abchf abchf ABC Heart Fail Cardiomyop ABC Heart Fail Cardiomyop 2764-3107 Sociedade Brasileira de Cardiologia - SBC 10.36660/abchf.20240060i Original Article Heart Failure Treatment with SGLT2 Inhibitors: A Systematic Review with Meta-Analysis 0009-0008-0269-6239 Peres-Filho Fernando Pierin Conception and design of the research Critical revision of the manuscript for content 1 0000-0003-3181-1423 Silva Suelen Umbelino da Analysis and interpretation of the data Statistical analysis Critical revision of the manuscript for content 2 0009-0005-6419-6967 Peres Fernando Pierin Conception and design of the research Critical revision of the manuscript for content 3 0000-0003-0997-084X Kerche Leandra Ernst Conception and design of the research Analysis and interpretation of the data Writing of the manuscript 1 Universidade do Oeste Paulista Departamento de Ciências Funcionais Presidente Prudente SP Brazil Universidade do Oeste Paulista – Departamento de Ciências Funcionais, Presidente Prudente, SP – Brazil Universidade do Oeste Paulista Departamento de Estatística Presidente Prudente SP Brazil Universidade do Oeste Paulista - Departamento de Estatística, Presidente Prudente, SP – Brazil Hospital do Oeste Paulista Departamento de Cardiologia Presidente Prudente SP Brazil Hospital do Oeste Paulista - Departamento de Cardiologia, Presidente Prudente, SP – Brazil : Leandra Ernst Kerche • Universidade do Oeste Paulista - Departamento de Ciências Funcionais – Rua José Bongiovani, 700. Postal Code 19050-920, Presidente Prudente, SP – Brasil E-mail: leakerche@gmail.com

No potential conflict of interest relevant to this article was reported.

Luis Beck-da-Silva

 26 12 2024 2024 4 4 e20240060 17 09 2024 04 11 2024 04 11 2024 This is an open-access article distributed under the terms of the Creative Commons Attribution License Abstract Background

Heart failure (HF) is a clinical diagnosis of a condition that develops secondary to either left ventricular systolic or diastolic functions. Lately, inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been added to the list of drugs used in the management of HF.

 Objectives

To compare the efficacy of SGLT2 inhibitors to traditional treatment in hospitalization and death for HF.

 Methods

Relevant databases were searched for articles published until October 2023. Out of 24 nonduplicated screened studies, 11 studies were selected. The primary analysis was for cardiovascular death, and the secondary analysis was for hospitalization for HF.

 Results

We selected 11 for the systematic review and 8 studies for quantitative analysis, accounting for 54,381 patients from over 800 health centers worldwide. The use of SGLT2 inhibitors significantly reduced cardiovascular death in all patients when compared to placebo (HR 0.85, 95%CI 0.78-0.91) and also reduced hospitalizations for HF (HR 0.71, 95%CI 0.67-0.76).

 Conclusions

Patients with HF in the use of SGLT2 inhibitors have a better outcome than those with conventional treatment; SGLT2 inhibitors protect 15% from cardiovascular death and 29% from hospitalizations.

 Sodium-Glucose Transporter 2 Inhibitors Heart Failure Mortality

: Heart Failure Treatment with SGLT2 Inhibitors: A Systematic Review with Meta-Analysis Cardiovascular death and hospitalizations for any cause in the use of SGLT2 inhibitors and placebo/conventional treatment.

Introduction

Heart failure (HF) is a clinical diagnosis of a condition that develops secondary to either left ventricular (LV) systolic and diastolic functions.1 Although there were significant advancements in therapies designed to prevent and/or treat HF once it is established, patients’ prognosis after the first hospitalization is still poor.2 The underlying causes of chronic HF (CFH) are divided into 4 categories: (i) traditional risk factors such as ischemic injury, hypertension, and metabolic syndrome;3,4 (ii) genetic cardiomyopathies, i.e., hypertrophic cardiomyopathy;5-7 (iii) valve dysfunction, most commonly aortic stenosis;3,4 (iv) autoimmune and infectious triggers where the innate and adaptative immune systems are activated to coordinate a primary response.8,9

CHF diagnosis requires the presence of symptoms, usually breathlessness, fatigue, paroxysmal nocturnal dyspnea, and/or signs of HF, such as elevated jugular venous pressure, hepatojugular reflux, and third heart sound, and objective evidence of cardiac dysfunction that can be presented by BNP ≥ 35 pg/ml (B-type natriuretic peptide), abnormal electrocardiogram and abnormal findings in echocardiography.10 After CHF diagnosis, traditional management consists of using an angiotensin-converting enzyme inhibitor or angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and loop diuretic for fluid retention.11-13

Lately, inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been added to the list of drugs used in the management of HF.10 Studies have shown that SGLT2 inhibitors reduce the risk of hospitalization for HF,14-17 and possible mechanisms of actions have been raised such as effects on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function that are associated with diuretic and hemodynamic actions and preservation of renal function.18-22 Therefore, this work aims to compare the efficacy of SGLT2 inhibitors to traditional treatment in hospitalization and death for HF.

 Methods Search Strategy

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA),23 Meta-Analysis of Observational Studies in Epidemiology (MOOSE),24 and Cochrane25 recommendations, and it was considered exempt from approval by an Institutional Review Board. The guiding question of this review was, “Patients with chronic heart failure using gliflozins have a better outcome than with conventional treatment?”. Two electronic databases (MEDLINE/Pubmed and SciELO) were searched for relevant articles using the following terms: “Heart Failure,”/ “Heart Failure with Reduced Ejection Fraction”/ “SGLT2 inhibitor”/ “Cardiovascular Outcome”/ “Dapagliflozin”/ “Empagliflozin”/ “Sotagliflozin”/ “Ertogliflozin”/ “Type 2 Diabetes”/ “Recommended therapy”/ “Outcome”/ “iSGLT2”/ “Insuficiência Cardíaca Crônica”/ “Gliflozina”/ “Empagloflozina”/ “Dapagliflozina”/ “Melhor prognóstico”/ “Tratamento convencional”. The search was performed from inception to October 2023 in English, Spanish, and Portuguese languages. Figure 1 displays the PRISMA flow diagram. Two pairs of authors independently screened all titles and abstracts, and relevant records were selected for full review.

