Effects of Empagliflozin in Different Phases of Diabetes Mellitus-related Cardiomyopathy

Effects of Empagliflozin in Different Phases of Diabetes Mellitus-related Cardiomyopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Original investigation Effects of Empagliflozin in Different Phases of Diabetes Mellitus-related Cardiomyopathy Satoshi Oka, Takahiko Kai, Katsuomi Hoshino, Kazunori Watanabe, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-117825/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: In diabetes mellitus-related cardiomyopathy (DMCMP), hyperglycemia causes endothelial dysfunction, fibrosis, and myocardial injury, which result in left ventricular (LV) dysfunction. Treatment with sodium–glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of heart failure (HF). The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also direct actions on the myocardium leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP. Methods: Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction (EF) greater than 40% and type 2 diabetes mellitus (T2DM) treated with administration of empagliflozin (10 mg/day) were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the patients were divided into the early DMCMP group (n = 16, ECV ≤ 30%) and advanced DMCMP group (n = 19, ECV > 30%) and followed-up prospectively. Echocardiography was performed at baseline and after 12 months. LV systolic function assessed as LV global longitudinal strain (GLS) and diastolic function assessed as the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) were compared. Results: ECV was strongly correlated with T2DM duration (r 2 = 0.65, p < 0.001). At baseline, both groups had similar backgrounds (LVGLS: 7.9 ± 2.4% vs. 6.7 ± 3.0%, p = 0.207, and E/e’: 13.2 ± 6.1 cm/s vs. 12.6 ± 3.8 cm/s, p = 0.694). After 12 months, the early DMCMP group showed greater improvement in LVGLS (ΔLVGLS: 4.6 ± 1.5% vs. 1.6 ± 3.3%, p = 0.003) and E/e’ (ΔE/e’: -3.4 ± 5.5 cm/s vs. -0.1 ± 3.5 cm/s, p = 0.043) than in the advanced DMCMP group. Conclusion: The positive effects of empagliflozin on LV dysfunction were more remarkable in DMCMP with mild cardiac fibrosis than with advanced fibrosis. Early intervention of SGLT2i for DMCMP is preferable. Cardiac & Cardiovascular Systems Diabetes mellitus-related cardiomyopathy Heart failure Sodium–glucose co-transporter 2 inhibitor Left ventricular dysfunction Left ventricular global longitudinal strain Figures Figure 1 Figure 1 Figure 1 Figure 2 Figure 2 Figure 2 Figure 3 Figure 3 Figure 3 Background Type 2 diabetes mellitus (T2DM) is an important risk factor for the development of cardiovascular disease and heart failure (HF) [ 1 ]. Diabetes mellitus-related cardiomyopathy (DMCMP), which manifests as left ventricular (LV) dysfunction that cannot be ascribed to hypertension, coronary artery disease, or significant valvular disease, is well described. Hyperglycemia drives microvascular endothelial dysfunction, LV dysfunction, and LV remodeling through progresses of myocardial hypertrophy, cardiomyocyte stiffening, and interstitial fibrosis, which lead to DMCMP with HF with preserved ejection fraction (HFpEF) phenotype [ 2 ]. Decreased LV global longitudinal strain (GLS) and the increased ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) are observed as signs of LV dysfunction from the early phase of DMCMP [ 3 , 4 ]. If LV remodeling progresses, DMCMP turns to HF with reduced ejection fraction (HFrEF) phenotype [ 2 ]. Several mega-trials have shown that treatment with sodium–glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of major adverse cardiovascular events, including exacerbation of HF [ 5 – 7 ]. Furthermore, it was recently shown that SGLT2i treatment was associated with lowering the risk of cardiovascular death and hospitalization for HFrEF consistently from the early to late phases after administration, regardless of the presence or absence of T2DM [ 8 , 9 ]. Thus, the beneficial effects of SGLT2i treatment on HF are not explained only by their actions on glycemic control or osmotic diuresis, but also by their direct actions on the myocardium [ 10 , 11 ]. One example of these is inhibition of the sodium-hydrogen exchanger (NHE), which may in turn lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and LV dysfunction [ 12 ]. However, it remains unclear whether SGLT2i treatment is equally effective for all patients with DMCMP. The aim of this cohort study was to compare the efficacy of SGLT2i treatment on LV dysfunction between the early and advanced phases of DMCMP. Methods Patients This was a prospective observational study conducted at a single center. Consecutive symptomatic HF patients with T2DM who were hospitalized in Fujieda Municipal General Hospital (Japan) and treated with administration of empagliflozin (at a dose of 10 mg daily) were screened for eligibility. The diagnosis of T2DM was based on the World Health Organization criteria [ 13 ]. After the cardiac assessment, patients diagnosed with DMCMP with LV ejection fraction (EF) greater than 40% were enrolled. Cardiac magnetic resonance (CMR) was performed in all participants, and their myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis, was evaluated. According to previous reports [ 14 , 15 ], global ECV > 30% was considered elevated with advanced replacement myocardial fibrosis. Therefore, the patients were divided into the early DMCMP group (global ECV ≤ 30%) and advanced DMCMP group (global ECV > 30%) and followed-up prospectively. Exclusion criteria were as follows: (1) age less than 20 or greater than 80 years, (2) in-hospital death, (3) New York Heart Association (NYHA) class I or brain natriuretic peptide (BNP) < 100 pg/mL, (4) LVEF ≤ 40%, (5) other cardiomyopathies, (6) valvular or congenital heart disease, (7) normal LV systolic function: LVGLS (absolute value) ≥ 18% [ 3 ], (8) type 1 diabetes mellitus or insulin-dependent T2DM: C-peptide immunoreactivity index < 0.8 [ 16 ] or insulin user, (9) newly diagnosed T2DM (less than 1 year) or no antidiabetic medications before administration of empagliflozin, (10) current or previous use of SGLT2i, (11) persistent arrhythmia, (12) pacemaker implantation, (13) contraindication for CMR (implanted metallic objects, allergy to contrast media, and bronchial asthma), (14) estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m 2 , (15) malignant tumor or inflammatory disease, (16) pregnancy, (17) refusal to informed consent, and (18) prior history of myocardial infarction, cerebral infarction, pancreatitis, and hospitalization for HF. For the exclusion of ischemic cardiomyopathy, coronary angiography was performed in all participants. Patients with ≥ 90% coronary artery stenosis were excluded. Patients with 75% stenosis were also excluded if functional ischemia was proven by over 10% ischemic area matched with angiography in myocardial perfusion scintigraphy. For the exclusion of hypertensive heart disease, patients with diastolic blood pressure ≥ 90 mmHg were excluded [ 2 ]. For the exclusion of other cardiomyopathies, patients with regional LV wall motion abnormalities, late gadolinium enhancement (LGE), excessive LV dilatation (LV end-diastolic volume index: > 97 mL/m 2 [ 2 ]), and excessive LV hypertrophy (LV myocardial mass index: > 69 g/m 2 for women or 91 g/m 2 for men [ 17 ]) as evaluated by CMR were not included. Outcomes The primary outcome was the improvement in LV function, defined as changes in LV systolic function assessed as LVGLS, and diastolic function assessed as E/e’ between baseline and 12 months after the administration of empagliflozin. The secondary outcomes were the NYHA class after 12 months and the changes in glycated hemoglobin (HbA1c) and BNP levels between baseline and after 12 months. Anthropometrics and blood examination At the time of enrollment, age, gender, height, body