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Sodium glucose cotransporter‐2 inhibitor was associated with an improvement in left ventricular systolic function in patients with type 2 diabetes mellitus with impaired left ventricular systolic function

Abstract Aims Recent studies indicated that sodium glucose cotransporter‐2 inhibitors (SGLT2i) reduced heart failure hospitalization in patients with type 2 diabetes mellitus (T2DM). However, whether SGTL2i can improve left ventricular (LV) systolic and diastolic function remained unclear. This study aimed to compare the change in echocardiographic parameters in T2DM patients receiving SGLT2i with a different baseline LV ejection fraction (LVEF). The change in echocardiographic parameters was also compared between T2DM patients treated with SGLT2i and those treated with dipeptidyl peptidase‐4 inhibitor (DPP4i). Methods and results This multicentre cohort study consecutively enrolled 665, 119, and 132 T2DM patients treated with SGLT2i with a preserved (≥50%), moderately reduced (40–50%), and reduced baseline LVEF (<40%), respectively, with paired baseline and post‐treatment echocardiographic data available between 1 June 2016 and 31 May 2018. There were 212 patients treated with DPP4i with paired baseline and post‐treatment echocardiographic data available at the same time. For those patients treated with DPP4i, 45 patients had impaired baseline LVEF of <50%. Echocardiographic parameters, including LVEF, LV end‐diastolic volume, LV end‐systolic volume (LVESV), and LV diastolic function, were analysed at baseline and after treatment. After a median SGLT2i treatment period of 230 days, patients with reduced LVEF were associated with an improvement in LVEF from 29.4 ± 7.4% to 42.2 ± 15.2% (P < 0.0001) and decrease in LVESV from 133.2 ± 49.2 to 117.4 ± 60.1 mL (P = 0.0002). Patients with moderately reduced LVEF were associated with an improvement in LVEF from 44.8 ± 2.9% to 49.7 ± 12.4% (P < 0.0001) and decrease in LVESV from 90.7 ± 31.1 to 80.0 ± 36.2 mL (P = 0.0017). Patients with preserved LVEF did not show an improvement in LVEF and LVESV after SGLT2i treatment. There were no significant changes of LV end‐diastolic volume, LV diastolic function, and LV wall thickness in three study groups after SGLT2i treatment. In contrast, patients with impaired baseline LVEF (<50%) did not show any change in LVEF and LVESV after DPP4i treatment. Conclusions Sodium glucose cotransporter‐2 inhibitor was associated with an improvement in LV systolic function in patients with T2DM with reduced and moderately reduced LVEF. In contrast, DPP4i treatment was not associated with any improvement in LVEF among patients with impaired LVEF.


Introduction
Type 2 diabetes mellitus (T2DM) increases the risk of heart failure, including reduced and preserved left ventricular ejection fraction (LVEF), and cardiovascular events and mortality. 1,2 Sodium glucose cotransporter-2 inhibitors (SGLT2i) are a new class of anti-hyperglycaemic agents that inhibit urinary glucose reabsorption. 3 Of note, SGTL2i reduced the blood sugar level and blood pressure, body weight, and albumin level via an insulin-independent mechanism in patients with T2DM. Furthermore, three large randomized controlled trials with EMPA-REG OUTCOME (empagliflozin), CANVAS Program (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin) all demonstrated that three SGLT2i, compared with the current standard-of-care diabetes management, significantly reduced the risk of heart failure hospitalization in patients with T2DM with/without established cardiovascular diseases. [4][5][6] In contrast, several dipeptidyl peptidase-4 inhibitor (DPP4i) (e.g. saxagliptin, alogliptin, vildagliptin, and linagliptin) increased adverse heart failure events in patients with T2DM with/without a history of heart failure when compared with placebo. 7-10 However, there was no objective evaluation of the change in cardiac function in patients with T2DM treated with SGLT2i or DPP4i in those pivotal trials, and it was unclear whether the reduced risk of hospitalization due to heart failure in patients with T2DM treated with SGLT2i resulted from the reduction in body loading (e.g. reduction in body weight or salt loading by SGLT2i treatment) or improvement in cardiac systolic or diastolic function mediated by SGLT2i treatment objectively. The underlying mechanism associated with a favourable outcome of SGLT2i treatment on cardiac function is not well known. The present study aimed to investigate the effect of SGLT2i on LV systolic and diastolic function and heart chamber size, as measured by two-dimensional (2D) echocardiography, in patients with T2DM with a different baseline LVEF in the real-world practice. The change in echocardiographic parameters was compared between patients with T2DM treated with SGLT2i and those treated with DPP4i.