– PRISMA flowchart. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Eligibility criteria

We included studies that evaluated cardiovascular death and hospitalization due to CHF with the use of traditional treatment and SGLT2 inhibitors. We excluded studies that had unclear reporting data or outcomes of interest or combined outcomes, making it impossible to analyze the data. For quantitative analysis, we excluded that exclusively evaluated subgroup populations that differed from participants in the review. We selected studies with large samples in prospective studies (randomized clinical trials and cohort studies). Retrospective studies, cross-sectional studies, case reports, abstracts, reviews, editorials, and conference reports were excluded.

 Data extraction and risk of bias assessments

Data were gathered by 2 authors using a pre-defined data extraction sheet that included study details, baseline patient demographics, clinical characteristics, and outcomes of interest. Disagreements were resolved by consensus after consulting a senior author. If the baseline patient characteristics were separated by groups, wherever possible, we pooled data attributable to the whole population using mean (SD).26 The 2 authors also assessed the risk of bias in the included studies, according to the criteria from the Cochrane Handbook for Systematic Reviews of Interventions.25

 Statistical analysis

All analyses were performed using Review Manager (RevMan) statistical software version 5.4 (Informer Technologies, Inc., Los Angeles, California, USA). Between-study heterogeneity was assessed with I2 statistic and classified as <25%, indicating low risk of heterogeneity, and > 75% indicated high heterogeneity. The risk of bias analysis was performed using the Risk-of-Bias Tool for Randomized Trials (RoB 2.0),27 which considers five domains for bias assessment: D1 – bias arising from randomization process; D2 – bias due to deviations from intended intervention; D3 – bias due to missing outcome data; D4 – bias in the measurement of the primary outcome; D5 – bias in the selection of the reported result. All the domains were classified as low risk, high risk, or unclear risk (or some concerns) for each of the domains.

 Results Study selection

Electronic searches yielded 24 nonduplicated studies. After the title and abstract assessment, 13 studies were excluded, and 11 were selected for full-text evaluation, and they were deemed eligible to be included in our systematic review. For quantitative analyses, 4 studies were excluded from the meta-analysis. A summary of the 11 selected studies for the systematic review is provided in Table 1.

– Main characteristics and results of the included studies in the systematic review
First author, year (Ref. No.) No. of participants Treatment Group Control Group Treatment in use Control in use Primary Outcome Results
Solomon, 202228 6,263 3,131 3,132 Dapagliflozin 10mg Placebo in addition to usual therapy Cardiovascular death Primary outcome occurred in 512 of 3,131 patients (16.4%) in the treatment group and in 610 of 3,132 patients (19.5%) in the control group (HR 0.82, 95%CI 0.73-0.92, p < 0.001).
Anker, 202129 5,988 2,997 2,991 Empagliflozin 10mg Placebo in addition to usual therapy Cardiovascular death Primary outcome occurred in 415 of 2,997 patients (13.8%) in the treatment group and in 511 of 2,991 patients (17.1%) in the control group (HR 0.79, 95%CI 0.69-0.90, p < 0.001).
Bhatt, 202130 1,222 608 614 Sotagliflozin 200 ou 400mg Placebo HF hospitalization or cardiovascular death Primary outcome occurred in 245 of 608 patients (40.3%) in the treatment group and in 355 of 614 patients (57.8%) in the control group (HR 0.67, 95%CI 0.52-0.85, p < 0.001).
Lee, 202131 105 52 53 Empagliflozin 10mg Placebo Change in LV end-systolic and diastolic volume indexed to body surface area and LV global longitudinal strain Treatment reduced LV end-systolic volume index by 6.0 mL/m2 (p = 0.015) and LV end-diastolic volume index by 8.2 mL/m2 (p = 0.0042). There was no significant difference in LV global longitudinal strain.
Santos-Gallego, 202132 84 42 42 Empagliflozin 10mg Placebo Change in LV systolic and diastolic volume Empagliflozin was associated with a significant reduction of LV end-systolic volume (p < 0.001) and LV end-diastolic volume (p < 0.001).
Cannon, 202033 8,246 5,493 2,745 Ertugliflozin 5 ou 15mg Placebo MACE There was no significant difference between both groups in this study.
Jensen, 202034 190 95 95 Empagliflozin 10mg Placebo Effects of Empagliflozin on NT-proBNP of HF patients There was no significant difference between both groups in this study.
Packer, 202035 3,730 1,863 1,867 Empagliflozin 10mg Placebo in addition to usual therapy HF hospitalization or cardiovascular death Primary outcome occurred in 361 of 1,863 patients (19.4%) in the treatment group and in 462 of 1,867 patients (24.7%) in the control group (HR 0.75, 95%CI 0.65-0.86, p < 0.001).
Mc Murray, 201936 4,744 2,373 2,371 Dapagliflozin 10mg Placebo in addition to usual therapy Cardiovascular death Primary outcome occurred in 386 of 2,373 patients (16.3%) in the treatment group and in 502 of 2,371 patients (21.2%) in the control group (HR 0.74, 95%CI 0.65-0.85, p < 0.001).
Wiviott, 201816 17,160 8,574 8,569 Dapagliflozin 10mg Placebo MACE or death for HF hospitalization Dapagliflozin did not result in a significant lower rate of MACE (HR 0.93, 95%CI 0.84-1.03, p = 0.17), but it did result in a significant lower rate of cardiovascular death for HF hospitalization (HR 0.83, 95%CI 0.73-0.95, p = 0.005).
Zinman, 201514 7,020 4,687 2,333 Empagliflozin 10 or 25mg Placebo MACE Primary outcome occurred in 490 of 4,687 patients (10.5%) in the treatment group and in 282 of 2,333 patients (12.1%) in the control group (HR 0.86, 95%CI 0.74-0.99, p = 0.04).

HF: heart failure; HR: hazard ratio; 95%CI: 95% confidence interval; MACE: major cardiovascular events; LV: left ventricle.