weight, blood pressure, and heart rate of all participants were recorded. NYHA class and blood samples including hemoglobin, HbA1c, sodium, eGFR, and BNP at admission were used as baseline data. Fasting C-peptide and plasma glucose was checked with hematocrit at the time of CMR, and the C-peptide immunoreactivity index was calculated using the following formula: fasting C-peptide/fasting plasma glucose × 100. Serum HbA1c and BNP levels were measured routinely at baseline and at 12 months. Ultrasonic echocardiography Ultrasonic echocardiography was performed at baseline and after 12 months using an Aplio 400® (Canon Medical Systems Corporation, Tochigi, Japan) by two cardiac ultrasonographers who were blinded to the patients' backgrounds. Two-dimensional gray-scale cine loops from three consecutive heartbeats were obtained at end-expiratory apnea from standard parasternal and apical views. According to the guidelines of the American Society of Echocardiography/European Association of Cardiovascular Imaging [ 18 ], standard echocardiographic measurements were performed. LVEF was measured using the modified Simpson method. The E-wave velocity was measured using pulsed-wave Doppler recording from the apical four-chamber view. Spectral pulsed-wave Doppler-derived e’ was obtained by averaging the septal and lateral mitral annulus, and the E/e’ ratio was calculated to obtain an estimate of LV filling pressure. LVGLS was measured using two-dimensional speckle-tracking echocardiography. Speckle-tracking strain was analyzed with the 2D Wall Motion Tracking Application® software (Canon Medical Systems Corporation, Tochigi, Japan). While maximizing the frame rate, the endocardial border was traced manually at the end-diastolic frame. The software automatically tracked the myocardium throughout the cardiac cycle. The peak values of six segmental longitudinal strains were obtained from the apical four-, three-, and two-chamber views, and GLS was calculated by averaging the values (Fig. 1 ). CMR scanning protocol All CMR exams were performed using a 3.0-Tesla scanner (Ingenia®, Philips, Eindhoven, Netherlands) with a 32-element cardiac receiver coil. Vector-electrocardiogram-gated standard steady-state free precession cine sequences were acquired in short axes covering the whole LV and long-axis (four-, three-, two-chamber) views. LGE images were acquired 10 min post-contrast (Gadovist® 0.1 mmol/kg) injection. T1 maps were generated before and 15 min after gadolinium contrast injection using a modified look-locker inversion recovery sequence [ 19 ] during breath-holding in end-expiration to produce 11 raw images with increasing inversion times (TI, 100–5000 ms) in a mid-ventricular short-axis view (TR/TE, 2.20/1.02 ms; flip angle, 20°). Blood samples were taken for hematocrit determination within 24 h before the scan. All maps were analyzed using Ziostation2® ver. 2.9 2–2 (Ziosoft, Tokyo, Japan). Myocardial T1 values and ECV were determined by drawing regions of interest in each segment of the mid-ventricular slice according to the American Heart Association 16-segment model (Fig. 1 ). ECV values were calculated according to the following formula: ECV = (1 - HCT) × (1/T1 value myocardium post − 1/T1 value myocardium pre )/(1/T1 value blood post − 1/T1 value blood pre ). The global ECV was calculated by averaging the values of the 16 segments. Statistical analysis We included data from all patients in the analysis of baseline characteristics and outcomes according to the intention-to-treat principle. Normally distributed continuous variables are expressed as the mean and standard deviation. Levene’s test showed that T2DM duration, eGFR, BNP, left atrial dimension, and LV end-diastolic dimension were not distributed normally. These variables are expressed as the median and interquartile range. Student’s t -test or Mann–Whitney U test was used to compare differences between the two groups, where appropriate. A simple linear regression analysis was performed to evaluate the correlations. All statistical tests were two-tailed, and values of p < 0.05 were considered to indicate statistical significance. IBM SPSS Statistics® version 19.0 (SPSS, Chicago, IL, USA) was used for statistical analyses. Results Baseline characteristics A total of 984 HF patients hospitalized between April 1, 2017 and June 1, 2019 were screened for eligibility. Therefore, 35 DMCMP patients were enrolled and divided into the early DMCMP (n = 16, global ECV: 27.5 ± 1.9%) and advanced DMCMP (n = 19, global ECV: 38.7 ± 5.3%) groups. The baseline characteristics of the two groups are summarized in Table 1. At baseline, both groups had similar backgrounds. There were no significant differences in age, gender, NYHA class, HbA1c, BNP, LVGLS, and E/e’. However, LVEF was significantly lower in the advanced DMCMP group than in the early DMCMP group (55.9 ± 10.0% vs. 48.4 ± 9.8%, p = 0.032). The T2DM duration of the advanced DMCMP group was significantly longer than that of the early DMCMP group (22 [19–28] vs. 99 [72–118] months, p < 0.001). Interestingly, the global ECV value was strongly correlated with T2DM duration (r 2 = 0.65, p < 0.001, Fig. 2 ). Finally, 32 patients had 12 months of complete follow-up. Two patients in the early DMCMP group and one patient in the advanced DMCMP group had an incomplete follow-up because of dropout and onset of cerebral infarction, respectively. Primary outcomes After 12 months, positive effects of empagliflozin on LV systolic and diastolic function were observed in both groups. However, the early DMCMP group showed more remarkable improvements in both LVGLS (ΔGLS: 4.6 ± 1.5% vs. 1.6 ± 3.3%, p = 0.003) and E/e’ (ΔE/e’: -3.4 ± 5.5 cm/s vs. -0.1 ± 3.5 cm/s, p = 0.043) than in the advanced DMCMP group (Fig. 3 ). Secondary outcomes There were no significant differences between the two groups in NYHA class after 12 months (1.2 ± 0.4 vs. 1.3 ± 0.5, p = 0.755) and the changes in HbA1c and BNP between baseline and after 12 months (ΔHbA1c: -1.6 ± 1.5% vs. -1.0 ± 1.4%, p = 0.249, ΔBNP: -305 [201–400] pg/mL vs. -398 [143–537] pg/mL, p = 0.594, Table 2). Discussion The present study showed positive effects of empagliflozin on LV systolic and diastolic functional parameters observed in both early and advanced DMCMP patients. However, the improvements in LV function were more remarkable in early DMCMP patients than in advanced DMCMP patients. HF parameters, such as NYHA class and BNP, were equally improved in both groups. Characteristics of DMCMP Hyperglycemia causes microvascular endothelial dysfunction, cardiac interstitial fibrosis, and structural cardiac changes such as LV hypertrophy, which leads to the development of DMCMP [ 2 ]. LV diastolic dysfunction is a classical LV functional abnormality observed in the preclinical phase of DMCMP [ 4 ]. LV longitudinal myocardial dysfunction has also been reported as one of the earliest markers of LV dysfunction in DMCMP [ 3 ]. If LV remodeling progresses, DMCMP develops into symptomatic HF showing restrictive HFpEF or dilated HFrEF phenotypes. Phenotype-specific pathophysiological mechanisms have recently been proposed for LV remodeling and dysfunction consisting of coronary microvascular endothelial dysfunction, interstitial fibrosis, and myocardial hypertrophy in HFpEF, and cardiomyocyte cell death and extensive replacement fibrosis in HFrEF [ 2 ]. In this study, symptomatic HF patients with T2DM were enrolled. Thus, although we named the group of patients with ECV ≤ 30% as the early DMCMP group, they were not strictly in the early phase of DMCMP. Their ECV values were as high as those reported in a previous report of T2DM patients with normal LV function [ 20 ], but their LVGLS and E/e’ were relatively worse than those reported in other DMCMP research targeting stable HF [ 10 , 11 ]. Baseline LVEF was lower in the advanced