*For medical professionals only
In recent years, with the accumulation of a large amount of evidence-based medical evidence, sodium-glucose co-transporter 2 inhibitor (SGLT2i) has become a “star” in the fields of cardiovascular, diabetes and chronic kidney disease Drugs, much concern and anticipation!
On May 21-24, 2022, the 2022 European Society of Cardiology Heart Failure Association (ESC-HFA 2022) Heart Failure Conference was held in Madrid, Spain. In this conference, a number of latest researches on SGLT2i were released, covering the efficacy, safety, mechanism and other aspects of SGLT2i. The content is now sorted as follows, let’s take a look!
Update on ESC-HFA SGLT2i in 2022
1. Pooled Analysis of DEFINE-HF and PRESERVED-HF
This pooled analysis assessed the effect of dapagliflozin on the entire LVEF range symptoms and effects of physical limitations.
Study Design: A 12-week, randomized, double-blind trial comparing dapagliflozin to placebo.
Inclusion criteria: chronic HF, NYHA grade ≥ II, elevated NTproBNP.
Primary endpoint: KCCQ.
Effect of dapagliflozin versus placebo on KCCQ-CSS p>
In a pooled analysis of DEFINE-HF and PRESERVED-HF, dapagliflozin improved symptoms and physical limitations in HF patients. Dapagliflozin was significant, both statistical and clinical. Compared with placebo, fewer patients treated with dapagliflozin had their disease worsened, and more patients had mild, moderate and substantial improvements in health. Benefit was highly consistent across the LVEF range, not attenuated in patients with very low or high ejection fraction, and there was no heterogeneity of treatment effect in any other subgroup.
Overall, these results support the use of dapagliflozin in HF patients, regardless of ejection fraction.
2. DELIVER trial design and baseline characteristics p>
DELIVER was designed to test the hypothesis that dapagliflozin reduces mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (LVEF>40%) compared to placebo (HFpEF) Cardiovascular death or worsening heart failure in patients.
Inclusion criteria: (1) age ≥40 years; (2) NYHA II-IV; (3) LVEF >40%; (4) structural heart disease ; (5) LVH or LA increased.
Primary endpoint: Time to first composite CV death or HF event (HF hospitalization or HF emergency visit).
Recently hospitalized patients may be particularly sensitive to treatment
The DELIVER study, the largest and most extensive trial in HFmrEF, will help clarify whether SGLT2i, similar to prior therapy, shows attenuation in patients with “normal” LVEF, and further assess the effect of SGLT2i on hospitalized or recent Benefit of hospitalized patients.
In addition, DELIVER will evaluate the benefit of SGLT2i in patients with improved HF and LVEF (HFimpEF) who were excluded from all other trials.
3. Metabolomics subgroup study of DEFINE-HF
This study is a double-blind, placebo-controlled RCT to identify metabolic pathways associated with dapagliflozin treatment using targeted metabolomics.
Inclusion criteria: HFrEF diagnosis time >16 weeks, EF≤40%, NYHA class II-III, elevated natriuretic peptide, eGFR≥30 mL/min/1.73m2
Primary endpoints: NT-proBNP and HF-related health status (KCCQ score).
primary endpoint
5. EMPEROR-Preserved: Results defined using surrogate endpoints span>
This study is a Phase III, randomized, double-blind, placebo-controlled trial to Efficacy and safety of empagliflozin versus placebo in patients with HFpEF.
Inclusion criteria: Type 2 diabetes (T2DM) and non-T2DM, age ≥18 years, chronic HF (NYHA II-IV), eGFR≥20ml/min/1.73 m², elevated NT-BNP (SR>300 pg/ml, AF>900 pg/ml).
Primary endpoint: Increased emergency HF visits to CV death or HHF.
Main synthesis of CV deaths and HF worsening events according to DELIVER criteria
img class=”content_title” height=”300″ layout=”responsive” sizes=”(min-width: 320px) 320px, 100vw” src=”https://mmbiz.qpic.cn/mmbiz_png/x5F5KAyDKw3lD6GoxGUCR1lg3ibQicFmTVmcbSk69newTSZbwavPyZzUGyMYGYWnwPs21vicibs57rCZso” widthATico =”600″>Effect of empagliflozin versus placebo: worsening heart failure events and CV death by DELIVER criteria
This study showed: (1) Empagliflozin treatment reduced the risk of CV death or worsening of HF events in patients with HFpEF using the DELIVER endpoint definition. This benefit was consistent across prespecified subgroups. (2) For CV events, the pattern of benefit was similar to that reported using the original endpoint definition of the EMPEROR-Preserved trial. (3) Using the DELIVER criteria, when patients with LVEF ≥60% were removed from the analysis, the effect of empagliflozin in reducing the risk of major renal events was significantly increased with statistical significance.