 Study population

This meta-analysis accounted for 54,381 patients from over 800 health centers worldwide, and the mean age was 69 years old for the treatment group and 70 years old for the control group. The population characteristics of the studies are summarized in Table 2.

– Population clinical features of the included studies in the meta-analysis
First author, year No. of participants No. of Centers Age (Mean) SGLT2i Age (Mean) Control Female SGLT2i (%) Female Control (%) Clinical Features SGLT2i (%) Clinical Features Control
Anker, 202129 5,988 622 71.8 71.9 1,338 (44.6) 1,338 (44.7) Mean LV ejection fraction 54.4 Mean LV ejection fraction 54.3
Bhatt, 202130 1,222 306 69.0 70.0 198 (32.6) 214 (34.9) Mean LV ejection fraction 35.0 Mean LV ejection fraction 35.0
Cannon, 202033 8,246 567 64.4 64.4 3,866 (70.3) 1,903 (69.3) Coronary revascularization 57.8 Coronary revascularization 58.7
McMurray, 201936 4,744 410 66.2 66.5 564 (23.8) 545 (23.0) Mean LV ejection fraction 31.2 Mean LV ejection fraction 30.9
Packer, 202035 3,730 520 67.2 66.5 437 (23.5) 456 (24.4) Mean LV ejection fraction 27.7 Mean LV ejection fraction 27.2
Solomon, 202228 6,263 353 71.8 71.5 1,364 (43.6) 1,383 (44.2) Mean LV ejection fraction 54.0 Mean LV ejection fraction 54.3
Wiviott, 201816 17,160 882 63.9 64.0 3,171 (36.9) 3,251 (37.9) Atherosclerotic CV disease 40.5 Atherosclerotic CV disease 40.8
Zinman, 201514 7,020 590 63.0 63.2 1,351 (28.8) 623 (28.0) Atherosclerotic CV disease 75.6 Atherosclerotic CV disease 75.6

SGLT2i: sodium-glucose linked transporter 2 inhibitors; CV: cardiovascular; LV: left ventricle.

 Primary analysis: Cardiovascular death

The analysis of the 8 studies revealed that the use of SGLT2 inhibitors significantly reduced cardiovascular death in all patients when compared to placebo or traditional therapy with low heterogeneity between the studies (HR 0.85, 95%CI 0.78-0.91, I2= 24%) (Figure 2).

– Forest plot comparing cardiovascular death between patients in use of SGLT2 inhibitors and placebo or conventional treatment. 95%CI: 95% confidence interval; HR: hazard ratio; SGLT2: sodium-glucose linked transporter 2.

Secondary analysis: Hospitalization

The analysis of the 8 studies also revealed that the use of SGLT2 inhibitors significantly reduced hospitalization for HF in all patients when compared to placebo or traditional therapy with no heterogeneity between the studies (HR 0.71, 95%CI 0.67-0.76, I2= 0%) (Figure 3).

– Forest plot hospitalization between patients in use of SGLT2 inhibitors and placebo or conventional treatment. 95%CI: 95% confidence interval; HR: hazard ratio; SGLT2: sodium-glucose linked transporter 2.

Risk bias assessments

Great companies and statistical centers supervised all studies used for quantitative analyses; they were all randomized and double-blinded. Therefore, the risk of bias was low for almost all evaluated domains (Figure 4).

– raffic light plot of the risk of bias assessment.

Discussion

HF is a chronic progressive disease that develops over LV systolic and/or diastolic dysfunction that is the leading cause of hospitalization for individuals older than 65 years old.37 The most common causes of hospitalization with HF are noncompliance with medications, diet, activity routines, and failure to report worsening symptoms. Since effective treatments have prolonged the survival of patients with myocardial infarction (MI) and acute coronary syndromes, the incidence of people living with HF is growing, and the number of patients at risk of developing HF is projected to rise dramatically.38

There are many risk factors for the development of HF, and hypertension may be the most important one. As the blood pressure rises and as the patient ages, the risk of developing HF also rises. Long-term treatment for hypertension can decrease HF by approximately 50%, approximately.39 Thus, diabetes mellitus (DM) and metabolic syndrome are also important risk factors for HF since these conditions lead to high blood pressure, high insulin levels, atherosclerosis, coronary artery disease, myocardial ischemia, thrombosis, MI, and other cardiac abnormalities, such as loss of cardiac muscle and ventricular dilation.40,41

Gliflozins or sodium-glucose linked transporter 2 (SGLT2) inhibitors are a class of oral drugs used preferentially in the treatment of type 2 DM.42 Their pharmacodynamics involves the inhibition of SGLT2 channels located in the renal proximal convoluted tubule reducing the renal threshold for glucose excretion from 180 mg/dl for 40 mg/dl.43 The consequence is lower blood glucose levels, reducing glucotoxicity, and improving β-cell function.44 Lately, many clinical trials are showing other effects of these drugs on cardiovascular (CV) outcomes, not only preventing CV diseases but reducing CV death and hospitalization for HF.29-31,36,44

In this meta-analysis, the use of SGLT2 inhibitors significantly reduced the risk of CV death in 15% (HR 0.85, 95%CI 0.78-091) and the hospitalization for HF in 29% (HR 0.71, 95%CI 0.67-0.76). This result corroborates with Zannad et al.45 meta-analyses, where they found a 14% reduction in cardiovascular death (HR 0.86, 95%CI 0.76-0.98) and a 25% decrease in hospitalization for HF (0.75, 95%CI 0.68-0.84). These results combine subgroups of patients that have HF + type 2 DM and patients with only HF. The exact mechanisms by which SGLT2 inhibitors can reduce cardiovascular death are not completely established. However, it seems that it can be related to sodium balance, energy homeostasis, and mitigation of cellular stress, and all of these combined can induce cardio- and nephroprotective effects.46-48