Methods Database
In the present study, all patients' data were obtained from the Chang Gung Memorial Hospital (CGMH) Medical System, which comprised four tertiary care medical centres and three major teaching hospitals with a total of 10 050 beds and admits approximately 280 000 patients annually in Taiwan. 11 The advantage of the CGMH medical database is that each patient's detailed chart record, diagnosis, imaging, and laboratory data are all available. 12 The identification number and personal information of each patient are encrypted and de-identified using a consistent encrypting procedure; therefore, informed consent was waived for this study.

Study design
The study is a retrospective, multicentre, and observational study. There were 42 561 patients with T2DM aged ≥18 years newly receiving SGLT2i or DPP4i from 1 June 2016 to 31 May 2018. Among these, a total of 1433 and 236 patients treated with SGLT2i and DPP4i have a paired data of baseline and post-treatment 2D echocardiography available. The date of baseline echocardiography was further restricted within 6 months before the drug index date, and the date of post-treatment echocardiography was limited to 3-18 months after drug index date. Finally, a total of 916 and 212 consecutive patients with T2DM receiving SGLT2i and DPP4i, respectively, were enrolled in the analysis. The study protocol complied with the Declaration of Helsinki and was approved by the Institutional Review Board of the CGMH.

Conventional echocardiography
The patients underwent transthoracic 2D echocardiography using a commercially available system (Vivid 9, General Electric Vingmed Ultrasound, Horten, Norway). Thickness of left ventricular (LV) intraventricular septum and free wall, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LVEF were assessed from parasternal or apical views using the standard M-mode or 2D Simpson method. Transmitral E wave, filling velocity during atrial systole (A wave), deceleration time, and e′ velocity were measured using tissue Doppler echocardiography. The e′ velocity was calculated from the average of the lateral and septal values.

Covariates
Baseline covariates referred to any claim record with the abovementioned diagnoses or medication codes prior to the index date. The ischaemic aetiology of patients with T2DM was defined by one of the following criteria: (i) ≥75% luminal diameter stenosis of the main epicardial coronary artery; (ii) history of myocardial infarction or coronary revascularization; and (iii) myocardial ischaemia or infarction documented by myocardial perfusion imaging. A history of any prescription drug was confined to medications used at least once within 3 months preceding the drug index date. Important laboratory data, including body weight, resting heart rate, systolic and diastolic blood pressure, serum haemoglobin A1c level, haemoglobin level, platelet count, estimated glomerular filtration rate, alanine aminotransferase level, lipid profiles, and uric acid level, were based on the measurements performed within 6 months before the drug index date.

Statistical analyses
Continuous variables were expressed as mean ± standard deviation or as median (range). Proportions were compared using analysis of variance. The change in all echocardiographic parameters before and after treatment was compared using paired t-test. Predictive variables for outcome were estimated using the multivariate Cox proportional hazard regression models. Variables with interest in Table 1 were selected to include in the multivariate model in Table 3. In all tests, a P value <0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA).