2022 ESC-HFA SGLT2i-Related Study
Efficacy and Safety
A meta-analysis of the efficacy of SGLT2i on HFpEF and HFrEF Analysis
SGLT2i significantly reduced the risk of HF hospitalization or CV death in patients with HFpEF compared with placebo.
SGLT2i versus renin-angiotensin-aldosterone system inhibitors Meta-analysis of the effects of HFpEF
ARNI and SGLT2i reduce composite CVD or HHF events in patients with HFpEF, with SLGT2i being the most effective option.
More well-designed RCTs are needed in the future to verify the statistical and clinical significance of ARNI and whether the combination therapy with SGLT2i has more effects on patients with HFpEF than monotherapy benefit.
Comprehensive medical benefit assessment of combination therapy in patients with HFmrEF and HFpEF p>
The combined benefit of MRA, ARNI and SGLT2i extended to at least 60% of LVEF, and the benefit range between 40% and 60% was considerable. These data further support recent calls for a reassessment of HF nomenclature and LVEF ceilings to define HFmrEF.
In the absence of outcome trials investigating combination regimens, this cross-trial pooled analysis could allow for the use of MRA, ARNI, and SGLT2i for patients with LVEF greater than 40% Shared decision-making and health system assessment of combination therapy informs.
The effect of SGLT2i on cardiovascular endpoints in HFrEF patients< /p>
These results differ from clinical trials that showed a reduction in HF hospitalizations, but not CV mortality. In this real-world population cohort study, the SGLT2i group had a lower risk of CV and non-CV mortality, tended to have a longer first hospital stay, and had fewer hospitalizations for HF (possibly due to sample size and FUP [follow-up] duration, not statistically significant).
SGLT2 inhibition in acute myocardial infarction with left ventricular systolic dysfunction Effects
This quasi-experimental study suggests that early initiation of SGLT2i may lead to lower HF in patients with AMI and reduced LVEF values associated events, lower all-cause mortality, and better functional class 1 year after the initial coronary event.
Initiation of SGLT2i in hospitalized patients with acute heart failure: strict Is follow-up still important?
This small study suggests that initiation of SGLT2i in patients hospitalized with acute HF may be beneficial in reducing HF events in the EMPULSE trial .
Despite the hampered benefit of inclusion in HF FUPP (HF Follow-up Program), when SGLT2i was not initiated, there was more decompensation of HF with outpatient treatment, suggesting that despite FUPP is very effective, but there is still some prognostic benefit in initiating SGLT2i in hospitalized patients.
SGLT2i empagliflozin reduces diuretic efficacy in outpatient heart failure patients Impact
Among outpatient HF patients treated with diuretics and empagliflozin, 20.3% showed a difference in diuretic dose. reduce. This suggests that SGLT2i has clinical benefit in outpatient HF patients.
The effect of SGLT2i on cardiorenal function
The results of this single-center HF clinical study are consistent with published data. SGLT2i was well tolerated, even in patients with stage 3 CKD, renal function There was no noticeable change either. Diuretic dose requirements are reduced. In this study, treatment with SGLT2i was associated with decreased NT ProBNP, improved functional capacity (NYHA grade), and modest improvement in EF.
Applicability of GDMT in hospitalized patients with HFrEF in 2019-2020 and its effect on mortality
GDMT was associated with significant mortality gains in patients with advanced HFrEF hospitalized for HF progression. benefit and good prognosis.
The cardioprotective effect of SGLT2i may be related to the normalization of the circadian index of heart rhythm
A new generation of type 2 diabetes (DM) therapy has positive effects on both autonomic dysfunction and volume load in patients with HFrEF, which are The population effect of SGLT2i generally begins in the first month of treatment.