One mechanism that is considered for the action of SGLT2 inhibitor to be beneficial for patients with HF is that SGLT2 colocalizes and functionally interacts with sodium-hydrogen exchanger (NHE) in the proximal renal tubule. The NHE is primarily responsible for the sodium reuptake after filtration.49 In HF, NHE activity is increased, and studies have shown that it may be responsible for resistance to diuretics and endogenous natriuretic peptides in these patients.50,51 However, it has been shown that SGLT2 inhibitors can also interfere with NHE activity, increasing natriuresis that can be potentiated with the use of drugs that block sodium reabsorption in the loop of Henle and distal collecting tubule. This effect largely decreases the intravascular volume, reducing cardiac wall stress and promoting a favorable effect on the development and progression of HF.52,53

This mechanism can also be associated with the reduction of hospitalization in HF patients with and without DM since the combined effect of inhibition of SGLT2 and NHE can attenuate cardiomyocyte injury, reducing, by consequence, cardiac hypertrophy, fibrosis, cardiac remodeling, systolic dysfunction, and HF. All these reductions have benefits on blood pressure, coronary artery occlusion, α- and β-adrenergic stimulation, and diabetes, reducing the risk for hospitalizations.54-61

This study presents limitations that can be highlighted, such as the fact that we only analyzed the endpoints and subgroups that were presented in the publications used in this meta-analysis. Since we did not have access to individual patient data, there was no possibility to perform corrections for the multiplicity of subgroup tests. However, this meta-analysis can complement other meta-analyses of this subject, presenting solid evidence that confirms the important role of SGLT2 inhibitors in the treatment of HF patients with or without type 2 DM to prevent premature cardiovascular death and multiple hospitalizations.

 Conclusions

Patients with HF in the use of SGLT2 inhibitors have a better outcome than with conventional treatment, having a lower risk of cardiovascular death and hospitalizations due to HF symptoms. SGLT2 inhibitors protected 15% from cardiovascular death and 29% from hospitalizations.

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Salvatore T Carbonara O Cozzolino D Torella R Nasti R Lascar N et al Kidney in Diabetes: From Organ Damage Target to Therapeutic Target Curr Drug Metab 2011 12 7 658 666 10.2174/138920011796504509 43. DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, et al. Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects with Type 2 Diabetes. Diabetes Care. 2013;36(10):3169-76. doi: 10.2337/dc13-0387. DeFronzo RA Hompesch M Kasichayanula S Liu X Hong Y Pfister M et al Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects with Type 2 Diabetes Diabetes Care 2013 36 10 3169 3176 10.2337/dc13-0387 44. Salvatore T, Galiero R, Caturano A, Rinaldi L, Di Martino A, Albanese G, et al. An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors. Int J Mol Sci. 2022;23(7):3651. doi: 10.3390/ijms23073651. 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Circulation. 2020;142(11):1028-39. doi: 10.1161/CIRCULATIONAHA.120.045691. Griffin M Rao VS Ivey-Miranda J Fleming J Mahoney D Maulion C et al Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects Circulation 2020 142 11 1028 1039 10.1161/CIRCULATIONAHA.120.045691 49. Layton AT, Vallon V, Edwards A. Modeling Oxygen Consumption in the Proximal Tubule: Effects of NHE and SGLT2 Inhibition. Am J Physiol Renal Physiol. 2015;308(12):F1343-57. doi: 10.1152/ajprenal.00007.2015. Layton AT Vallon V Edwards A Modeling Oxygen Consumption in the Proximal Tubule: Effects of NHE and SGLT2 Inhibition Am J Physiol Renal Physiol 2015 308 12 F1343 F1357 10.1152/ajprenal.00007.2015 50. Inoue BH, Santos L, Pessoa TD, Antonio EL, Pacheco BP, Savignano FA, et al. Increased NHE3 Abundance and Transport Activity in Renal Proximal Tubule of Rats with Heart Failure. Am J Physiol Regul Integr Comp Physiol. 2012;302(1):R166-74. doi: 10.1152/ajpregu.00127.2011. Inoue BH Santos L Pessoa TD Antonio EL Pacheco BP Savignano FA et al Increased NHE3 Abundance and Transport Activity in Renal Proximal Tubule of Rats with Heart Failure Am J Physiol Regul Integr Comp Physiol 2012 302 1 R166 R174 10.1152/ajpregu.00127.2011 51. Lütken SC, Kim SW, Jonassen T, Marples D, Knepper MA, Kwon TH, et al. Changes of Renal AQP2, ENaC, and NHE3 in Experimentally Induced Heart Failure: Response to Angiotensin II AT1 Receptor Blockade. Am J Physiol Renal Physiol. 2009;297(6):F1678-88. doi: 10.1152/ajprenal.00010.2009. Lütken SC Kim SW Jonassen T Marples D Knepper MA Kwon TH et al Changes of Renal AQP2, ENaC, and NHE3 in Experimentally Induced Heart Failure: Response to Angiotensin II AT1 Receptor Blockade Am J Physiol Renal Physiol 2009 297 6 F1678 F1688 10.1152/ajprenal.00010.2009 52. Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, et al. Acute Pharmacodynamic Effects of Empagliflozin with and without Diuretic Agents in Patients with Type 2 Diabetes Mellitus. Clin Ther. 2016;38(10):2248-2264.e5. doi: 10.1016/j.clinthera.2016.08.008. Heise T Jordan J Wanner C Heer M Macha S Mattheus M et al Acute Pharmacodynamic Effects of Empagliflozin with and without Diuretic Agents in Patients with Type 2 Diabetes Mellitus Clin Ther 2016 38 10 2248 2264 e5 10.1016/j.clinthera.2016.08.008 53. Imai T, Akimoto T, Ito C, Masuda T, Nagata D. Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention. Drug Target Insights. 2015;9:29-31. doi: 10.4137/DTI.S31710. Imai T Akimoto T Ito C Masuda T Nagata D Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention Drug Target Insights 2015 9 29 31 10.4137/DTI.S31710 54. 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Enhanced Activity of the Myocardial Na+/H+ Exchanger Contributes to Left Ventricular Hypertrophy in the Goto-Kakizaki Rat Model of Type 2 Diabetes: Critical Role of Akt. Diabetologia. 2007;50(6):1335-44. doi: 10.1007/s00125-007-0628-x. Darmellah A Baetz D Prunier F Tamareille S Rücker-Martin C Feuvray D Enhanced Activity of the Myocardial Na+/H+ Exchanger Contributes to Left Ventricular Hypertrophy in the Goto-Kakizaki Rat Model of Type 2 Diabetes: Critical Role of Akt Diabetologia 2007 50 6 1335 1344 10.1007/s00125-007-0628-x 58. Aker S, Snabaitis AK, Konietzka I, van de Sand A, Böngler K, Avkiran M, et al. Inhibition of the Na+/H+ Exchanger Attenuates the Deterioration of Ventricular Function During Pacing-Induced Heart Failure in Rabbits. Cardiovasc Res. 2004;63(2):273-82. doi: 10.1016/j.cardiores.2004.04.014. 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This article is part of the thesis of master submitted by Fernando Pierin Peres Filho, from Universidade do Oeste Paulista.