Results
Baseline characteristics of patients treated with SGLT2i with a preserved (≥50%), moderately reduced (40-50%), and reduced (<40%) baseline LVEF A total of 916 consecutive patients treated with SGLT2i with paired baseline and post-treatment echocardiographic data available between 1 June 2016 and 31 May 2018 were enrolled. Of these patients, 595 and 321 were using empagliflozin and dapagliflozin, respectively. Moreover, 665, 119, and 132 patients treated with SGLT2i have preserved (≥50%), moderately preserved (40-50%), and reduced (<40%) baseline LVEF, respectively. Compared with patients with preserved LVEF of ≥50%, patients with moderately reduced or reduced LVEF were younger, were less likely female, and had a higher prevalence of ischaemic heart disease. Patients with moderately reduced or reduced LVEF had a higher haemoglobin A1c level but a comparable estimated glomerular filtration rate compared with patients with preserved LVEF. For baseline medication, patients with moderately reduced or reduced LVEF had a higher prescription of heart failure medications, such as beta-blocker, renin-angiotensin system blocker, mineralocorticoid receptor antagonist, diuretics, nitrate, and digoxin, than patients with preserved LVEF ( Table 1).
Change in haemodynamics and echocardiographic parameters in patients with preserved (≥50%), moderately reduced (40-50%), and reduced (<40%) baseline LVEF after SGLT2i treatment The changes in haemodynamics and echocardiographic parameter in the three study groups before and after treatment are summarized in Table 2 and Figure 1. After a median treatment period of 230 (25th-75th percentile, 161-316) days, the reduced LVEF group was associated with an improvement in LVEF from 29.4 ± 7.4% to 42.2 ± 15.2% (P < .0001) and decrease in LVESV from 133.2 ± 49.3 to 117.4 ± 60.1 mL (P = 0.0002) after SGLT2i treatment. After a median treatment period of 243 (25th-75th percentile, 173-330) days, the moderately reduced LVEF group was associated with an improvement in LVEF from 44.8 ± 2.9% to 49.7 ± 12.4% (P < .0001) and decrease in LVESV from 90.7 ± 31.1 to 80.0 ± 36.2 mL (P = 0.0017). In contrast, the preserved LVEF group did not show any change in LVEF and LVESV after SGLT2i treatment. There were no significant changes in other echocardiographic parameters, including LVEDV, LV diastolic function, or LV wall thickness, in the three study groups after SGLT2i treatment ( Table 2). In the haemodynamic change after SGLT2i treatment, both patients with preserved and reduced baseline LVEF were associated with a decrease in body weight (both P < 0.01). Of note, patients with moderately reduced and reduced baseline LVEF were both associated with a decrease in resting heart rate as well as diastolic blood pressure ( Table 2).
We further analysed our patients according to ischaemic (n = 390) or non-ischaemic aetiology (n = 526). Generally, the result of subgroup analysis persisted in both subgroups: moderately reduced and reduced LVEF were both associated with an improvement in LVEF and decrease in LVESV after SGLT2i treatment. In contrast, the preserved LVEF group did not show any change in LVEF and LVESV in either the ischaemic or non-ischaemic subgroup after SGLT2i treatment ( Table  2).
We further compared the change in LVEF and LVESV in patients with impaired LVEF (<50%) according to different time periods after SGLT2i treatment. Of 251 patients with impaired LVEF (<50%), 84, 79, 47, and 41 patients had paired echocardiography data after 3-6, 6-9, 9-12, and ≥12 months of SGLT2i treatment. It is noted that the use of SGLT2i was associated with improved LVEF and LVESV as early as 3-6 months after treatment ( Figure 2).

