This study investigated the effect of luseogliflozin on diastolic function in patients with T2DM and CVD. The results showed that the septal E/e′ ratios were not significantly changed among all patients after 24 weeks of luseogliflozin treatment. However, patients with an e′ velocity of less than 6 cm/sec at baseline had improved e′ velocity and septal E/e′ ratios. These results suggest that luseogliflozin may improve LV diastolic function in patients with T2DM and overt LV diastolic dysfunction at baseline. Also, luseogliflozin improved weight loss, glycemic control, and liver function.
Weight loss, lower systolic blood pressure, and decreased HbA1c are common effects of treatment with SGLT2 inhibitors, including luseogliflozin. Previous studies suggested the decrease in BW occurs during the initiation of treatment. This weight loss may be attributed to osmotic diuresis due to increased urinary glucose excretion [18]. The decrease in blood pressure is thought to be caused by a decrease in body fluid volume, and the increased excretion of glucose lowers HbA1c levels. Furthermore, the loss of extra energy likely improved the body’s metabolic function which helped improve liver function.
Echocardiographic findings that are used to evaluate LV diastolic function include structural changes, such as an increase in left atrial volume index or LV mass index; functional changes, such as an increased E/e′ ratio or reduced e′ velocity; and indirect measurements, such as increased tricuspid regurgitant velocity [19]. Among these metrics, e′ velocity obtained by tissue Doppler imaging is useful for estimating LV myocardial relaxation activity. Furthermore, decreased e′velocity may indicate the progression of LV diastolic dysfunction [20]. Previous studies have shown that the average E/e′ ratio of diabetic patients increases consistently compared to nondiabetic patients [7]. The present study provides us the meaningful clinical implications because this is the first prospective study examining the effects of luseogliflozin on LV diastolic function in patients with T2DM and CVD. While there was no significant change in the septal E/e′ ratio after 24 weeks of luseogliflozin treatment, luseogliflozin improved LV diastolic function assessed by e′ velocity and E/e′ ratio in patients with overt LV diastolic dysfunction at baseline. Recently, several studies have demonstrated the effects of SGLT2 inhibitors on LV diastolic function in patients with diabetes using echocardiography. Verma et al. reported that using empagliflozin for 3 months improved the LV diastolic function based on changes in e′ velocity among 10 diabetic patients with CVD [21]. Dapagliflozin [22] and canagliflozin [23,24] significantly reduced the E/e′ ratio in T2DM patients, and dapagliflozin was associated with improvement of LV longitudinal myocardial function [25]. This study further confirms the cardioprotective effects of SGLT2 inhibitors.
Cardiovascular prognosis in patients with diabetes is poor because diabetes has been linked to HFrEF and HFpEF [26]. The prevalence of HFpEF has been increasing since 2000 and accounts for more than 50% of hospital admissions for heart failure [27]. ACE inhibitors, ARBs [28], and β-blockers [29] are useful for treating HErEF, and SGLT2 inhibitors have improved cardiovascular outcomes, including HFrEF, in three large clinical trials: EMPA-REG OUTCOME [11], CANVAS Program [12], and DECLARE-TIMI 58 [13]. On the other hand, few studies are focusing on effective therapeutic agents for treating patients with HFpEF. Considering these clinical studies and our present study, we propose that luseogliflozin may be particularly effective in treating patients with HFpEF.
Some studies showed that SGLT2 inhibitors reduced all-cause mortality [30], and other meta-analyses and systematic reviews suggested that SGLT2 inhibitors protect against CVD and death in diverse subsets of the patients with T2DM regardless of CVD history [31]. Several mechanisms through which SGLT2 inhibitors have improved cardiovascular events have been studied; however, it is unclear which mechanism is most crucial [15]. The potential effects of SGLT2 inhibitors on LV structure and function are multifaceted, and these effects may be due to effects on systemic hemodynamics and metabolism [32]. SGLT2 inhibitors reduce circulating blood volume through osmosis and natriuresis. The diuretic effect of SGLT2 inhibitors reduces plasma volume, which is a potential factor in reducing hospitalizations due to heart failure [33]. The most commonly used loop diuretics and thiazides also reduce the intravascular volume and pure sodium balance as well as or better than SGLT2 inhibitors. However, in contrast to empagliflozin, these diuretics have not been proven to reduce cardiovascular mortality. This is probably because SGLT2 inhibitors, unlike loop and thiazide diuretics, do not cause reflex activation of the sympathetic nervous system. Such hemodynamic changes in intravascular volume and blood pressure observed during SGLT2 treatment are not accompanied by an increase in heart rate. Therefore, SGLT2 inhibitors may reduce the activation of the reflex sympathetic nervous system or implicate other neurohormonal pathways that affect the heart [34,35]. The significant effects of SGLT2 inhibitors on cardiovascular outcomes may also be attributed to the anti-oxidative, anti-inflammatory, or anti-apoptotic properties of SGLT2 inhibitors as shown in experimental models [15,36,37]. However, whether such effects seen in such preclinical studies affect humans remains to be determined. In the present study, we could not assess the mechanism through which luseogliflozin improved LV diastolic function in patients with T2DM and overt LV diastolic dysfunction at baseline. Further basic experiments are necessary for the future.
In this study, we selected luseogliflozin because it is highly selective for SGLT2 and was previously launched in Japan to treat the patients with T2DM. The structural feature of luseogliflozin is a 5-thioglucose analog that has a sulfur atom in place of oxygen in the glucose ring [38]. Clinical studies have shown that once-daily administration of luseogliflozin, unlike other SGLT2 inhibitors, leads to significant improvement of HbA1c levels at a very low dose of 2.5 mg. Luseogliflozin has the lowest effective dose among all SGLT2 inhibitors prescribed in Japan [18]. Recent inhibition kinetics and binding studies of luseogliflozin have shown that the dissociation of luseogliflozin from SGLT2 appears to be much slower than those of other SGLT2 inhibitors. For instance, the dissociation halftime of luseogliflozin–SGLT2 was approximately 7 h [39]. These characteristics of luseogliflozin might contribute to its long duration of action; however, the exact mechanism of binding is not revealed. Luseogliflozin lowers plasma glucose concentration and BW and has beneficial effects on other clinically relevant parameters, including blood pressure and uric acid, among patients with T2DM [38]. The decreases in HbA1c and BW from baseline to the end of treatment were − 0.63% and − 2.70 kg after 24 weeks of treatment; these results were similar to those produced by other SGLT2 inhibitors [39].
This study contained several limitations that need to be addressed. For instance, it was a single-center study and included a small number of patients without a placebo-controlled group. Further prospective studies with larger populations are needed to confirm our study results. In general, long-term observation is required to investigate the suppression of CV events; since this study was short term, a relationship between CV events could not be confirmed. Furthermore, detail hemodynamic evaluations were not performed using a cardiac catheter examination. Finally, we could not verify whether these effects were specific to luseogliflozin or shared by other SGLT2 inhibitors.