ISGLT en IC - Inicio Temprano para Beneficios Rapidos
ISGLT en IC - Inicio Temprano para Beneficios Rapidos
ISGLT en IC - Inicio Temprano para Beneficios Rapidos
F a i l u re
Early Initiation to Achieve Rapid Clinical
Benefits
Neal M. Dixit, MD, MBAa, Boback Ziaeian, MD, PhDa,b,c,
Gregg C. Fonarow, MDa,b,*
KEYWORDS
Heart failure with reduced ejection fraction Heart failure with preserved ejection fraction
Initiation and sequencing Guideline-directed medical therapy
KEY POINTS
SGLT2i are high-value medications that demonstrate morbidity and mortality benefits within
30 days of initiation.
SGLT2i should be initiated simultaneously or in rapid sequence with the other core pillars of GDMT
before device therapy consideration.
In-hospital initiation of SGLT2i is well tolerated and safe and reduces the risk of rehospitalization
and death.
SGLT2i reduce heart failure (HF) hospitalization in HF patients with EF greater than 40% and are a
valuable potential therapy in a population with few therapeutic options.
a
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; b Division of Car-
diology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; c Division of Cardiology, Veteran Af-
fairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
* Corresponding author. A2-237 CHS, Mail Code: 167917650 Charles E Young Dr. S, Los Angeles, CA 90095-
1679.
E-mail address: [email protected]
Twitter: @NealDixit (N.M.D.); @boback (B.Z.); @gcfmd (G.C.F.)
Varies
Fig. 1. Ideal characteristics of medical therapy for HF. ARNi, angiotensin receptor-neprilysin inhibitors; CKD,
chronic kidney disease; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection
fraction; MRA, mineralocorticoid-receptor antagonists; QALY, quality-adjusted life year; SGLT2i, sodium-glucose
cotransporter-2 inhibitors.
Fig. 2. Suggested method of simultaneous or rapid-sequence initiation of quadruple medical therapy for HFrEF
with associated clinical benefits. ARNi, angiotensin receptor-neprilysin inhibitors; HF, heart failure; HFrEF, heart
failure with reduced ejection fraction; MRA, mineralocorticoid-receptor antagonists; RRR, relative risk reduction;
SGLT2i, sodium-glucose cotransporter-2 inhibitors. a Computed versus putative placebo in analysis of PARADIGM-
HF Trial.
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Table 1
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Time to AE Leading to
Sample Overall Treatment Significant Discontinuation
Trial Size (n) Intervention Inclusion Criteria Setting Primary Outcome Effect (95% CI) Benefit (days) (Drug vs Placebo)
DAPA-HF 4744 Dapagliflozin LVEF 40%; Outpatient Worsening HF or HR 5 0.74 (0.65– 28 4.7% vs 4.9%
10 mg O.D. vs NYHA II–IV; CV death 0.85)
placebo eGFR 30 mL/
min/1.73 m2
EMPEROR- 3730 Empagliflozin LVEF 40%; Outpatient HF hospitalization HR 5 0.75 (0.65– 12a 8.5% vs 8.9%
Reduced 10 mg O.D. vs NYHA II–IV; or CV death 0.86)
placebo eGFR 20 mL/
min/1.73 m2
EMPA- 79 Empagliflozin Hospitalized for Inpatient Change in NS – 17.5% vs 12.8%
RESPONSE- 10 mg O.D. vs acute HF; eGFR dyspnea,
AHF placebo 30 mL/min/ diuretic
1.73 m2 response,
length of initial
hospital stay,
and change in
NT-proBNP
SOLOIST-WHF 1222 Sotagliflozin Type-2 diabetes; 48.8% Total number of HR 5 0.67 (0.52– 28 7.8% vs 6.6%
200 mg O.D. vs recent initiated CV deaths and 0.85)
589
590
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Table 1
uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
(continued )
Dixit et al
Time to AE Leading to
Sample Overall Treatment Significant Discontinuation
Trial Size (n) Intervention Inclusion Criteria Setting Primary Outcome Effect (95% CI) Benefit (days) (Drug vs Placebo)
EMPULSE 530 Empagliflozin Hospitalized for Inpatient Win ratio Win ratio 5 1.36 90b NR
10 mg O.D. vs acute HF; eGFR (composite of (1.09–1.68)
placebo 30 mL/min/ death, HF
1.73 m2 events, and
change in
KCCQ-TSS)
Abbreviations: AE, adverse event; CI, confidence interval; CV, cardiovascular; DAPA-HF, dapagliflozin and prevention of adverse outcome in heart failure; eGFR, estimated glomerular
filtration rate; EMPA-RESPONSE-AHF, randomized, Double-Blind, Placebo-Controlled, Multicenter Pilot Study On The Effects Of Empagliflozin On Clinical Outcomes In Patients With
Acute Decompensated Heart Failure; EMPEROR-Preserved, Empagliflozin Outcome Trial In Patients With Chronic Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced,
Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; EMPULSE, A Study to Test the Effect of Empagliflozin in Patients Who Are in
Hospital for Acute Heart Failure; HF, heart failure; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaires total summary score; LVEF, left ventricular ejection fraction; NR, not re-
ported; NS, non-significant; NT-proBNP, N-terminal (NT)-prohormone BNP; NYHA, New York Heart Association; O.D., once a day; SGLT2i, sodium-glucose cotransporter 2 inhibitor;
SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure
a
Statistical significance was first reached at 12 d but was sustained from day 34.