DMCMP group than in the early DMCMP group; thus, the advanced DMCMP group patients might be having the nearly dilated HFrEF phenotype. Their ECV values were very high and suggested extensive replacement fibrosis. Impact of SGLT2i on LV functional parameters In line with previous reports using dapagliflozin [ 10 , 11 ], the administration of empagliflozin also improved LV functional parameters such as LVGLS and E/e’. Tanaka et al. showed that dapagliflozin was more effective in improving LVGLS in DMCMP with HFpEF phenotype than the HFrEF phenotype [ 11 ]. Furthermore, regarding DMCMP with non-HFrEF phenotype, our research revealed that patients with mild myocardial fibrosis showed greater improvements in LV systolic and diastolic function than patients with advanced myocardial fibrosis after the administration of empagliflozin. We also found that the progression of myocardial fibrosis correlated with T2DM duration. Combined with a previous report and our research results, SGLT2i treatment is more effective for LV dysfunction in an earlier phase than the later phase of DMCMP. Thus, it is recommended that SGLT2i treatment should be used for DMCMP from the early phase. Mechanisms of direct cardiac effects It is hypothesized that the direct cardiac effects of SGLT2i depend on a reduction in intracellular sodium by inhibiting NHE-1 which is expressed in the heart and vasculature [ 12 ]. In patients with T2DM and HF, the activity of NHE-1 is markedly enhanced. This increase facilitates the accumulation of intracellular sodium, which stimulates the reverse activity of the sodium-calcium exchanger, leading to an increase in intracellular calcium and myocardial injury [ 21 ]. The inhibition of NHE-1 reduces intracellular sodium and calcium concentrations, increases mitochondrial calcium, which restores mitochondrial function and redox state, activates ATP production in the failing heart, and improves LV function [ 12 ]. In animal models, SGLT2i treatment, via the inhibition of NHE-1, reduces cardiac hypertrophy and fibrosis, slows the progression of DMCMP, and improves systolic and diastolic function [ 22 – 24 ]. These findings suggest that empagliflozin promotes reverse LV remodeling; thus, the lesser the degree of myocardial fibrosis and injury, the greater is the extent to which LV function could be restored by SGLT2i treatment. Considering that there was no significant difference between the two groups in ΔHbA1c, the reverse remodeling through the inhibition of NHE-1 is independent of the main effect: glycemic control by blocking glucose reabsorption thorough SGLT2. Side effects, such as osmotic diuresis and inhibition of NHE-1, may be the reason why SGLT2i treatment is associated with lowering of the risk of HF exacerbation regardless of the presence or absence of T2DM. The composite of direct and indirect cardiac actions of SGLT2i could improve HF parameters even in advanced DMCMP patients. Clinical implications LV longitudinal myocardial dysfunction and diastolic dysfunction are the earliest markers observed in the preclinical phase of DMCMP [ 3 , 4 ], leading to HF. In the present study, symptomatic HF patients with T2DM were enrolled. Because of the study population, LV systolic function assessed as LVGLS and diastolic function assessed as E/e’ were relatively lower than those reported in similar studies targeting stable HF patients [ 10 , 11 ]. However, empagliflozin improved LV functional parameters. Moreover, the improvements in LVGLS and E/e’ after empagliflozin administration were more remarkable in DMCMP patients with milder cardiac fibrosis whose progression was correlated with T2DM duration. These are clinically important findings that lead to early intervention of SGLT2i for HF patients with T2DM. Study limitations This study has some limitations. First, this was a small observational study conducted at a single center. Therefore, several biases were possible. Second, a myocardial biopsy was not performed. Although we performed coronary angiography and CMR to increase the diagnostic accuracy of DMCMP, the possibility that patients with another cardiomyopathy were still included cannot be denied. Third, we performed only a short-term assessment of LV function. If the follow-up period was longer, LV functional parameters might have improved further in the advanced DMCMP group. Conclusions Empagliflozin had a positive effect on LV systolic and diastolic function and was more remarkable in DMCMP patients with lower ECV values than in those with higher ECV values. The ECV increase was strongly correlated with T2DM duration. Thus, early SGLT2i treatment for HF patients with T2DM is preferable. Abbreviations BNP brain natriuretic peptide, CMR:cardiac magnetic resonance, DMCMP:diabetes mellitus-related cardiomyopathy, ECV:extracellular volume fraction, EF:ejection fraction, eGFR:estimated glomerular filtration rate, E/e':ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity, GLS:global longitudinal strain, HbA1c:glycated hemoglobin, HF:heart failure, HFpEF:heart failure with preserved ejection fraction, HFrEF:heart failure with reduced ejection fraction, LGE:late gadolinium enhancement, LV:left ventricular, NHE:sodium-hydrogen exchanger, NYHA:New York Heart Association, SGLT2i:sodium-glucose co-transporter 2 inhibitor, T2DM:type 2 diabetes mellitus. Declarations Ethics approval and consent to participate The study was approved by the ethics committee of the Fujieda Municipal General Hospital. All participants provided written informed consent before enrollment. Consent for publication The consent to publish was obtained from all participants. Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors’ contributions SO designed the study, carried out participant recruitment, performed coronary angiography, analyzed the data, and wrote the manuscript. TK, KH, KW, JN, MA, and AW assisted recruitment and coronary angiography. JN and AW assisted in the manuscript revision. All authors have read and approved the final manuscript. Acknowledgements Not applicable References Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. 1979;241(19):2035–8. Petar MS, Walter JP. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive or dilated phenolypes. Euro Heart J. 2015;36:1718–27. Ernande L, Bergerot C, Girerd N, Thibault H, Davidsen ES, Pignon-Blanc PG, et al. 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Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017 Jan;16(1):9-23. Tables Due to technical limitations, table 1-2 is only available as a download in the Supplemental Files section. Supplementary Files Tables.pptx Tables.pptx Tables.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-117825","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Original investigation","associatedPublications":[],"authors":[{"id":5487653,"identity":"bb00810e-9666-4068-b51b-4410f182f589","order_by":0,"name":"Satoshi Oka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYHACNoaKAgYGxvb2gw+APB4+orScMQBq6TmTbADSwka0FgaJBDMJCJcAkG9vYHtwwOAwA3NDQlrl1xw7GTYG5oePbuDRYnDmALsBSAtjw8Fjt2W3JQMdxmZsnINPi0QCm/QHkJbGhrTbktuYgVp42KTxaZGfkcAmAbalmcGsWHJbPWEtDDdgWtoYzBg/bjtMWIvBmYPtQL+k8zD28CRLM247zsPGTMAv8u3Nxx4cqLCWM5z//ODHn9uq7fnZmx8+xuswYFABiWYeQyDFzAMSYMarHA7qGORBun8Qp3oUjIJRMApGGAAARbpGIwf55dQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-6257-1421","institution":"Fujieda Municipal General Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Oka","suffix":""},{"id":5487654,"identity":"8c094244-3a70-4040-ad2b-49beab54bf74","order_by":1,"name":"Takahiko Kai","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahiko","middleName":"","lastName":"Kai","suffix":""},{"id":5487655,"identity":"0063efa3-2385-4d66-9d06-5e68c3936975","order_by":2,"name":"Katsuomi Hoshino","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Katsuomi","middleName":"","lastName":"Hoshino","suffix":""},{"id":5487656,"identity":"a043c1f0-d9f2-4d9d-87fd-d0804aa19d97","order_by":3,"name":"Kazunori