Type 2 diabetes mellitus (T2DM) is a worldwide growing public health problem that is associated with a rising prevalence. T2DM is a complex, chronic disease that affects about 463 million people worldwide (9.3% of the global population aged 20–79 years). The increase in T2DM prevalence in Japan has been attributed to economic development, aging and adoption of Westernized lifestyles, the number of “persons in whom diabetes is strongly suspected” was estimated to be approximately 10 million, and the number of “persons in whom the possibility of diabetes cannot be ruled out” is also estimated to be approximately 10 million. In most people this disease is progressive, and it is associated with risks of micro- and macrovascular complications, including cardiovascular disease (CVD). Patients with T2DM are at two-to three-fold increased risk of develo** CVD throughout their lifetime, the leading cause of morbidity and mortality in developed countries and beyond. Hypertension occurs in more than two thirds of patients with T2DM and is associated with a further marked increase of cardiovascular events and mortality. Therefore, the management of T2DM should focus on not only controlling the blood glucose levels but also addressing cardiovascular risk factors such as hypertension. In fact, several previous landmark clinical trials demonstrated that only strict glucose-lowering therapy failed to improve the prognosis of patients with T2DM [1, 2]. Interestingly, the United Kingdom Prospective Diabetes Study (UKPDS) 36 reported that the decrease in risk for each 10 mmHg reduction of updated mean systolic blood pressure (BP) was between 12% and 19% for both macrovascular and microvascular complications [3]. Furthermore, it has been reported that for every 10 mmHg decrease in systolic BP was associated with a significantly lower risk of mortality (relative risk [RR], 0.87; 95% CI, 0.78–0.96); absolute risk reduction (ARR) in events per 1000 patient-years (3.16; 95% CI, 0.90–5.22), cardiovascular events (RR, 0.89 [95% CI, 0.83–0.95]; ARR, 3.90 [95% CI, 1.57–6.06]), coronary heart disease (RR, 0.88 [95% CI, 0.80–0.98]; ARR, 1.81 [95% CI, 0.35–3.11]), stroke (RR, 0.73 [95% CI, 0.64–0.83]; ARR, 4.06 [95% CI, 2.53–5.40]), albuminuria (RR, 0.83 [95% CI, 0.79–0.87]; ARR, 9.33 [95% CI, 7.13–11.37]), and retinopathy (RR, 0.87 [95% CI, 0.76–0.99]; ARR, 2.23 [95% CI, 0.15–4.04]) in patients with T2DM [4]. Therefore, reducing BP is one of the most effective interventions to reduce mortality in patients with T2DM. Although target BP level in patients with T2DM is currently recommended to be <130/80 mmHg in the Japanese Society of Hypertension Guidelines for Management of Hypertension, it has proved difficult to achieve these BP targets in clinical practice in Japan and Western countries [5, 6]. From that point of view, there is a need for further implementation of individualized optimal and clinically meaningful antihypertensive care in patients with T2DM, especially those at high risk of cardiovascular events.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors facilitating glucose excretion and lowering the blood glucose levels, initially developed for T2DM treatment. Beyond glycemic control, accumulated evidence demonstrated that SGLT2 inhibitors modestly reduce BP in patients with T2DM. Furthermore, it has been reported that in patients with T2DM and hypertension, empagliflozin reduced systolic BP and diastolic BP versus placebo, irrespective of the use of background number of antihypertensives agents [7]. However, clinical evidence regarding their detailed effects on BP in Asian populations is still limited. Therefore, the authors investigate the detailed effects of 24 weeks of empagliflozin therapy on BP in Japanese patients with T2DM and at higher risk of cardiovascular events, according to the clinical characteristics and background uses of anti-hypertensive medications. The present study was a post-hoc sub-analysis of the EMBLEM trial, an investigator-initiated, multicenter, placebo-controlled, double-blinded, randomized clinical trial conducted in 16 centers in Japan. The primary result of the EMBLEM trial suggests that 24 weeks of empagliflozin treatment is not associated with an improvement in endothelial function evaluated using the reactive hyperemia-peripheral arterial tonometry index in patients with T2DM and CVD. First of all, in this post-hoc sub-analysis of the EMBLEM trial, the authors demonstrated that empagliflozin treatment significantly reduced the systolic/diastolic BPs and mean arterial pressure (MAP) over 24 weeks, and the estimated mean absolute reduction from baseline to week 24 was −8.7 (95% confidence interval [CI], −11.9 to −5.5) mmHg in systolic BP, −3.6 (95% CI, −5.9 to −1.3) mmHg in diastolic BP, and −5.6 (95% CI, −7.8 to −3.3) mmHg in MAP, and empagliflozin treatment, compared to placebo, reduced systolic/diastolic BPs and MAP over 24 weeks in Japanese patients with T2DM and established CVD [8]. Similar to the EMBLEM trial, an initial landmark trials (the EMPA-REG OUTCOME, the CANVAS, and the DECLARE-TIMI 58) investigating the effect of SGLT2 inhibitors in patients with T2DM and high cardiovascular risk reduced systolic/diastolic BPs by 2.7–5 mmHg/0.7–3 mmHg, respectively. Compared to these studies, the reductions in systolic/diastolic BPs in the present analysis were seemingly slightly greater. The reason for this difference remains uncertain. However, Asians and American Africans in general have higher salt intake and higher salt sensitivity than Westerners and therefore, possibility that Asians and those of African American ethnicity may be responders to the BP-lowering effects of SGLT2i compared with Caucasian populations [9]. Secondly, the group difference in change in mean systolic BP with empagliflozin minus placebo was apparently greater in the subgroup with a higher baseline systolic BP (≥130 mmHg) than in the subgroup with a lower baseline systolic BP (<130 mmHg) (p = 0.020). Thirdly, most patients (87.6%) in this study cohort had been taking at least one anti-hypertensive medication at baseline, the addition of SGLT2 inhibitors merits effective BP-lowering in patients with T2DM at a high risk of CVD, irrespective of BP control and background treatment with anti-hypertensive medications including the use of diuretics. Furthermore, the number of anti-hypertensive medications did not affect the effect of empagliflozin on systolic BP reduction, although the larger the number of anti-hypertensive medications taken, the greater the reduction in systolic BP with empagliflozin. Since anti-hypertensive treatment has been reported to reduce the risk of mortality and cardiovascular morbidity in people with T2DM and a systolic BP more than 140 mm Hg, these results obtained in this analysis are very significant in clinical practice [10]. The initial BP-lowering effect of SGLT2 inhibitors is thought to be a decrease in circulating plasma volume caused by osmotic diuresis, followed by an increase in urinary sodium excretion. Furthermore, it has been reported that each 1% reduction in body weight was associated with a 0.62 mmHg reduction in systolic BP in patients with T2DM [11]. Interestingly, 24-week changes in the systolic BP were positively correlated with those in the body mass index in the empagliflozin-treated group in this post-hoc sub-analysis of the EMBLEM trial. Thus, this result suggests that weight loss may also influence the BP-lowering effect of SGLT2 inhibitors in Asian populations, similar to previous reports. A number of other clinical and experimental evidences suggest that SGLT2 inhibitors exert BP-lowering effects involving mechanisms that may act independently their glucose-lowering effects (Fig. 1). The results obtained in this post hoc analysis suggests that the addition of SGLT2 inhibitors merits effective BP-lowering in patients with T2DM at a high risk of cardiovascular disease with inadequate BP control despite background treatment with conventional anti-hypertensive medications in Asian populations.

Fig. 1
figure 1

Possible mechanisms of blood pressure-lowering effects of SGLT2 inhibitors

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