Abstract
The EMPA-REG OUTCOME study revealed that a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, can remarkably reduce cardiovascular (CV) mortality and heart failure in patients with high-risk type 2 diabetes. Recently, the CANVAS program also showed that canagliflozin, another SGLT2 inhibitor, induces a lower risk of CV events. However, the precise mechanism by which an SGLT2 inhibitor elicits CV protective effects is still unclear. Possible sympathoinhibitory effects of SGLT2 inhibitor have been suggested, as significant blood pressure (BP) reduction, following treatment with an SGLT2 inhibitor, did not induce compensatory changes in heart rate (HR). We have begun to characterize the effects of SGLT2 inhibitor on BP and sympathetic nervous activity (SNA) in salt-treated obese and metabolic syndrome rats, who develop hypertension with an abnormal circadian rhythm of BP, a non-dipper type of hypertension, and do not exhibit a circadian rhythm of SNA. Treatment with SGLT2 inhibitors significantly decreased BP and normalized circadian rhythms of both BP and SNA, but did not change HR; this treatment was also associated with an increase in urinary sodium excretion. Taken together, these data suggest that an SGLT2 inhibitor decreases BP by normalizing the circadian rhythms of BP and SNA, which may be the source of its beneficial effects on CV outcome in high-risk patients with type 2 diabetes. In this review, we briefly summarize the effects of SGLT2 inhibitors on BP and HR, with a special emphasis on SNA.
Highlights
Sodium-glucose cotransporter 2 (SGLT2) is located at the S1 and S2 segments of the proximal tubule epithelium, which reabsorbs approximately 90% of filtered glucose [1]
We briefly summarize the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on blood pressure (BP) and heart rate (HR) in patients with type 2 diabetes
We have recently shown that SGLT2 inhibitors improve disrupted circadian rhythms of BP in metabolic syndrome rats [SHR/NDmcr-cp(+/+) rats; SHRcp] [37] and salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats [44], both of which show non-dipper type of hypertension
Summary
Sodium-glucose cotransporter 2 (SGLT2) is located at the S1 and S2 segments of the proximal tubule epithelium, which reabsorbs approximately 90% of filtered glucose [1]. SGLT2 inhibitors induce glycosuria [2] and are widely used as antihyperglycemic agents in patients with type 2 diabetes [3]. The EMPA-REG OUTCOME study demonstrated that treatment with empagliflozin, an SGLT2 inhibitor, significantly decreased the primary composite outcome of cardiovascular (CV) events, thereby reducing CV mortality by 38% [4]. Further studies have shown that empagliflozin reduced heart failure hospitalization and CV death, with a consistent benefit in patients with and without baseline heart failure [5]. The CANVAS program has shown that canagliflozin, another SGLT2 inhibitor, lowers the risk of CV events by providing renal protection in type 2 diabetes patients [6].
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