External validation of SGLT2i landmark trials in HFrEF
Cross-sectional studies showed good external validity of the DAPA-HF and EMPEROR-Reduced trials, thus indicating that the results are applicable to the HFrEF population.
This analysis identified opportunities for improved HFrEF management as only 11% of eligible patients were receiving SGLT2i despite their proven benefit in this population of. Follow-up studies are needed to continue to assess the impact of this change on SGLT2i uptake in this population.
The effect of SGLT2i on RV function in hypertensive women with diabetes and HFpEF
In hypertensive women with type 2 diabetes mellitus (T2DM) and HFpEF, SGLT2i was beneficial to increase RV-PA coupling, improve RV function, reducing pulmonary hypertension, thereby reducing pulmonary congestion.
l Post hoc analysis of the DAPA-HF trial:
To observe the efficacy and safety of dapagliflozin according to the degree of frailty in patients with HFrEF. In patients with HFrEF, dapagliflozin improved all test outcomes compared with placebo, regardless of frailty status.
Baseline serum sodium concentration was important for prognosis, but did not alter the benefit of dapagliflozin on HFrEF morbidity and mortality. Dapagliflozin caused a small, early, and transient increase in the risk of hyponatremia that continued to decrease over time.
Effects of dapagliflozin on iron status and its effect on iron metabolism Iron deficiency is common in HFrEF patients and does not alter DAPA – Beneficial effects of dapagliflozin in HF. Dapagliflozin decreased ferritin, hemoglobin, and transferrin saturation (TSAT) and increased total iron binding capacity (TIBC) and soluble transferrin receptor (sTfR). These changes may reflect increased iron utilization following increased erythropoiesis.
SGLT2i in heart failure with different ejection fractionsSuitability analysis in patients
In this real-world analysis, HF patients who may be suitable to initiate SGLT2i across the range of LVEF The proportions are the same.
The findings of this study may herald the widespread use of SGLT2i in the treatment of HF, resulting in a significant beneficial effect on cardiovascular outcomes in eligible patients.
Initiation of SGLT2i in HFrEF patients without diabetes p>
Addition of SGLT2i was well tolerated in the symptomatic cohort of HFrEF patients, especially with regard to renal status.
Compared with the DAPA-HF study, patients in this cohort were more likely to use sacubitril-valsartan and higher doses of Tolerance was also good.
Assessing initial therapy and true tolerability of SGLT2i in HFrEF span>
In clinical practice, early initiation of SGLT2i is safe and well tolerated.
Current National Institute for Health and Management Excellence (NICE) guidelines follow the traditional medication sequencing strategy adopted from landmark clinical trials, resulting in SGLT2i as a additional therapy.
The latest European Society of Cardiology (ESC) guidelines recognize incremental and independent benefits of each underlying HF drug and support earlier initiation of SGLT2i to minimize HF Delayed treatment optimization and subsequent minimization of hospitalization.
This study supports the safety position of the ESC guidelines, which can translate into National Health Service (NHS) healthcare costs by reducing HF hospitalizations and increasing the availability of hospital beds.
Diuretic downregulation had no deleterious effect on pulmonary congestion when SGLT2i was introduced
Introduction of SGLT2i resulted in a significant reduction in diuretics in patients with chronic HF and diabetes, but not in lungs assessed by LUS or HF biomarkers Evidence of worsening external congestion.
EMPEROR-Preserved trial: empagliflozin improves outcomes in patients with HFpEF Cardiovascular and renal status, independent of blood pressure
In EMPEROR-Preserved, empagliflozin was effective in patients with HFpEF based on baseline SBP and It is safe, and there is no significant interaction between the therapeutic effects.
Prospective left heart echocardiographic parameters in the EMPAG-HF patient population Sexual Assessment
These data suggest that immediate treatment with empagliflozin in patients with acute decompensated HF improves cardiac burden Echocardiographic parameters, especially left atrial volume index.
This result may be a favorable indicator of hemodynamic improvement and faster achievement of blood volume in acute HF patients treated with SGLT2i. A quicker return to normal filling pressures and blood volumes may shorten hospital stays and may improve outcomes.
Insights from Indian Cardiologists: HFpEF Management and EMPEROR-Preserved The clinical significance of
HFpEF is underdiagnosed in India and more efforts are needed for early diagnosis.