Watanabe","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazunori","middleName":"","lastName":"Watanabe","suffix":""},{"id":5487657,"identity":"3b0ed81d-7aba-48b0-9f22-c4ccbab29b36","order_by":4,"name":"Jun Nakamura","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Nakamura","suffix":""},{"id":5487658,"identity":"14b19420-4549-44fe-8b24-e5c421438483","order_by":5,"name":"Makoto Abe","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Abe","suffix":""},{"id":5487659,"identity":"e4518e25-764d-4a89-b3c9-0cb082b71d0f","order_by":6,"name":"Akinori Watanabe","email":"","orcid":"","institution":"Fujieda Municipal General Hospital Department of Cardiology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Akinori","middleName":"","lastName":"Watanabe","suffix":""}],"badges":[],"createdAt":"2020-11-28 15:17:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-117825/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-117825/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":3997956,"identity":"042f7cbc-0a74-4089-a5ff-7f87b83017d8","added_by":"auto","created_at":"2020-12-03 19:33:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93453,"visible":true,"origin":"","legend":"Example of assessment of left ventricular global longitudinal strain (LVGLS) and extracellular volume fraction (ECV): Apical four- (A), three- (B), and two-chamber (C) views of two-dimensional speckle-tracking echocardiography imaging are shown. LVGLS was calculated by averaging these results. Maps of the LV middle short-axis segment with a modified Look-Locker inversion recovery sequence; native T1 mapping (D), post-contrast T1 mapping (E), and calculated ECV mapping (F) of the same segment are shown. Global ECV value was calculated by averaging the values of the American Heart Association 16-segment model (G).","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/ac1224f32adbc41c6d2ce35a.JPG"},{"id":3997952,"identity":"1760656f-1a47-4d8e-9819-45e07cb41154","added_by":"auto","created_at":"2020-12-03 19:33:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93453,"visible":true,"origin":"","legend":"Example of assessment of left ventricular global longitudinal strain (LVGLS) and extracellular volume fraction (ECV): Apical four- (A), three- (B), and two-chamber (C) views of two-dimensional speckle-tracking echocardiography imaging are shown. LVGLS was calculated by averaging these results. Maps of the LV middle short-axis segment with a modified Look-Locker inversion recovery sequence; native T1 mapping (D), post-contrast T1 mapping (E), and calculated ECV mapping (F) of the same segment are shown. Global ECV value was calculated by averaging the values of the American Heart Association 16-segment model (G).","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/5f9eb56f1c93ede2f530fc1e.JPG"},{"id":3997946,"identity":"80c2cf6b-da26-4244-9c94-8ff3e404aa79","added_by":"auto","created_at":"2020-12-03 19:33:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93453,"visible":true,"origin":"","legend":"Example of assessment of left ventricular global longitudinal strain (LVGLS) and extracellular volume fraction (ECV): Apical four- (A), three- (B), and two-chamber (C) views of two-dimensional speckle-tracking echocardiography imaging are shown. LVGLS was calculated by averaging these results. Maps of the LV middle short-axis segment with a modified Look-Locker inversion recovery sequence; native T1 mapping (D), post-contrast T1 mapping (E), and calculated ECV mapping (F) of the same segment are shown. Global ECV value was calculated by averaging the values of the American Heart Association 16-segment model (G).","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/3c7093a36dc20fb0bde6c5c1.JPG"},{"id":3997958,"identity":"09065fbf-6298-44ff-b9dc-ff280920eb46","added_by":"auto","created_at":"2020-12-03 19:33:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29581,"visible":true,"origin":"","legend":"Scatter plot of global extracellular volume fraction (ECV) value (y-axis) and type 2 diabetes mellitus (T2DM) duration (x-axis) showing the basic linear regression line and a strong correlation","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/87f7a2b81f99b2743a45fe06.JPG"},{"id":3997954,"identity":"5daac27d-d71f-45c2-8c4c-b330e8935bce","added_by":"auto","created_at":"2020-12-03 19:33:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29581,"visible":true,"origin":"","legend":"Scatter plot of global extracellular volume fraction (ECV) value (y-axis) and type 2 diabetes mellitus (T2DM) duration (x-axis) showing the basic linear regression line and a strong correlation","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/5f829743db73c38d0b8809bd.JPG"},{"id":3997948,"identity":"a2bdf349-3cac-4bd1-8dd0-8ea7ac2530a2","added_by":"auto","created_at":"2020-12-03 19:33:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29581,"visible":true,"origin":"","legend":"Scatter plot of global extracellular volume fraction (ECV) value (y-axis) and type 2 diabetes mellitus (T2DM) duration (x-axis) showing the basic linear regression line and a strong correlation","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/47a467356a40d902fcdecf5c.JPG"},{"id":3997959,"identity":"17244dc6-354a-496f-90de-c09dd0a8859d","added_by":"auto","created_at":"2020-12-03 19:33:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49428,"visible":true,"origin":"","legend":"Results of primary outcomes, showing significant improvements in left ventricular global longitudinal strain (LVGLS; absolute value) and ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) 12 months after administration of empagliflozin, especially in the early diabetes mellitus-related cardiomyopathy (DMCMP) group","description":"","filename":"Fig3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/90fa67d996f73a1e46fcd5c0.JPG"},{"id":3997955,"identity":"50f0706a-7c11-4383-b206-85a654b8c349","added_by":"auto","created_at":"2020-12-03 19:33:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49428,"visible":true,"origin":"","legend":"Results of primary outcomes, showing significant improvements in left ventricular global longitudinal strain (LVGLS; absolute value) and ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) 12 months after administration of empagliflozin, especially in the early diabetes mellitus-related cardiomyopathy (DMCMP) group","description":"","filename":"Fig3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/404eefd992d51f0ee25aff60.JPG"},{"id":3997949,"identity":"2e6db9fc-1258-4383-af6c-460b8876649b","added_by":"auto","created_at":"2020-12-03 19:33:45","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49428,"visible":true,"origin":"","legend":"Results of primary outcomes, showing significant improvements in left ventricular global longitudinal strain (LVGLS; absolute value) and ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) 12 months after administration of empagliflozin, especially in the early diabetes mellitus-related cardiomyopathy (DMCMP) group","description":"","filename":"Fig3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/9e5ed50ef55ad19132750a7f.JPG"},{"id":13623158,"identity":"b9e64092-c0ad-432a-a16e-2dea628b3567","added_by":"auto","created_at":"2021-09-17 07:17:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":787850,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/b9b16610-0c20-40fb-bb95-fa6140616585.pdf"},{"id":3997957,"identity":"eb60ae4a-26e5-4572-a651-c4aa50a9304d","added_by":"auto","created_at":"2020-12-03 19:33:52","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1486308,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.pptx","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/414c9eb21ee3cc5e81db7773.pptx"},{"id":3997953,"identity":"93416f94-6651-41a6-8c82-64c71d2f452d","added_by":"auto","created_at":"2020-12-03 