b
Analysis at a time point before 90 d not currently available.
SGLT2 Inhibitors in Heart Failure 591
from SGLT2i have been identified.13 A few mecha- group compared with the placebo group during
nisms that have been shown to occur early and the first 4 days of hospitalization.
may be the basis for the observed clinical benefits Similarly, a single-center crossover placebo-
are outlined. controlled trial of stable HFrEF patients with dia-
betes showed that empagliflozin significantly
Reverse Ventricular Remodeling increased fractional excretion of sodium with a
resultant 138 mL (P 5 .04) reduction in plasma vol-
Pathologic cardiac remodeling associated with
ume at 14 days compared with placebo.20 Inter-
HFrEF increases the risk for hospitalization and
estingly, plasma norepinephrine levels measured
death by increasing the likelihood of volume over-
at 14 days increased only 0.09 nmol/L in the empa-
load, pump failure, or ventricular arrhythmia.14
gliflozin group compared with 0.7 nmol/L in the
Reverse ventricular remodeling is observed with
placebo group (P 5 .023). There was no difference
BB, RAASi/ARNi, and MRA usage.15 The impact
in levels of other neurohormones (renin, aldoste-
of SGLT2i on reverse ventricular remodeling was
rone, copeptin).
studied in the Randomized Trial of Empagliflozin
These two studies suggest that SGLT2i induce a
in Nondiabetic Patients With Heart Failure and
greater reduction in plasma volume by way of
Reduced Ejection Fraction (EMPA-TROPISM)
increased diuresis and natriuresis without the in-
trial.16 In the 6-month trial period, the empagliflozin
crease in compensatory neurohormonal activation
arm (compared with placebo) had large improve-
that precedes ventricular remodeling.21
ments in left ventricle (LV) end-diastolic volume
( 25.1 vs 1.5 mL, P < .001), LV end-systolic vol-
ume ( 26.6 vs 0.5 mL, P < .001), LV mass ( 17.8 Increase in Erythropoietin
vs 4.1 g, P < .001), and LV sphericity. Left ventric- In a substudy of the Effects of Empagliflozin on
ular ejection fraction (LVEF) was also improved Cardiac Structure in Patients With Type 2 Diabetes
(6.0 vs 0.1, P < .001). (EMPA-HEART) trial, investigators measured
Although the change in LV architecture was erythropoietin levels at 0, 1, and 6 months after
assessed at 6 months, the magnitude of the effect initiation of empagliflozin.22 At just 1 month, eryth-
combined with known early clinical benefits of ropoietin levels were significantly increased in the
SGLT2i implies that these changes are likely empagliflozin arm (compared with placebo). Addi-
occurring soon after initiation. The mechanism tionally, hematocrit level was found to be signifi-
for the rapid reverse remodeling was speculated cantly increased by 6 months in the empagliflozin
by the same group to be due to, in part, to SGLT2i arm. Hematocrit was similarly increased in the
induced switching of myocardial energy consump- Empagliflozin in Heart Failure with a Preserved
tion from glucose to fatty acids, ketone bodies, Ejection Fraction (EMPEROR-Preserved) trial at
and branched-chain amino acids.17 However, just 1 month. Erythropoietin has previously been
further research to elucidate the complete mecha- shown to have systemic cardioprotective effects23
nism of SGLT2i-induced reverse ventricular in addition to reducing the likelihood of anemia, a
remodeling is needed. known risk factor of HF morbidity and mortal-
ity.22,24 In patients with HFrEF, improvements in
Decongestion Without Neurohormonal erythropoietin and hematocrit levels may be an
Compensation additional early protective mechanism of SGLT2i.