This article does not contain any studies with human participants or animals performed by any of the authors.

There were no external funding sources for this study.

 10.36660/abchf.20240060 Artigo Original Tratamento da Insuficiência Cardíaca com Inibidores de SGLT2: Uma Revisão Sistemática com Metanálise 0009-0008-0269-6239 Peres-Filho Fernando Pierin Concepção e desenho da pesquisa Obtenção de dados Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0003-3181-1423 Silva Suelen Umbelino da Obtenção de dados Análise e interpretação dos dados Análise estatística Revisão crítica do manuscrito quanto ao conteúdo 2 0009-0005-6419-6967 Peres Fernando Pierin Concepção e desenho da pesquisa Obtenção de dados Revisão crítica do manuscrito quanto ao conteúdo 3 0000-0003-0997-084X Kerche Leandra Ernst Concepção e desenho da pesquisa Obtenção de dados Análise e interpretação dos dados Redação do manuscrito 1 Brasil Universidade do Oeste Paulista – Departamento de Ciências Funcionais, Presidente Prudente, SP – Brasil Brasil Universidade do Oeste Paulista – Departamento de Estatística, Presidente Prudente, SP – Brasil Brasil Hospital do Oeste Paulista – Departamento de Cardiologia, Presidente Prudente, SP – Brasil : Leandra Ernst Kerche • Universidade do Oeste Paulista - Departamento de Ciências Funcionais – Rua José Bongiovani, 700. CEP 19050-920, Presidente Prudente, SP – Brasil E-mail: leakerche@gmail.com

Luis Beck-da-Silva

Não há conflito com o presente artigo

 Resumo Fundamento

A insuficiência cardíaca (IC) é um diagnóstico clínico de uma condição que se desenvolve secundariamente às funções sistólica ou diastólica do ventrículo esquerdo. Ultimamente, inibidores do cotransportador de sódio-glicose 2 (SGLT2) foram adicionados à lista de medicamentos usados no tratamento da IC.

 Objetivos

Comparar a eficácia dos inibidores de SGLT2 ao tratamento tradicional em hospitalização e morte por IC.

 Métodos

Bancos de dados relevantes foram pesquisados para artigos publicados até outubro de 2023. De 24 estudos selecionados não duplicados, 11 estudos foram selecionados. A análise primária foi para morte cardiovascular, e a análise secundária foi para hospitalização por IC.

 Resultados

Selecionamos 11 para a revisão sistemática e 8 estudos para análise quantitativa, contabilizando 54.381 pacientes de mais de 800 centros de saúde em todo o mundo. O uso de inibidores de SGLT2 reduziu significativamente a morte cardiovascular em todos os pacientes quando comparado ao placebo (HR 0,85, IC 95% 0,78-0,91) e reduziu as hospitalizações por IC (HR 0,71, IC 95% 0,67-0,76).

 Conclusões

Pacientes com IC em uso de inibidores de SGLT2 apresentam melhor evolução do que aqueles com tratamento convencional; os inibidores de SGLT2 protegem 15% de morte cardiovascular e 29% de hospitalizações.

 Inibidores do Transportador 2 de Sódio-Glicose Insuficiência cardíaca Mortalidade

: Tratamento da Insuficiência Cardíaca com Inibidores de SGLT2: Uma Revisão Sistemática com Metanálise Morte cardiovascular e hospitalizações por qualquer causa no uso de inibidores de SGLT2 e tratamento placebo/convencional.

Introdução

A insuficiência cardíaca (IC) é um diagnóstico clínico de uma condição que se desenvolve secundariamente às funções sistólica e diastólica do ventrículo esquerdo (VE).1 Embora tenha havido avanços significativos em terapias projetadas para prevenir e/ou tratar a IC uma vez estabelecida, o prognóstico dos pacientes após a primeira hospitalização ainda é ruim.2 As causas subjacentes da IC crônica (ICC) são divididas em 4 categorias: (i) fatores de risco tradicionais, como lesão isquêmica, hipertensão e síndrome metabólica;3,4 (ii) cardiomiopatias genéticas, ou seja, cardiomiopatia hipertrófica;5-7 (iii) disfunção valvar, mais comumente estenose aórtica;3,4 (iv) gatilhos autoimunes e infecciosos onde os sistemas imunológicos inato e adaptativo são ativados para coordenar uma resposta primária.8,9

O diagnóstico de ICC requer a presença de sintomas, geralmente falta de ar, fadiga, dispneia paroxística noturna e/ou sinais de IC, como pressão venosa jugular elevada, refluxo hepatojugular e terceira bulha cardíaca, e evidência objetiva de disfunção cardíaca que pode ser apresentada por BNP ≥ 35 pg/ml (peptídeo natriurético tipo B), eletrocardiograma anormal e achados anormais na ecocardiografia.10 Após o diagnóstico de ICC, o tratamento tradicional consiste no uso de um inibidor da enzima de conversão da angiotensina ou inibidor do receptor da angiotensina-neprilisina, betabloqueador, antagonista do receptor mineralocorticoide e diurético de alça para retenção de líquidos.11-13

Ultimamente, os inibidores do cotransportador sódio-glicose 2 (SGLT2) foram adicionados à lista de medicamentos utilizados no tratamento da IC.10 Estudos demonstraram que os inibidores do SGLT2 reduzem o risco de hospitalização por IC,14-17 e possíveis mecanismos de ação foram levantados, como efeitos no metabolismo miocárdico, transportadores de íons, fibrose, adipocinas e função vascular que estão associados a ações diuréticas e hemodinâmicas e preservação da função renal.18-22 Portanto, este trabalho tem como objetivo comparar a eficácia dos inibidores do SGLT2 ao tratamento tradicional em hospitalização e morte por IC.