19:33:51","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1486308,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.pptx","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/22acee7dbed5cd7683275cba.pptx"},{"id":3997947,"identity":"228f50df-e13c-4d1f-868e-e6034dd81c7b","added_by":"auto","created_at":"2020-12-03 19:33:45","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1486308,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.pptx","url":"https://assets-eu.researchsquare.com/files/rs-117825/v1/d27d373ec44dfb7e8ac0677e.pptx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffects of Empagliflozin in Different Phases of Diabetes Mellitus-related Cardiomyopathy\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eType 2 diabetes mellitus (T2DM) is an important risk factor for the development of cardiovascular disease and heart failure (HF) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Diabetes mellitus-related cardiomyopathy (DMCMP), which manifests as left ventricular (LV) dysfunction that cannot be ascribed to hypertension, coronary artery disease, or significant valvular disease, is well described. Hyperglycemia drives microvascular endothelial dysfunction, LV dysfunction, and LV remodeling through progresses of myocardial hypertrophy, cardiomyocyte stiffening, and interstitial fibrosis, which lead to DMCMP with HF with preserved ejection fraction (HFpEF) phenotype [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Decreased LV global longitudinal strain (GLS) and the increased ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e\u0026rsquo;) are observed as signs of LV dysfunction from the early phase of DMCMP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. If LV remodeling progresses, DMCMP turns to HF with reduced ejection fraction (HFrEF) phenotype [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral mega-trials have shown that treatment with sodium\u0026ndash;glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of major adverse cardiovascular events, including exacerbation of HF [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Furthermore, it was recently shown that SGLT2i treatment was associated with lowering the risk of cardiovascular death and hospitalization for HFrEF consistently from the early to late phases after administration, regardless of the presence or absence of T2DM [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Thus, the beneficial effects of SGLT2i treatment on HF are not explained only by their actions on glycemic control or osmotic diuresis, but also by their direct actions on the myocardium [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. One example of these is inhibition of the sodium-hydrogen exchanger (NHE), which may in turn lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and LV dysfunction [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, it remains unclear whether SGLT2i treatment is equally effective for all patients with DMCMP. The aim of this cohort study was to compare the efficacy of SGLT2i treatment on LV dysfunction between the early and advanced phases of DMCMP.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis was a prospective observational study conducted at a single center. Consecutive symptomatic HF patients with T2DM who were hospitalized in Fujieda Municipal General Hospital (Japan) and treated with administration of empagliflozin (at a dose of 10\u0026nbsp;mg daily) were screened for eligibility. The diagnosis of T2DM was based on the World Health Organization criteria [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. After the cardiac assessment, patients diagnosed with DMCMP with LV ejection fraction (EF) greater than 40% were enrolled. Cardiac magnetic resonance (CMR) was performed in all participants, and their myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis, was evaluated. According to previous reports [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], global ECV\u0026thinsp;\u0026gt;\u0026thinsp;30% was considered elevated with advanced replacement myocardial fibrosis. Therefore, the patients were divided into the early DMCMP group (global ECV\u0026thinsp;\u0026le;\u0026thinsp;30%) and advanced DMCMP group (global ECV\u0026thinsp;\u0026gt;\u0026thinsp;30%) and followed-up prospectively.\u003c/p\u003e \u003cp\u003eExclusion criteria were as follows: (1) age less than 20 or greater than 80 years, (2) in-hospital death, (3) New York Heart Association (NYHA) class I or brain natriuretic peptide (BNP)\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026nbsp;pg/mL, (4) LVEF\u0026thinsp;\u0026le;\u0026thinsp;40%, (5) other cardiomyopathies, (6) valvular or congenital heart disease, (7) normal LV systolic function: LVGLS (absolute value)\u0026thinsp;\u0026ge;\u0026thinsp;18% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], (8) type 1 diabetes mellitus or insulin-dependent T2DM: C-peptide immunoreactivity index\u0026thinsp;\u0026lt;\u0026thinsp;0.8 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] or insulin user, (9) newly diagnosed T2DM (less than 1\u0026nbsp;year) or no antidiabetic medications before administration of empagliflozin, (10) current or previous use of SGLT2i, (11) persistent arrhythmia, (12) pacemaker implantation, (13) contraindication for CMR (implanted metallic objects, allergy to contrast media, and bronchial asthma), (14) estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026le;\u0026thinsp;30\u0026nbsp;mL/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e, (15) malignant tumor or inflammatory disease, (16) pregnancy, (17) refusal to informed consent, and (18) prior history of myocardial infarction, cerebral infarction, pancreatitis, and hospitalization for HF. For the exclusion of ischemic cardiomyopathy, coronary angiography was performed in all participants. Patients with \u0026ge;\u0026thinsp;90% coronary artery stenosis were excluded. Patients with 75% stenosis were also excluded if functional ischemia was proven by over 10% ischemic area matched with angiography in myocardial perfusion scintigraphy. For the exclusion of hypertensive heart disease, patients with diastolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;90\u0026nbsp;mmHg were excluded [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For the exclusion of other cardiomyopathies, patients with regional LV wall motion abnormalities, late gadolinium enhancement (LGE), excessive LV dilatation (LV end-diastolic volume index: \u0026gt; 97\u0026nbsp;mL/m\u003csup\u003e2\u003c/sup\u003e [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]), and excessive LV hypertrophy (LV myocardial mass index: \u0026gt; 69\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e for women or 91\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e for men [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]) as evaluated by CMR were not included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was the improvement in LV function, defined as changes in LV systolic function assessed as LVGLS, and diastolic function assessed as E/e\u0026rsquo; between baseline and 12 months after the administration of empagliflozin.