Initiation of SGLT2i has been shown to cause
diuresis and natriuresis without the compensatory INITIATION OF SGLT2i WITH OR WITHOUT
neurohormonal activation that results from BACKGROUND THERAPY
diuresis with traditional diuretics.18 In the Ran-
domized, double-blind, placebo-controlled, multi- The most effective method to maximize relative
center pilot study on the effects of empagliflozin risk reduction of HF hospitalization and all-cause
on clinical outcomes in patients with acute decom- mortality is simultaneous or rapid sequence initia-
pensated heart failure (EMPA-RESPONSE-AHF) tion of all four pillars of GDMT.25 Traditional
trial, hospitalized patients with HFrEF were initi- sequencing methods, aiming to maximize BB
ated on empagliflozin or placebo.19 Although the and RAASi dosage before MRA or SGLT2i initia-
trial showed no significant differences in the pri- tion, result in unnecessary delays in the initiation
mary endpoints (change in dyspnea, diuretic of crucial GDMT agents. In fact, the effectiveness
response, length of stay, and N-terminal probrain of SGLT2i is not dependent on the presence or
natriuretic peptide level), the data reported in the absence of background HFrEF therapy, and they
exploratory outcomes suggests increased net are well tolerated (and even act synergistically)
urine output (w850 mL/d) in the empagliflozin with other GDMT agents.
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592 Dixit et al
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SGLT2 Inhibitors in Heart Failure 593
evidence to suggest that in-hospital initiation is Initiation of GDMT in-hospital is crucially impor-
unsafe. On the contrary, ample evidence exists tant with one in four patients dying or re-
that support the notion for in-hospital initiation hospitalized within 30 days of discharge of an HF
of SGLT2i. In the EMPA-RESPONSE-AHF trial, hospitilizaiton.42 In-hospital initiation of SGLT2i is
empagliflozin was initiated in stable hospitalized safe and results in rapid clinical benefits that
HFrEF patients and continued for 30 days.19 As reduce hospitalization and death in the high-risk
previously mentioned, the study did not meet its post-discharge period.
primary outcomes, but all safety outcomes were
met, with no difference in adverse events or COST AND VALUE CONSIDERATIONS
drug discontinuation with the empagliflozin group
compared with placebo. In the SOLOIST-WHF SGLT2i are relatively new drugs on the market and
(Effect of Sotagliflozin on Cardiovascular Events as such will likely be under patent in the United
in Patients With Type 2 Diabetes Post Worsening States until at least 2025. Consequentially, out-
Heart Failure) trial, the dual SGLT1/SGLT2 inhibi- of-pocket drug costs for SGLT2i, which can be up-
tor, sotagliflozin, reduced the primary endpoint of wards of $300 per month, are unaffordable for
cardiovascular mortality or HF hospitalization/ur- many patients without extra efforts to increase
gent care visit by 33% versus placebo in patients the accessiblity.41 Because of additional time
with HF and diabetes.40 In the trial, sotagliflozin and resources needed to obtain SGLT2i for pa-
was initiated before or shortly after hospital tients, clinicians may feel reluctant to use SGLT2i
discharge, and there was no heterogeneity in effi- alongside other pillars of GDMT. Due to costs,
cacy between the subgroups started in-hospital hospitals and payers may avoid adding SGLT2i
or shortly after hospital discharge. Benefits were to covered formularies. However, these barriers
seen in the first 28 days from initiation. Serious are worth overcoming to realize the impressive
adverse events led to a discontinuation rate in morbidity and mortality benefit of the medication
the sotagliflozin group of only 3.0% (vs 2.8% in class. A cost-effectiveness analysis by Isaza and
the placebo group). Most recently, the EMPULSE colleagues showed that in the United States,
trial demonstrated the safety rapid clinical bene- dapagliflozin costs $68,300 per quality-adjusted
fits in hemodynamically stable HF patients initi- life year (QALY) gained.43 This figure is far below
ated on SGLT2i early during hospitalizations for the $150,000 per QALY threshold that the ACC/
acute HF.27 Patients initiated on empagliflozin AHA set for low-value interventions and on par
were 36% more likely to receive clinical benefit with ARNi, which also remain under patent.44,45
than those initiated on placebo during the 3- Moreover, more frequent in-hospital initiation
month study period. Significant improvement in may further increase value due to a larger absolute
symptoms was noted at just 15 days. No safety risk reduction in the high-risk postdischarge
concerns were identified, and there was more period.46 In the treatment of HF, where few medi-
drug discontinuation in the placebo arm. cations have demonstrated mortality benefit and
Although there are clear and compelling benefits the four pillars of therapy have additive clinical
with in-hospital initiation of SGLT2i, there is no benefit, it is the best interests of patients and the
consensus at which point during a hospitalization health care system to ensure access to SGLT2i.
