue (5%)
- PAD (5%)

Ivabradine improved clinical condition in HF patients
Zugck C, et al. Int J Cardiol 2017;240:258

Ivabradine improved QOL in HF patients
1. Ekman l, et al. Eur Heart J 2011;32:2395, 2. Green CP, et al. J Am Coll Cardiol 2000;35:1245

Ivabradine reversed cardiac remodeling in failing heart
(Results despite treatment of BBs and RAAS inhibitors, each used in more than 90% of patients)
Tardif JC, et al. Eur Heart J 2011;32:2507

WHY before discharge is important?

Despite wide use of beta-blockers, heart rate
remains elevated even in well-managed patients
Eriksen-Volnes T, et al. Biomed Hub 2020;5:9

Optimize Heart Failure Care programs
Lopatin YM, et al. Int J Cardiol 2018;260:113

Ivabradine may contribute to optimal HF treatment

Earlier initiation of Ivabradine with BB reduced all cause
mortality or HF re-hospitalization

Combination of ivabradine and sacubitril/valsartan
Lee YH, et al. ESC Heart Fail 2021;8:1204

Ivabradine treatment at discharge reduced risks of death within
1 year among patients with HFrEF in real-world populations
Liao CT, et al. ESC Heart Fail 2021;8:4199

Ivabradine treatment at discharge reduced risks of HF rehospitalization
within 1 year among patients with HFrEF in real-world populations

The prescription of ivabradine at discharge is independently
associated with a lower risk of 1-year all-cause mortality

The prescription of ivabradine at discharge is independently
associated with a lower heart rate and HF severity

Efficacy of ivabradine is consistent across different
background HF medications and devices

Ivabradine facilitated Beta blocker up-titration
Bagriy AE, et al. Adv Ther 2015;32:108

Patient profiling in heart failure for tailoring medical therapy
IVABRADINE

Complementary mode of action to Beta blocker
1. Reil JC, et al. J Am Coll Cardiol 2013;62:1977, 2. Zugck C, et al. Int J Cardiol 2017;240:258, 3. Thollon C, et al. Adv Pharmacol 2010;59:53, 4.
Volterrani M, et al. Int J Cardiol 2011;151:218, 5. Ekman l, et al. Eur Heart J 2011;32:2395, 6. Böhm M, et al. Clin Res Cardiol 2013;102:11

Reimbursement guideline and dosage

1. Böhm M, et al. Clin Res Cardiol 2013;102:11, 2. Cleland JG, et al. Eur Heart J 2017;38(Suppl_1):ehx501.246, 3. Ekman l, et
al. Eur Heart J 2011;32:2395, 4. Bagriy AE, et al. Adv Ther 2015;32:108, 5. Liao CT, et al. ESC Heart Fail 2021;8:4199

Cardiovascular diseases
: the number one cause of non-communicable death globally
https://ourworldindata.org/causes-of-death#what-do-people-die-from accessed on March 2023

Global burden of CVD and Risk
Vaduganathan M, et al. J Am Coll Cardiol 2022;80:2361
Modifiable #CV Targets:
1) ↑Blood pressure
2) Dietary risk
3) ↑LDL-C
4) Smoking
5) Obesity
6) ↑FPG

AMI and ASHD 3.38
CHF 3.06
CVA 2.23
Arrhythmia/Cardiac Arrest 42.79
Other Cardiac 0.27
Septicemia 5.79
COVID-19 7.63
Other Infection 3.31
Malignancy 2.31
Hyperkalemia 0.21
Withdrawal 16.95
All Other Causes 12.08

1. Avogaro A, et al. Cardiovasc Diabetol 2016;15:111, 2. Emerging Risk Factors Collaboration. JAMA 2014;311;1225, 3. Tenenbaum A, et al.
Am J Med 2003;114:271, 4. Demant M, et al. Diabetologia 2014;57:1595, 5. Field AE, et al. Arch Intern Med 2001;161:1581, 6. Lautamäki R,
et al. Am J Physiol Endocrin Metab 2006;291:E282, 7. Targher G, et al. Diabetes Care 2007;30:1212, 8. Ballestri S, et al. World J Gastroent
2014;20:1724, 9. Bongartz LG, et al. Eur Heart J 2005;26:11, 10. Go AS, et al. N Engl J Med 2004;351:1296, 11. Levin A, et al. Am J Kidney
Dis 1996;27:347, 12. Shiba N, Shimokawa H. J Cardiol 2011; 57(1):8, 13. McMahon GM, et al. J Am Soc Nephrol 2014;25:2633, 14. de Boer
IH, et al. JAMA 2011;305:2532, 15. Hsu CY, et al. Ann Intern Med 2006;144:21, 16. Mantovani A, et al. Metabolism 2018;79:64