Baseline characteristics of patients with an impaired baseline LVEF (<50%) treated with DPP4i vs. SGLT2i
We further compared the change in echocardiographic parameters between patients with impaired LVEF (<50%) treated with SGLT2i and those treated with DPP4i. Among the 212 patients treated with DPP4i, 45 patients had impaired baseline LVEF <50%. Table 3 summarized the baseline characteristics between the DPP4i and SGLT2i groups. Generally, there was no difference in the baseline co-morbidities, heart failure and anti-diabetic medications, and baseline echocardiographic parameters between the DPP4i and SGLT2i groups.  Change in haemodynamics and echocardiographic parameters in patients with an impaired baseline LVEF (<50%) treated with DPP4i vs. SGLT2i In the haemodynamic change after treatment, both DPP4i and SGLT2i groups were associated with a decrease in body weight (both P < 0.05). Of note, only the SGLT2i group had a decrease in resting heart rate (P < 0.0001) as well as diastolic blood pressure (P = 0.0001) ( Table 4). Regarding the change in echocardiographic parameters after treatment, patients with impaired baseline LVEF had an improvement in LVEF from 36.7 ± 9.6% to 45.8 ± 14.4% (P < 0.0001) and decrease in LVESV from 113.3 ± 46.8 to 99.9 ± 53.6 mL (P < 0.0001) after SGLT2i treatment. In contrast, patients with impaired baseline LVEF did not show any change in LVEF and LVESV after DPP4i treatment ( Table 4 and Figure 3). There were no significant changes in other echocardiographic parameters including LVEDV, LV diastolic function, or LV wall thickness in both DPP4i and SGLT2i groups. Sensitivity analyses were performed using a 1:3 matching of DPP4i (n = 39) to SGLT2i (n = 117) by baseline characteristics presented in Table 3 to test if the results were still consistent with the main analysis as shown in Table 4 and Figure 3.
Supporting Information, Table S1 shows the baseline characteristics between the paired DPP4i and SGLT2i groups. There was no difference in the baseline characteristics, laboratory data, medications, and echocardiographic parameters between the paired DPP4i and SGLT2i groups after propensity score matching. Consistent with the main analysis, use of SGLT2i, rather than DPP4i, was associated with a decrease in body weight, resting heart rate, and diastolic blood pressure (Supporting Information, Table S2). In contrast to DPP4i treatment, SGLT2i treatment was associated with improvement in LVEF and reverse remodelling of LVESV (Supporting Information, Table S2 and Figure S1).

Main findings
To our best knowledge, this is the largest study to evaluate the change in cardiac function using 2D echocardiography in patients with T2DM after SGLT2i treatment in the real-world daily practice. The main findings of this study are as follows: (i) in a total of 665, 119, and 132 patients with T2DM treated with SGLT2i with a baseline preserved (≥50%), moderately reduced (40-50%), and reduced (<40%) LVEF, a patient with a reduced or moderately reduced LVEF was associated with a significant improvement in LVEF and reverse remodelling of LVESV after SGLT2i treatment. In contrast, there were no significant changes in LVEF or reverse    Change in echocardiographic parameters in patients with type 2 diabetes mellitus treated with SGLT2i with preserved (≥50%), moderately reduced (40-50%), and reduced (<40%) baseline LVEF. Both the moderately reduced and reduced LVEF groups had improvement in LVEF and decrease in LVESV after SGLT2i treatment. In contrast, the preserved LVEF group did not show any change in LVEF and LVESV after SGLT2i treatment. There were no significant changes in LVEDV for three study groups after SGLT2i treatment. LVEDV, left ventricular (LV) end-diastolic volume; LVEF, LV ejection fraction; LVESV, LV end-systolic volume; SGLT2i, sodium glucose cotransporter-2 inhibitor. investigated the change in cardiac function using cardiac magnetic resonance imaging in 48 patients with T2DM using empagliflozin of 10 mg/day. Compared with placebo treatment, empagliflozin was associated with significant reduction in LV mass index after 6 months. There was no  difference in LVEF and LVESV after empagliflozin treatment. 13 Soga et al. also evaluated 53 patients with T2DM with stable heart failure receiving dapagliflozin of 5 mg/day using echocardiography. There were significantly improved LVEF, LV mass, left atrial volume, and E/e′ ratio after the 6 months of treatment. 14 Matsutani et al. evaluated the effects of additional treatment with canagliflozin on LV function using echocardiography in 37 patients with T2DM.
There was an improvement in E/e′ ratio and reduced LV mass index but without change in cardiac chamber size and LVEF after the 3 months of treatment. 15 Otagaki et al. studied 26 consecutive patients with T2DM receiving tofogliflozin and performed echocardiography before and ≥6 months after tofogliflozin administration. Compared with the placebo group, tofogliflozin was associated with an improvement in systolic (LVEF) and diastolic (E/e′ ratio) function after treatment. 16 Generally, the abovementioned studies had an extremely limited patient population, but all of them showed an improvement in LV diastolic function after different SGLT2i treatments. However, the outcomes regarding the improvement in LV systolic function and reverse remodelling of cardiac chamber after SGLT2i treatment showed conflicting results. In contrast, our study was the largest real-world study enrolling 916 patients treated with SGLT2i, showing that SGLT2i treatment was indeed associated with a significant improvement in LVEF and reverse remodelling of LVESV in T2DM patients with moderately reduced or reduced baseline LVEF specifically. The discrepancy between our findings and those of previous studies might be attributed to the different study populations and increased severity of baseline heart function impairment in our study (27% of patients with an impaired baseline LVEF <50%). Nevertheless, our results are in accordance with the recent study showing that patients with T2DM with worse baseline characteristics benefit more from the SGLT2i treatment. 17 Recently, the subgroup analysis of the DECLARE-TIMI 58 indicated that SGLT2i with dapagliflozin reduced the risk of cardiovascular death or heart failure hospitalization to a greater extent in 671 patients with reduced baseline LVEF (LVEF <45%) than in those without reduced LVEF. This difference was driven by large reductions in cardiovascular death and all-cause mortality in patients with reduced LVEF. 18 However, the major limitation is that the post hoc analysis did not report the following change in echocardiographic parameters in patients with reduced LVEF after SGLT2i treatment. Nevertheless, the improvement in LV systolic function and reverse in LVESV specifically in patients with impaired baseline LVEF in our present study may echo the greater benefit in patients with reduced LVEF as demonstrated in the pivotal trial. Further prospective and randomized controlled studies investigating the cardiovascular outcome and change in cardiac function in SGLT2i treatment are warranted.