to initiate SGLT2i relative to other GDMT. Although
some would point to the augmented diuresis with SGLT2i USE IN PATIENTS WITH HEART
SGLT2i seen in the EMPA-RESPONSE-AHF trial FAILURE AND EJECTION FRACTION GREATER
as a reason to initiate as early as possible (before THAN 40%
ARNi, BB, and MRA), this did not result in a shorter
length of stay.19 In EMPULSE, the median time of Patients with HFmrEF and HFpEF have tradition-
initiation was 3 days into admission with patients ally been a difficult patient population to treat.47
having to demonstrate clinical stability as evi- RAASi, ARNi, and MRA may have modest benefits.
denced by an SBP greater than 100 mm Hg, no However, SGLT2i have recently been shown in
symptomatic hypotension, no increase in intrave- multiple trials to improve morbidity and symptoms
nous (IV) diuretics or use of IV vasodilators within across the entire EF spectrum of HF to a much
6 h, and no IV ionotropic support within 24 h. Fac- greater degree than RAASi, ARNi, and MRA.5,27,40
tors such as upcoming procedures, renal function, The SOLOIST-WHF trial was the first to suggest
and adjustment of diabetes medications may also the benefit of the SGLT inhibitor mechanism in pa-
influence the timing of initiation.41 Fortunately, as tients with HFpEF.40 In prespecified subgroup
complete benefits of SGLT2i are obtained at the analysis of patients with EF 50%, sotagliflozin
initial dosage, the main priority should simply be reduced the primary endpoint of cardiovascular
the initiation of the medication beforedischarge. death or urgent visits/hospitalizations for HF by
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594 Dixit et al
52% compared with placebo. Subsequently, the reduced congestion, and increases in the car-
EMPEROR-Preserved trial, showed a 21% dioprotective and hematocrit-stimulating
decrease in the primary outcome of cardiovascu- hormone, erythropoietin
lar death or HF hospitalization with empagliflozin
To maximize total relative risk reduction in
versus placebo in patients with HF and an morbidity and mortality, SGLT2i should be
EF 40%.5,48 This benefit reached statistical sig- initiated simultaneously or in rapid sequence
nificance only 18 days after randomization. Of with the other core pillars of GDMT
note, the reduction in the primary outcome was Due to LVEF and cardiac structure improve-
driven almost entirely from a reduction in HF hos- ments induced by SGLT2i, consideration for
pitalizations. Additionally, in prespecified sub- device therapies such as ICD, CRT, and TEER
group analysis, benefit was found across all EF should occur after SGLT2i initiation
ranges but was greatest in the EF 50% group. In-hospital initiation of SGLT2i is well toler-
Unfortunately, both trials failed to achieve the ated and safe and reduces the risk of rehospi-
elusive goal of all-cause mortality benefit with talization and death
drug therapy in an HF population with EF greater
SGLT2i are lifesaving, high-value medications,
than 40%. Even still, SGLT2i are an effective treat-
and patient affordability is a key issue
ment to reduce HF hospitalizations for patients
with HFmrEF or HFpEF. In the EMPULSE trial, SGLT2i have more recently shown to reduce
heart failure (HF) hospitalization in HF pa-
the clinical benefits achieved were similar for pa-
tients with EF greater than 40% and are a
tients with EF 40% and greater than 40% further
valuable potential therapy in a population
demonstrating the benefits of SGLT2i therapy with few therapeutic options
apply irrespective of EF group.27 The totality of ev-
idence suggests that early in-hospital initiation of
SGLT2i should be the standard of care for patients
with HF, irrespective of EF.
FUNDING
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SGLT2 Inhibitors in Heart Failure 595
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