 Métodos Estratégia de busca

Este estudo foi conduzido de acordo com as recomendações Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA),23 Meta-Analysis of Observational Studies in Epidemiology (MOOSE)24 e Cochrane,25 e foi considerado isento de aprovação por um Conselho de Revisão Institucional. A questão norteadora desta revisão foi: “Pacientes com insuficiência cardíaca crônica usando gliflozinas têm um resultado melhor do que com tratamento convencional?”. Duas bases de dados eletrônicas (MEDLINE/Pubmed e SciELO) foram pesquisadas para artigos relevantes usando os seguintes termos: “Heart Failure,”/ “Heart Failure with Reduced Ejection Fraction”/ “SGLT2 inhibitor”/ “Cardiovascular Outcome”/ “Dapagliflozin”/ “Empagliflozin”/ “Sotagliflozin”/ “Ertogliflozin”/ “Type 2 Diabetes”/ “Recommended therapy”/ “Outcome”/ “iSGLT2”/ “Insuficiência Cardíaca Crônica”/ “Gliflozina”/ “Empagloflozina”/ “Dapagliflozina”/ “Melhor prognóstico”/ “Tratamento convencional”. A busca foi realizada desde o início até outubro de 2023 em inglês, espanhol e português. A Figura 1 exibe o diagrama de fluxo PRISMA. Dois pares de autores selecionaram independentemente todos os títulos e resumos, e os registros relevantes foram selecionados para revisão completa.

– Fluxograma PRISMA. PRISMA = Itens de Relatórios Preferenciais para Revisões Sistemáticas e Metanálises.

Critérios de elegibilidade

Incluímos estudos que avaliaram morte cardiovascular e hospitalização devido a ICC com o uso de tratamento tradicional e inibidores de SGLT2. Excluímos estudos que tinham dados de relatórios pouco claros ou resultados de interesse ou resultados combinados, impossibilitando a análise dos dados. Para análise quantitativa, excluímos aqueles que avaliaram exclusivamente populações de subgrupos que diferiam dos participantes na revisão. Selecionamos estudos com grandes amostras em estudos prospectivos (ensaios clínicos randomizados e estudos de coorte). Estudos retrospectivos, estudos transversais, relatos de caso, resumos, revisões, editoriais e relatórios de conferências foram excluídos.

 Extração de dados e avaliações de risco de viés

Os dados foram coletados por 2 autores usando uma planilha de extração de dados predefinida que incluía detalhes do estudo, dados demográficos basais dos pacientes, características clínicas e resultados de interesse. As discordâncias foram resolvidas por consenso após consulta a um autor sênior. Se as características basais dos pacientes fossem separadas por grupos, sempre que possível, reunimos dados atribuíveis a toda a população usando média (DP).26 Os 2 autores também avaliaram o risco de viés nos estudos incluídos, de acordo com os critérios do Cochrane Handbook for Systematic Reviews of Interventions.25 Análise estatística

Todas as análises foram realizadas usando o software estatístico Review Manager (RevMan) versão 5.4 (Informer Technologies, Inc., Los Angeles, Califórnia, EUA). A heterogeneidade entre estudos foi avaliada com estatística I2 e classificada como <25%, indicando baixo risco de heterogeneidade, e >75% indicaram alta heterogeneidade. A análise de risco de viés foi realizada usando a Risk-of-Bias Tool for Randomized Trials (RoB 2.0),27 que considera cinco domínios para avaliação de viés: D1 – viés decorrente do processo de randomização; D2 – viés devido a desvios da intervenção pretendida; D3 – viés devido a dados de desfecho ausentes; D4 – viés na medição do desfecho primário; D5 – viés na seleção do resultado relatado. Todos os domínios foram classificados como baixo risco, alto risco ou risco pouco claro (ou algumas preocupações) para cada um dos domínios.

 Resultados Seleção de estudo

As buscas eletrônicas renderam 24 estudos não duplicados. Após a avaliação do título e do resumo, 13 estudos foram excluídos, e 11 foram selecionados para avaliação do texto completo, e foram considerados elegíveis para inclusão em nossa revisão sistemática. Para análises quantitativas, 4 estudos foram excluídos da metanálise. Um resumo dos 11 estudos selecionados para a revisão sistemática é fornecido na Tabela 1.