\u003c/p\u003e \u003cp\u003eThe secondary outcomes were the NYHA class after 12 months and the changes in glycated hemoglobin (HbA1c) and BNP levels between baseline and after 12 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnthropometrics and blood examination\u003c/h2\u003e \u003cp\u003eAt the time of enrollment, age, gender, height, body weight, blood pressure, and heart rate of all participants were recorded. NYHA class and blood samples including hemoglobin, HbA1c, sodium, eGFR, and BNP at admission were used as baseline data. Fasting C-peptide and plasma glucose was checked with hematocrit at the time of CMR, and the C-peptide immunoreactivity index was calculated using the following formula: fasting C-peptide/fasting plasma glucose\u0026thinsp;\u0026times;\u0026thinsp;100. Serum HbA1c and BNP levels were measured routinely at baseline and at 12 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eUltrasonic echocardiography\u003c/h2\u003e \u003cp\u003eUltrasonic echocardiography was performed at baseline and after 12 months using an Aplio 400\u0026reg; (Canon Medical Systems Corporation, Tochigi, Japan) by two cardiac ultrasonographers who were blinded to the patients' backgrounds. Two-dimensional gray-scale cine loops from three consecutive heartbeats were obtained at end-expiratory apnea from standard parasternal and apical views. According to the guidelines of the American Society of Echocardiography/European Association of Cardiovascular Imaging [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], standard echocardiographic measurements were performed. LVEF was measured using the modified Simpson method. The E-wave velocity was measured using pulsed-wave Doppler recording from the apical four-chamber view. Spectral pulsed-wave Doppler-derived e\u0026rsquo; was obtained by averaging the septal and lateral mitral annulus, and the E/e\u0026rsquo; ratio was calculated to obtain an estimate of LV filling pressure. LVGLS was measured using two-dimensional speckle-tracking echocardiography. Speckle-tracking strain was analyzed with the 2D Wall Motion Tracking Application\u0026reg; software (Canon Medical Systems Corporation, Tochigi, Japan). While maximizing the frame rate, the endocardial border was traced manually at the end-diastolic frame. The software automatically tracked the myocardium throughout the cardiac cycle. The peak values of six segmental longitudinal strains were obtained from the apical four-, three-, and two-chamber views, and GLS was calculated by averaging the values (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCMR scanning protocol\u003c/h2\u003e \u003cp\u003eAll CMR exams were performed using a 3.0-Tesla scanner (Ingenia\u0026reg;, Philips, Eindhoven, Netherlands) with a 32-element cardiac receiver coil. Vector-electrocardiogram-gated standard steady-state free precession cine sequences were acquired in short axes covering the whole LV and long-axis (four-, three-, two-chamber) views. LGE images were acquired 10\u0026nbsp;min post-contrast (Gadovist\u0026reg; 0.1\u0026nbsp;mmol/kg) injection. T1 maps were generated before and 15\u0026nbsp;min after gadolinium contrast injection using a modified look-locker inversion recovery sequence [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] during breath-holding in end-expiration to produce 11 raw images with increasing inversion times (TI, 100\u0026ndash;5000\u0026nbsp;ms) in a mid-ventricular short-axis view (TR/TE, 2.20/1.02\u0026nbsp;ms; flip angle, 20\u0026deg;). Blood samples were taken for hematocrit determination within 24\u0026nbsp;h before the scan. All maps were analyzed using Ziostation2\u0026reg; ver. 2.9 2\u0026ndash;2 (Ziosoft, Tokyo, Japan). Myocardial T1 values and ECV were determined by drawing regions of interest in each segment of the mid-ventricular slice according to the American Heart Association 16-segment model (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). ECV values were calculated according to the following formula: ECV = (1 - HCT) \u0026times; (1/T1 value \u003csub\u003emyocardium post\u003c/sub\u003e \u0026minus;\u0026thinsp;1/T1 value \u003csub\u003emyocardium pre\u003c/sub\u003e)/(1/T1 value \u003csub\u003eblood post\u003c/sub\u003e \u0026minus;\u0026thinsp;1/T1 value \u003csub\u003eblood pre\u003c/sub\u003e). The global ECV was calculated by averaging the values of the 16 segments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eWe included data from all patients in the analysis of baseline characteristics and outcomes according to the intention-to-treat principle. Normally distributed continuous variables are expressed as the mean and standard deviation. Levene\u0026rsquo;s test showed that T2DM duration, eGFR, BNP, left atrial dimension, and LV end-diastolic dimension were not distributed normally. These variables are expressed as the median and interquartile range. Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or Mann\u0026ndash;Whitney U test was used to compare differences between the two groups, where appropriate. A simple linear regression analysis was performed to evaluate the correlations. All statistical tests were two-tailed, and values of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance. IBM SPSS Statistics\u0026reg; version 19.0 (SPSS, Chicago, IL, USA) was used for statistical analyses.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eA total of 984 HF patients hospitalized between April 1, 2017 and June 1, 2019 were screened for eligibility. Therefore, 35 DMCMP patients were enrolled and divided into the early DMCMP (n\u0026thinsp;=\u0026thinsp;16, global ECV: 27.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9%) and advanced DMCMP (n\u0026thinsp;=\u0026thinsp;19, global ECV: 38.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3%) groups. The baseline characteristics of the two groups are summarized in Table\u0026nbsp;1. At baseline, both groups had similar backgrounds. There were no significant differences in age, gender, NYHA class, HbA1c, BNP, LVGLS, and E/e\u0026rsquo;. However, LVEF was significantly lower in the advanced DMCMP group than in the early DMCMP group (55.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0% vs. 48.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8%, p\u0026thinsp;=\u0026thinsp;0.032). The T2DM duration of the advanced DMCMP group was significantly longer than that of the early DMCMP group (22 [19\u0026ndash;28] vs. 99 [72\u0026ndash;118] months, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Interestingly, the global ECV value was strongly correlated with T2DM duration (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.65, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Finally, 32 patients had 12 months of complete follow-up. Two patients in the early DMCMP group and one patient in the advanced DMCMP group had an incomplete follow-up because of dropout and onset of cerebral infarction, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcomes\u003c/h2\u003e \u003cp\u003eAfter 12 months, positive effects of empagliflozin on LV systolic and diastolic function were observed in both groups. However, the early DMCMP group showed more remarkable improvements in both LVGLS (ΔGLS: 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5% vs. 1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3%, p\u0026thinsp;=\u0026thinsp;0.003) and E/e\u0026rsquo; (ΔE/e\u0026rsquo;: -3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u0026nbsp;cm/s vs. -0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u0026nbsp;cm/s, p\u0026thinsp;=\u0026thinsp;0.043) than in the advanced DMCMP group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eThere were no significant differences between the two groups in NYHA class after 12 months (1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 vs. 1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5, p\u0026thinsp;=\u0026thinsp;0.755) and the changes in HbA1c and BNP between baseline and after 12 months (ΔHbA1c: -1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5% vs. -1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4%, p\u0026thinsp;=\u0026thinsp;0.249, ΔBNP: -305 [201\u0026ndash;400] pg/mL vs. -398 [143\u0026ndash;537] pg/mL, p\u0026thinsp;=\u0026thinsp;0.594, Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe present study showed positive effects of empagliflozin on LV systolic and diastolic functional parameters observed in both early and advanced DMCMP patients. However, the improvements in LV function were more remarkable in early DMCMP patients than in advanced DMCMP patients. HF parameters, such as NYHA class and BNP, were equally improved in both groups.