Embagliflozin may be a powerful option for the treatment of HFpEF and common complications, and more trials are needed to clarify.
Mechanism
1 p>
LV reverse remodeling and prognosis in HFrEF patients treated with SGLT2i
This study indicated that SGLT2i has a significant role in HFrEF and suggest that SGLT2i treatment represents an important opportunity to improve patient outcomes.
These findings reinforce the notion thatSGLT2i’s primary benefit on hard endpoints is mediated by its cardiac-related effects.
2
SGLT2i: far more effective than ‘smart diuretics’
< p>These data support:SGLT2i functions beyond its diuretic properties and extends toanti-remodeling processes, as in NT-proBNP, LVEF and diastolic function Differences are described.
These processes have a major impact on prognosis and events during FUP, reinforcing the importance of new foundational therapies.
3
SGLT2i: far more effective than ‘smart diuretics’
< p>These data support:The role of SGLT2i extends beyond its diuretic properties and extends to anti-remodeling processes, as described by differences in NT-proBNP, LVEF, and diastolic function.
These processes have a major impact on prognosis and events during FUP, reinforcing the importance of new foundational therapies.
4
Myocardial iron supplementation in patients with heart failure following carboxymethyl iron: the effect of pretreatment with empagliflozin< /span>
In this hypothesis-generating study, patients with HF, LVEF <50%, and ID were pre-treated with Enpagliflozin Net treatment identified greater short-term myocardial iron replenishment after FCM treatment.
5
The effect of SGLT2i on cardiac function index
In this systematic review and meta-analysis, the use of SGLT2i was associated with improvements in markers of cardiac function, confirming the importance of SGLT2i in reversing cardiac remodeling.
Other categories
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TIDY-HF Registry: Is Quadruple Therapy Initiated in Real-Life Patients With Newly Diagnosed Heart Failure?
In this cohort studyUp to 65% of patients started quadruple therapy after HF diagnosis, with a predominant preference for INRA, in line with current European guidelines for HF recommendations.
The most common reasons for not starting quadruple therapy drugs were arterial hypotension and renal impairment.
2
SGLT2i: The Key to HFrEF Basic Therapy
This study suggests that co-administration of ARNI and MRA may facilitate increased introduction and titration of ARNI and MRA due to the effect of SGLT2i on serum potassium levels.
3
EMPEROR-Preserved: Effect of Baseline Body Mass Index on Primary Outcome span>
These studies demonstrate that empagliflozin reduces body weight regardless of baseline BMI and similarly reduces important HF endpoints across different BMI categories in patients with HFpEF.
4
Circulating ketone bodies in patients with acute HF treated with SGLT2i empagliflozin
In patients hospitalized with acute HF, there was a marked rise and fall in circulating ketone bodies, especially acetone. Higher acetone concentrations on admission were associated with worse 30-day clinical outcomes.
Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.
5
Can SGLT2i save high-risk patients with heart failure?
These results suggest that early improvement in systolic and diastolic echocardiographic parameters may contribute to the development of SGLT2i in patients at risk of HF and DM. The underlying mechanism of action in patients with cardiomyopathy provides insights, particularly through its hemodynamic effects, alterations in the neurohumoral system and cardiac fuel energy, and direct cardiac effects on inhibition of sodium-hydrogen exchange.
Further clinical and mechanistic studies are needed to address this issue.
6
Patients with heart failure treated with SGLT2i: requiring the same dose of furosemide ?
Since most HF patients are now also treated with SGLTi, physicians should consider that the furosemide dose may need to be reduced in such patients to Return to normal capacity and provide them with the best possible medical care.
Summary
This ESC-HFA heart failure The latest research results of SGLTi announced at the conference verified the benefits of SGLTi in cardiovascular, kidney, diabetes and other aspects. SGLT2i can produce cardiovascular protection in patients with or without T2DM, and has renal protection, adding evidence for the application of SGLT2i in patients with chronic kidney disease. The SGLT2i-related research released in this conference brings more options for the drug treatment of heart failure. In the future, efforts should be made to improve the clinical utilization of SGLT2i and improve the prognosis of heart failure patients.
Source:
[1]2022 ESC-HFA SGLT2i related Late-Breaking Scien ce Presentation.
[2]SGLT2i-related abstracts in 2022 ESC-HFA poster.
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