Contents
Cardiorenal risk in T2D
SGLT2i potential mechanism
Cardiorenal benefit of Dapagliflozin for T2D patients
DECLARE-TIMI58

RRR for MACE* in T2D patients with prior MI stratified by time from last coronary event1
The greatest RRR in MACE was seen in
T2D patients initiated on dapagliflozin
12–24 months after their MI
Time
since MI
Dapagliflozin
%/N
Placebo
%/N
15.2%/1777 17.8%/1807
Overall
≤12 months
>12 to 24 months
>24 to 36 months
>36 months
13.8%/217
11.8%/169
15.8%/181
15.8%/1233
20.3%/271
25.7%/187
18.8%/181
15.8%/1167
0.25 0.50 1.00 2.00 4.00
HR (95% CI)
P interaction
(trend)
0.84 (0.72, 0.99)
0.66 (0.42, 1.03)
0.42 (0.25, 0.71)
0.83 (0.50, 1.40)
1.01 (0.82, 1.23)
0.007
Placebo better
Dapagliflozin better

Mosenzon O, et al. Diabetes Care 2021;44:1805

Contents
제2형 당뇨병 환자에서의 효과 및 안전성
심부전 환자에서의 효과 및 안정성
임상 현장에서의 진료지침

특히, 제2형 당뇨병과 만성콩팥병은 심부전으로 인한 위험을 증가시킵니다

DAPA-HF 연구에서 이뇨제 사용 용량은 군간 유사했습니다.

DAPA-HF의 탐색적 분석에서는 당뇨병 병력이 없는 HFrEF 환자들의 새로
운 당뇨병 발생은 포시가 복용군에서 위약군 대비 낮았습니다.

Green
for Class of
recommendation I
Grey
for Class of
recommendation IIa

Stage A
At-Risk for HF
Stage B
Pre-HF
Stage C and D
Stage C: Symptomatic HF and Stage D: Advanced HF
ARNI in NYHA II-III;
ACEi or ARB in NYHA II-IV
Class 1
Diuretics, as needed
Class 1
Class 1
Beta-blocker
Class 1
MRA
Class 1
SGLT2i
Class 1
Class 1
Hydral-nitrates for
NYHA III-IV in
African American pts
Class 1
SGLT2i
Class 2a
ACEI, ARB, ARNI
Class 2b
MRA
Class 2b
Beta-blocker
Class 2b
SGLT2i
Class 2a
ARNI
Class 2b
MRA
Class 2b
ARB
Class 2b
GDMT Across HF stages
GDMT
Of major
medication
classes
HFrEF : LVEF≤40% HFmrEF : LVEF 41~49% HFpEF : LVEF≥50%
ACEi
Class 1
ARB if ACEi intolerant
Class 1
Beta-blocker
Class 1
SGLT2i in pts with DM
Class 1
SGLT2i in pts with DM
Class 1

DELIVER vs. EMPEROR-Preserved
치료 효과가 감소하는 것으로 나타난 환자군의 박출률 범위가
높았고
입원 동안 또는 입원 직후 치료를 시작한 환자에 대한 데이터가
제한적
감소한 박출률이 개선돼 40% 초과한 환자들이 연구에서 제외

DELIVER vs. EMPEROR-Preserved
EMPEROR-Preserved
DELIVER

DELIVERing Therapeutic Efficacy
Across the EF spectrum of HF
LVEF가 가장 높은 환자군에서도 포시가의 치료 혜택이 감소하
지 않았고, 환자 치료 환경과 관계없이 유의한 효과가 나타남
Lam et al. Circulation 2022,
DOI: 10.1161/CIRCULATIONAHA.122.062022
“심부전 환자가 박출률을 측정하고 어떤 치료가
필요한지 결정하기 위해 심장스캔 결과를 기다려
야 한다는 점을 고려하면 이번 연구가 임상적으
로 중요하다. 포시가는 모든 심부전 환자에게 효
과적이다. 금기사항이 없다면 박출률을 측정하기
전 포시가를 처방해야 생명을 구하는 약물에 대
한 환자 접근성을 높일 수 있다”
Jhund PS, et al. Nat Med 2022, doi: 10.1038/s41591-022-01971-4

Cardiorenal Benefits of SGLT2 Inhibitors in Heart Failure

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