Underlying mechanism of SGLT2i in the improvement in cardiac function
In patients with T2DM, LV hypertrophy and impaired diastolic function are more prevalent compared with those in individuals without T2DM. 19 'Diabetic cardiomyopathy' is thought to be multifactorial, which is initially characterized by myocardial fibrosis and dysfunctional remodelling and associated with LV diastolic dysfunction, followed by progressive LV systolic dysfunction in the late stage. 20 Because only SGLT1 but not SGLT2 receptors were identified in the cardiac tissue, 21 the potential effect of SGLT2i on LV function and structure is hypothesized to be multifactorial and mediated predominantly by metabolic effects and systemic haemodynamics. 19 A number of other biological effects have also been demonstrated with SGLT2i, including improvement in arterial stiffness, vascular resistance, vascular endothelial function, and myocardial fibrosis. 22,23 SGLT2i can also shift myocardial fuel metabolism away from fat/glucose oxidation to a more energy-efficient fuel like ketone bodies, thereby improving myocardial work efficiency and function. 24 Although many hypotheses currently exist, the biological effects of SGLT2i on cardiac function and structure remain uncertain and need further investigation through detailed mechanistic studies.

Effect of DPP4i on cardiac function in T2DM
In contrast to the SGLT2i treatment, DPP4i treatment did not show significant improvement in LVEF or diastolic function in patients with T2DM. The relative effect of DPP4i on the risk of heart failure in patients with T2DM is uncertain, given the relatively short follow-up and low quality of evidence. However, both randomized controlled trials and observational studies suggest that DPP4i may increase risk of heart failure hospitalization in patients with T2DM with existing cardiovascular diseases or multiple cardiovascular risk factors. 25 Nevertheless, our data were compatible with those of recent studies showing that SGLT2i use was associated with a reduced risk of heart failure among patients with T2DM when compared with DPP4i use. 26,27 Further prospective and randomized controlled studies investigating the cardiovascular outcome and change in LV function in patients with T2DM treated with SGLT2i vs. DPP4i are warranted.