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of DMCMP\u003c/h2\u003e \u003cp\u003eHyperglycemia causes microvascular endothelial dysfunction, cardiac interstitial fibrosis, and structural cardiac changes such as LV hypertrophy, which leads to the development of DMCMP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. LV diastolic dysfunction is a classical LV functional abnormality observed in the preclinical phase of DMCMP [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. LV longitudinal myocardial dysfunction has also been reported as one of the earliest markers of LV dysfunction in DMCMP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. If LV remodeling progresses, DMCMP develops into symptomatic HF showing restrictive HFpEF or dilated HFrEF phenotypes. Phenotype-specific pathophysiological mechanisms have recently been proposed for LV remodeling and dysfunction consisting of coronary microvascular endothelial dysfunction, interstitial fibrosis, and myocardial hypertrophy in HFpEF, and cardiomyocyte cell death and extensive replacement fibrosis in HFrEF [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, symptomatic HF patients with T2DM were enrolled. Thus, although we named the group of patients with ECV\u0026thinsp;\u0026le;\u0026thinsp;30% as the early DMCMP group, they were not strictly in the early phase of DMCMP. Their ECV values were as high as those reported in a previous report of T2DM patients with normal LV function [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], but their LVGLS and E/e\u0026rsquo; were relatively worse than those reported in other DMCMP research targeting stable HF [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Baseline LVEF was lower in the advanced DMCMP group than in the early DMCMP group; thus, the advanced DMCMP group patients might be having the nearly dilated HFrEF phenotype. Their ECV values were very high and suggested extensive replacement fibrosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImpact of SGLT2i on LV functional parameters\u003c/h2\u003e \u003cp\u003eIn line with previous reports using dapagliflozin [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], the administration of empagliflozin also improved LV functional parameters such as LVGLS and E/e\u0026rsquo;. Tanaka et al. showed that dapagliflozin was more effective in improving LVGLS in DMCMP with HFpEF phenotype than the HFrEF phenotype [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, regarding DMCMP with non-HFrEF phenotype, our research revealed that patients with mild myocardial fibrosis showed greater improvements in LV systolic and diastolic function than patients with advanced myocardial fibrosis after the administration of empagliflozin. We also found that the progression of myocardial fibrosis correlated with T2DM duration. Combined with a previous report and our research results, SGLT2i treatment is more effective for LV dysfunction in an earlier phase than the later phase of DMCMP. Thus, it is recommended that SGLT2i treatment should be used for DMCMP from the early phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eMechanisms of direct cardiac effects\u003c/h2\u003e \u003cp\u003eIt is hypothesized that the direct cardiac effects of SGLT2i depend on a reduction in intracellular sodium by inhibiting NHE-1 which is expressed in the heart and vasculature [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In patients with T2DM and HF, the activity of NHE-1 is markedly enhanced. This increase facilitates the accumulation of intracellular sodium, which stimulates the reverse activity of the sodium-calcium exchanger, leading to an increase in intracellular calcium and myocardial injury [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The inhibition of NHE-1 reduces intracellular sodium and calcium concentrations, increases mitochondrial calcium, which restores mitochondrial function and redox state, activates ATP production in the failing heart, and improves LV function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In animal models, SGLT2i treatment, via the inhibition of NHE-1, reduces cardiac hypertrophy and fibrosis, slows the progression of DMCMP, and improves systolic and diastolic function [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These findings suggest that empagliflozin promotes reverse LV remodeling; thus, the lesser the degree of myocardial fibrosis and injury, the greater is the extent to which LV function could be restored by SGLT2i treatment.\u003c/p\u003e \u003cp\u003eConsidering that there was no significant difference between the two groups in ΔHbA1c, the reverse remodeling through the inhibition of NHE-1 is independent of the main effect: glycemic control by blocking glucose reabsorption thorough SGLT2. Side effects, such as osmotic diuresis and inhibition of NHE-1, may be the reason why SGLT2i treatment is associated with lowering of the risk of HF exacerbation regardless of the presence or absence of T2DM. The composite of direct and indirect cardiac actions of SGLT2i could improve HF parameters even in advanced DMCMP patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications\u003c/h2\u003e \u003cp\u003eLV longitudinal myocardial dysfunction and diastolic dysfunction are the earliest markers observed in the preclinical phase of DMCMP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], leading to HF. In the present study, symptomatic HF patients with T2DM were enrolled. Because of the study population, LV systolic function assessed as LVGLS and diastolic function assessed as E/e\u0026rsquo; were relatively lower than those reported in similar studies targeting stable HF patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, empagliflozin improved LV functional parameters. Moreover, the improvements in LVGLS and E/e\u0026rsquo; after empagliflozin administration were more remarkable in DMCMP patients with milder cardiac fibrosis whose progression was correlated with T2DM duration. These are clinically important findings that lead to early intervention of SGLT2i for HF patients with T2DM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThis study has some limitations. First, this was a small observational study conducted at a single center. Therefore, several biases were possible. Second, a myocardial biopsy was not performed. Although we performed coronary angiography and CMR to increase the diagnostic accuracy of DMCMP, the possibility that patients with another cardiomyopathy were still included cannot be denied. Third, we performed only a short-term assessment of LV function. If the follow-up period was longer, LV functional parameters might have improved further in the advanced DMCMP group.\u003c/p\u003e \u003c/div\u003e "},{"header":"Conclusions","content":" \u003cp\u003eEmpagliflozin had a positive effect on LV systolic and diastolic function and was more remarkable in DMCMP patients with lower ECV values than in those with higher ECV values. The ECV increase was strongly correlated with T2DM duration. Thus, early SGLT2i treatment for HF patients with T2DM is preferable.\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebrain natriuretic peptide, CMR:cardiac magnetic resonance, DMCMP:diabetes mellitus-related cardiomyopathy, ECV:extracellular volume fraction, EF:ejection fraction, eGFR:estimated glomerular filtration rate, E/e':ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity, GLS:global longitudinal strain, HbA1c:glycated hemoglobin, HF:heart failure, HFpEF:heart failure with preserved ejection fraction, HFrEF:heart failure with reduced ejection fraction, LGE:late gadolinium enhancement, LV:left ventricular, NHE:sodium-hydrogen exchanger, NYHA:New York Heart Association, SGLT2i:sodium-glucose co-transporter 2 inhibitor, T2DM:type 2 diabetes mellitus.