– Principais características e resultados dos estudos incluídos na revisão sistemática
Primeiro autor, ano (Número de ref.) Nº de participantes Tratamento Grupo Grupo de controle Tratamento em uso Controle em uso Resultado Primário Resultados
Solomon, 202228 6.263 3.131 3.132 Dapagliflozina 10mg Placebo além da terapia usual Morte cardiovascular O desfecho primário ocorreu em 512 de 3.131 pacientes (16,4%) no grupo de tratamento e em 610 de 3.132 pacientes (19,5%) no grupo de controle (HR 0,82, IC 95% 0,73-0,92, p < 0,001).
Anker, 202129 5.988 2.997 2.991 Empagliflozina 10mg Placebo além da terapia usual Morte cardiovascular O desfecho primário ocorreu em 415 de 2.997 pacientes (13,8%) no grupo de tratamento e em 511 de 2.991 pacientes (17,1%) no grupo de controle (HR 0,79, IC 95% 0,69-0,90, p < 0,001).
Bhatt, 202130 1.222 608 614 Sotagliflozina 200 ou 400mg Placebo Hospitalização por IC ou morte cardiovascular O desfecho primário ocorreu em 245 de 608 pacientes (40,3%) no grupo de tratamento e em 355 de 614 pacientes (57,8%) no grupo de controle (HR 0,67, IC 95% 0,52-0,85, p < 0,001).
Lee, 202131 105 52 53 Empagliflozina 10mg Placebo Alteração no volume sistólico e diastólico final do VE indexado à área de superfície corporal e à deformação longitudinal global do VE O tratamento reduziu o índice de volume sistólico final do VE em 6,0 mL/m2 (p = 0,015) e o índice de volume diastólico final do VE em 8,2 mL/m2 (p = 0,0042). Não houve diferença significativa na deformação longitudinal global do VE.
Santos-Gallego, 202132 84 42 42 Empagliflozina 10mg Placebo Alteração no volume sistólico e diastólico do VE A empagliflozina foi associada a uma redução significativa do volume sistólico final do VE (p < 0,001) e do volume diastólico final do VE (p < 0,001).
Cannon, 202033 8.246 5.493 2.745 Ertugliflozina 5 ou 15mg Placebo MACE Não houve diferença significativa entre os dois grupos neste estudo.
Jensen, 202034 190 95 95 Empagliflozina 10mg Placebo Efeitos da empagliflozina no NT-proBNP de pacientes com IC Não houve diferença significativa entre os dois grupos neste estudo.
Packer, 202035 3.730 1.863 1.867 Empagliflozina 10mg Placebo além da terapia usual Hospitalização por IC ou morte cardiovascular O desfecho primário ocorreu em 361 de 1.863 pacientes (19,4%) no grupo de tratamento e em 462 de 1.867 pacientes (24,7%) no grupo de controle (HR 0,75, IC 95% 0,65-0,86, p < 0,001).
Mc Murray, 201936 4.744 2.373 2.371 Dapagliflozina 10mg Placebo além da terapia usual Morte cardiovascular O desfecho primário ocorreu em 386 de 2.373 pacientes (16,3%) no grupo de tratamento e em 502 de 2.371 pacientes (21,2%) no grupo de controle (HR 0,74, IC 95% 0,65-0,85, p < 0,001).
Wiviott, 201816 17.160 8.574 8.569 Dapagliflozina 10mg Placebo MACE ou morte por hospitalização por IC A dapagliflozina não resultou em uma taxa significativamente menor de MACE (HR 0,93, IC 95% 0,84-1,03, p = 0,17), mas resultou em uma taxa significativamente menor de morte cardiovascular para hospitalização por IC (HR 0,83, IC 95% 0,73-0,95, p = 0,005).
Zinman, 201514 7.020 4.687 2.333 Empagliflozina 10 ou 25mg Placebo MACE O desfecho primário ocorreu em 490 de 4.687 pacientes (10,5%) no grupo de tratamento e em 282 de 2.333 pacientes (12,1%) no grupo de controle (HR 0,86, IC 95% 0,74-0,99, p = 0,04).

IC: insuficiência cardíaca; HR: razão de risco; IC 95%: intervalo de confiança de 95%; MACE: eventos cardiovasculares maiores; VE: ventrículo esquerdo.

 População do estudo

Esta metanálise foi responsável por 54.381 pacientes de mais de 800 centros de saúde em todo o mundo, e a idade média foi de 69 anos para o grupo de tratamento e 70 anos para o grupo de controle. As características populacionais dos estudos estão resumidas na Tabela 2.

– Características clínicas populacionais dos estudos incluídos na metanálise
Primeiro autor, ano Nº de participantes Nº de Centros Idade (média) SGLT2i Idade (média) Controle Feminino SGLT2i (%) Feminino Controle (%) Características clínicas SGLT2i (%) Características Clínicas de Controle
Anker, 202129 5.988 622 71,8 71,9 1.338 (44,6) 1.338 (44,7) Fração média de ejeção do VE 54,4 Fração média de ejeção do VE 54,3
Bhatt, 202130 1.222 306 69,0 70,0 198 (32,6) 214 (34,9) Fração média de ejeção do VE 35,0 Fração média de ejeção do VE 35,0
Cannon, 202033 8.246 567 64,4 64,4 3.866 (70,3) 1.903 (69,3) Revascularização coronária 57,8 Revascularização coronária 58,7
McMurray, 201936 4.744 410 66,2 66,5 564 (23,8) 545 (23,0) Fração média de ejeção do VE 31.2 Fração média de ejeção do VE 30,9
Packer, 202035 3.730 520 67,2 66,5 437 (23,5) 456 (24,4) Fração média de ejeção do VE 27,7 Fração média de ejeção do VE 27.2
Solomon, 202228 6.263 353 71,8 71,5 1.364 (43,6) 1.383 (44,2) Fração média de ejeção do VE 54,0 Fração média de ejeção do VE 54,3
Wiviott, 201816 17.160 882 63,9 64,0 3.171 (36,9) 3.251 (37,9) Doença cardiovascular aterosclerótica 40,5 Doença cardiovascular aterosclerótica 40,8
Zinman, 201514 7.020 590 63,0 63,2 1.351 (28,8) 623 (28,0) Doença cardiovascular aterosclerótica 75,6 Doença cardiovascular aterosclerótica 75,6

SGLT2i: inibidores do transportador ligado à glicose e sódio 2; VE: ventrículo esquerdo.

 Análise primária: Morte cardiovascular

A análise dos 8 estudos revelou que o uso de inibidores de SGLT2 reduziu significativamente a morte cardiovascular em todos os pacientes quando comparado ao placebo ou à terapia tradicional, com baixa heterogeneidade entre os estudos (HR 0,85, IC 95% 0,78-0,91, I2 = 24%) (Figura 2).

– Gráfico de floresta comparando morte cardiovascular entre pacientes em uso de inibidores de SGLT2 e placebo ou tratamento convencional. IC 95%: intervalo de confiança de 95%; HR: razão de risco; SGLT2: transportador ligado a sódio-glicose 2.

Análise secundária: Hospitalização

A análise dos 8 estudos também revelou que o uso de inibidores de SGLT2 reduziu significativamente a hospitalização por IC em todos os pacientes quando comparado ao placebo ou à terapia tradicional, sem heterogeneidade entre os estudos (HR 0,71, IC 95% 0,67-0,76, I2 = 0%) (Figura 3).

– Gráfico de floresta de hospitalização entre pacientes em uso de inibidores de SGLT2 e placebo ou tratamento convencional. IC 95%: intervalo de confiança de 95%; HR: razão de risco; SGLT2: transportador ligado a sódio-glicose 2.