Study limitations
The present study had several limitations. First, this is a retrospective and multicentre study. The follow-up echocardiography was performed 6 months before and 3-18 months after the initiation of treatment. We categorized our patients into different time periods after SGLT2i treatment and found that SGLT2i treatment was associated with SGLT2 inhibitor in cardiac systolic function improved LVEF and LVESV as early as 3-6 months after treatment. The long range in post-treatment echocardiography is a major limitation in the present study. Although our study is the largest study investigating the change in echocardiographic parameters at baseline and after treatment in patients with T2DM treated with SGLT2i, further welldesigned, prospective, and randomized controlled studies with enrolment of more patient populations are still necessary to validate our findings. Second, SGLT2i treatment was associated with a decrease in body weight, resting heart rate, and diastolic blood pressure in our present study, and it is unclear whether the improvement in cardiac systolic function and reverse remodelling of LVESV in patients with T2DM using SGLT2i partially resulted from the weight loss caused by SGLT2i itself or adequate control of hypertension. However, the SGLT2i group with a preserved baseline LVEF and the DPP4i group with an impaired baseline LVEF showed a decrease in body weight but did not show any improvement in cardiac systolic function or reverse LV remodelling in the present study. Third, we also did not report the B-type natriuretic peptide (BNP) data due to limited BNP data available in our database. In the present study, the data of baseline and post-treatment echocardiography were obtained in the outpatient service for each patient with T2DM; therefore, the serum BNP level was not routinely checked in stable patients with T2DM in our daily practice. Fourth, the baseline and post-treatment echocardiography in each patient with T2DM may be performed by different cardiologists. Although all our cardiologists were qualified to perform echocardiography based on a standardized protocol in the CGMH medical system, echocardiography remains largely an operator-dependent technique; therefore, the intra-observer and inter-observer variability of echocardiography cannot be ruled out. Finally, our present study only enrolled Asian patients; therefore, whether the results can be extrapolated to other non-Asian ethnicities remains unclear.

Conclusions
The largest real-world study indicated that SGLT2i treatment was associated with an improvement in LV systolic function in T2DM patients with reduced or moderately reduced rather than preserved baseline LVEF. The advantage of SGLT2i treatment in improving cardiac function persisted in the patient subgroup with an ischaemic or non-ischaemic aetiology. In contrast, patients with impaired baseline LVEF did not show any improvement in LVEF or reverse remodelling of LVESV after DPP4i treatment. Figure S1. The change of echocardiographic parameter for paired T2DM patients with an impaired baseline LVEF (< 50%) treated with DPP4i versus SGLT2i after 1:3 propensity score matching. Those patients with an impaired baseline LVEF were associated with an improvement of LVEF and decrease of LVESV after SGLT2i treatment (n = 117). In the contrast, the patients with an impaired baseline LVEF did not showed any change of LVEF and LVESV after DPP4i treatment (n = 39). There were no significant change of LVEDV for both DPP4i and SGLT2i groups. DPP4i = dipeptidyl peptidase-4 inhibitor; LVEF = left ventricular (LV) ejection fraction; LVEDV = LV end diastolic volume; LVESV = LV end systolic volume; SGLT2i = sodium glucose cotransporter-2 inhibitor; T2DM = type 2 diabetes mellitus Table S1. Clinical and echocardiographic characteristics in paired type 2 diabetes mellitus (T2DM) patients treated with dipeptidyl peptidase-4 inhibitor (DPP4i) vs. sodium glucose co-transporter-2 inhibitor (SGLT2i) with a reduced LVEF of < 50% after 1:3 propensity score matching Table S2. The changes of hemodynamics and echocardiographic parameter for paired T2DM patients treated with DPP4i and SGLT2i after 1:3 propensity score matching with a reduced baseline LVEF of <50% at baseline and after treatment