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of the Fujieda Municipal General Hospital. All participants provided written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe consent to publish was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSO designed the study, carried out participant recruitment, performed coronary angiography, analyzed the data, and wrote the manuscript. TK, KH, KW, JN, MA, and AW assisted recruitment and coronary angiography. JN and AW assisted in the manuscript revision. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. 1979;241(19):2035\u0026ndash;8. \u2028\u003c/li\u003e\n\u003cli\u003ePetar MS, Walter JP. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive or dilated phenolypes. Euro Heart J. 2015;36:1718\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eErnande L, Bergerot C, Girerd N, Thibault H, Davidsen ES, Pignon-Blanc PG, et al. Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus. J Am Soc Echocardiogr. 2014 May;27(5):479-88.\u003c/li\u003e\n\u003cli\u003eChavali V, Tyagi SC, Mishra PK. Predictors and prevention of diabetic cardiomyopathy. Diabetes Metab Syndr Obes. 2013;6:151\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eZinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.\u003c/li\u003e\n\u003cli\u003eNeal B, Perkovic V, Mahaffey KW, Zeeuw de D, Fulcher G, Erondu N, et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 17;377(7):644-57.\u003c/li\u003e\n\u003cli\u003eWiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. DECLARE-TIMI 58 Investigators. N Engl J Med. 2019 Jan 24;380(4):347-57.\u003c/li\u003e\n\u003cli\u003eMcMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al.DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019 Nov21;381(21):1995-2008.\u003c/li\u003e\n\u003cli\u003ePacker M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020 Oct 8;383(15):1413-24.\u003c/li\u003e\n\u003cli\u003eSoga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H, et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol. 2018;17:132-9.\u003c/li\u003e\n\u003cli\u003eTanaka H, Soga F, Tatsumi K, Mochizuki Y, Sano H, Toki H, et al. Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure. Cardiovasc Diabetol. 2020;19:6-14.\u003c/li\u003e\n\u003cli\u003ePacker M, Anker SD, Butler J, Fillippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017; 2(9):1025-29.\u003c/li\u003e\n\u003cli\u003eAlberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eYang EY, Ghosn MG, Khan MA, Gramze NL, Brunner G, Nabi F, et al. Myocardial extracellular volume fraction adds prognostic information beyond myocardial replacement fibrosis. Circ Cardiovasc Imaging. 2019 Dec;12(12):e009535.\u003c/li\u003e\n\u003cli\u003eWong TC, Piehler KM, Kang IA, Kadakkal A, Kellman P, Schwartzman DS, et al. Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission. Euro Heart J. 2014 Mar;35(10):657-64.\u003c/li\u003e\n\u003cli\u003eIwata M, Matsushita Y, Fukuda K, Wakura T, Okabe K, Koshimizu Y, et al. Secretory units of islets in transplantation index is a useful predictor of insulin requirement in Japanese type 2 diabetic patients. J Diabetes Investig. 2014 Sep;5(5):570-80.\u003c/li\u003e\n\u003cli\u003eOlivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;52(7):559\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eLang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015 Mar;16(3):233\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eMessroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway JP. Modified Look-Locker inversion recovery (MOLLI) for high-resolution T1 mapping of the heart. Magn Reson Med. 2004;52:141-6.\u003c/li\u003e\n\u003cli\u003eCao Y, Zeng W, Cui Y, Kong X, Wang M, Yu J, et al. Increased myocardial extracellular volume assessed by cardiovascular magnetic resonance T1 mapping and its determinants in type 2 diabetes mellitus patients with normal myocardial systolic strain. Cardiovasc Diabetol. 2018 Jan 4;17(1):7-18.\u003c/li\u003e\n\u003cli\u003eKohlhaas M, Maack C. Adverse bioenergetic consequences of Na+-Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes. 2010 Nov 30;122(22): 2273-80.\u003c/li\u003e\n\u003cli\u003eBaartscheer A, Schumacher CA, Wust RC, Fiolet Jan WT, Stienen Ger JM, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na \u003csup\u003e+\u003c/sup\u003ethrough inhibition of the cardiac Na\u0026nbsp;\u003csup\u003e+\u003c/sup\u003e/H\u0026nbsp;\u003csup\u003e+\u003c/sup\u003e\u0026nbsp;exchanger in rats and rabbits. 2017; 60(3): 568-73.\u003c/li\u003e\n\u003cli\u003eLin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014 Oct 26;13:148-62.\u003c/li\u003e\n\u003cli\u003eHabibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017 Jan;16(1):9-23.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, table 1-2 is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diabetes mellitus-related cardiomyopathy, Heart failure, Sodium–glucose co-transporter 2 inhibitor, Left ventricular dysfunction, Left ventricular global longitudinal strain","lastPublishedDoi":"10.21203/rs.3.rs-117825/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-117825/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e In diabetes mellitus-related cardiomyopathy (DMCMP), hyperglycemia causes endothelial dysfunction, fibrosis, and myocardial injury, which result in left ventricular (LV) dysfunction. Treatment with sodium–glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of heart failure (HF). The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also direct actions on the myocardium leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction (EF) greater than 40% and type 2 diabetes mellitus (T2DM) treated with administration of empagliflozin (10 mg/day) were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the patients were divided into the early DMCMP group (n = 16, ECV ≤ 30%) and advanced DMCMP group (n = 19, ECV \u0026gt; 30%) and followed-up prospectively. Echocardiography was performed at baseline and after 12 months. LV systolic function assessed as LV global longitudinal strain (GLS) and diastolic function assessed as the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) were compared.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eECV was strongly correlated with T2DM duration (r\u003csup\u003e2\u003c/sup\u003e = 0.65, p \u0026lt; 0.001). At baseline, both groups had similar backgrounds (LVGLS: 7.9 ± 2.4% vs. 6.7 ± 3.0%, p = 0.207, and E/e’: 13.2 ± 6.1 cm/s vs. 12.6 ± 3.8 cm/s, p = 0.694). After 12 months, the early DMCMP group showed greater improvement in LVGLS (ΔLVGLS: 4.6 ± 1.5% vs. 1.6 ± 3.3%, p = 0.003) and E/e’ (ΔE/e’: -3.4 ± 5.5 cm/s vs. -0.1 ± 3.5 cm/s, p = 0.043) than in the advanced DMCMP group.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The positive effects of empagliflozin on LV dysfunction were more remarkable in DMCMP with mild cardiac fibrosis than with advanced fibrosis. Early intervention of SGLT2i for DMCMP is preferable.\u003c/p\u003e","manuscriptTitle":"Effects of Empagliflozin in Different Phases of Diabetes Mellitus-related Cardiomyopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-03 19:33:43","doi":"10.21203/rs.3.rs-117825/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb5d7ffe-0782-43ca-9b5c-ab8a3d191358","owner":[],"postedDate":"December 3rd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":1323096,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-12-03T19:33:45+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-03 19:33:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-117825","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-117825","identity":"rs-117825","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}