Avaliações de viés de risco

Grandes empresas e centros estatísticos supervisionaram todos os estudos usados para análises quantitativas; todos eles foram randomizados e duplo-cegos. Portanto, o risco de viés foi baixo para quase todos os domínios avaliados (Figura 4).

– Gráfico de semáforo da avaliação de risco de viés.

Discussão

A IC é uma doença crônica progressiva que se desenvolve sobre disfunção sistólica e/ou diastólica do VE, sendo a principal causa de hospitalização para indivíduos com mais de 65 anos.37 As causas mais comuns de hospitalização com IC são a não adesão a medicamentos, dieta, rotinas de atividade e falha em relatar sintomas de piora. Como tratamentos eficazes prolongaram a sobrevivência de pacientes com infarto do miocárdio (IM) e síndromes coronarianas agudas, a incidência de pessoas vivendo com IC está crescendo, e o número de pacientes em risco de desenvolver IC deve aumentar drasticamente.38

Existem muitos fatores de risco para o desenvolvimento de IC, e a hipertensão pode ser o mais importante. À medida que a pressão arterial aumenta e o paciente envelhece, o risco de desenvolver IC também aumenta. O tratamento de longo prazo para hipertensão pode diminuir a IC em aproximadamente 50%, aproximadamente.39 Assim, diabetes mellitus (DM) e síndrome metabólica também são fatores de risco importantes para IC, uma vez que essas condições levam à pressão alta, altos níveis de insulina, aterosclerose, doença arterial coronariana, isquemia miocárdica, trombose, IM e outras anormalidades cardíacas, como perda de músculo cardíaco e dilatação ventricular.40,41

As gliflozinas ou inibidores do transportador ligado à glicose e sódio 2 (SGLT2) são uma classe de medicamentos orais usados preferencialmente no tratamento do DM tipo 2.42 Sua farmacodinâmica envolve a inibição dos canais SGLT2 localizados no túbulo contorcido proximal renal, reduzindo o limiar renal para excreção de glicose de 180 mg/dl para 40 mg/dl.43 A consequência são níveis mais baixos de glicose no sangue, reduzindo a glicotoxicidade e melhorando a função das células β.44 Ultimamente, muitos ensaios clínicos estão mostrando outros efeitos desses medicamentos nos resultados cardiovasculares (CV), não apenas prevenindo doenças CV, mas reduzindo a morte CV e a hospitalização por IC.29-31,36,44

Nesta metanálise, o uso de inibidores de SGLT2 reduziu significativamente o risco de morte CV em 15% (HR 0,85, IC 95% 0,78-0,91) e a hospitalização por IC em 29% (HR 0,71, IC 95% 0,67-0,76). Este resultado corrobora com as metanálises de Zannad et al.,45 onde encontraram uma redução de 14% na morte cardiovascular (HR 0,86, IC 95% 0,76-0,98) e uma diminuição de 25% na hospitalização por IC (0,75, IC 95% 0,68-0,84). Estes resultados combinam subgrupos de pacientes que têm IC + DM tipo 2 e pacientes com apenas IC. Os mecanismos exatos pelos quais os inibidores de SGLT2 podem reduzir a morte cardiovascular não estão completamente estabelecidos. No entanto, parece que pode estar relacionado ao equilíbrio de sódio, à homeostase energética e à mitigação do estresse celular, e todos esses efeitos combinados podem induzir efeitos cardio e nefroprotetores.46-48

Um mecanismo que é considerado para a ação do inibidor de SGLT2 ser benéfico para pacientes com IC é que o SGLT2 colocaliza e interage funcionalmente com o trocador de sódio-hidrogênio (NHE) no túbulo renal proximal. O NHE é o principal responsável pela recaptação de sódio após a filtração.49 Na IC, a atividade do NHE é aumentada, e estudos têm mostrado que ele pode ser responsável pela resistência a diuréticos e peptídeos natriuréticos endógenos nesses pacientes.50,51 No entanto, foi demonstrado que os inibidores de SGLT2 também podem interferir na atividade do NHE, aumentando a natriurese que pode ser potencializada com o uso de drogas que bloqueiam a reabsorção de sódio na alça de Henle e no túbulo coletor distal. Esse efeito diminui amplamente o volume intravascular, reduzindo o estresse da parede cardíaca e promovendo um efeito favorável no desenvolvimento e progressão da IC.52,53

Este mecanismo também pode estar associado à redução de hospitalização em pacientes com IC com e sem DM, uma vez que o efeito combinado da inibição do SGLT2 e do NHE pode atenuar a lesão dos cardiomiócitos, reduzindo, por consequência, a hipertrofia cardíaca, a fibrose, a remodelação cardíaca, a disfunção sistólica e a IC. Todas essas reduções têm benefícios sobre a pressão arterial, a oclusão da artéria coronária, a estimulação α- e β-adrenérgica e o diabetes, reduzindo o risco de hospitalizações.54-61

Este estudo apresenta limitações que podem ser destacadas, como o fato de termos analisado apenas os endpoints e subgrupos que foram apresentados nas publicações utilizadas nesta metanálise. Como não tivemos acesso aos dados individuais dos pacientes, não houve possibilidade de realizar correções para a multiplicidade de testes de subgrupos. No entanto, esta metanálise pode complementar outras metanálises deste assunto, apresentando evidências sólidas que confirmam o importante papel dos inibidores de SGLT2 no tratamento de pacientes com IC com ou sem DM tipo 2 para prevenir morte cardiovascular prematura e múltiplas hospitalizações.

 Conclusões

Pacientes com IC em uso de inibidores de SGLT2 apresentam melhor desfecho do que com tratamento convencional, tendo menor risco de morte cardiovascular e hospitalizações devido aos sintomas de IC. Os inibidores de SGLT2 protegeram 15% de morte cardiovascular e 29% de hospitalizações.

Este artigo é parte de trabalho de conclusão de curso de Fernando Pierin Peres Filho pela Universidade do Oeste Paulista.

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

O presente estudo não teve fontes de financiamento externas.