The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Sympathetic Nervous Activity

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.

Keywords: CANVAS program; EMPA-REG OUTCOME trial; blood pressure; heart rate; sodium-glucose cotransporter 2 (SGLT2) inhibitor; sympathetic nervous activity.

Figures

Figure 1

Effects of empagliflozin treatment on systolic blood pressure (SBP), and on circadian rhythm of SBP, in Otsuka Long Evans Tokushima Fatty (OLETF) rats. (A) 24-h SBP. (B) Average of 24-h SBP. (C) SBP in dark and light periods. (D) Differences between dark and light period in SBP. OLETF rats were treated with vehicle (vehicle, n = 7), 1% NaCl drinking water (high-salt, n = 5), or 1% NaCl drinking water and empagliflozin (high-salt + empagliflozin, n = 8), for 5 weeks. Values are mean ± SEM. ***P < 0.0001 vs. vehicle and high-salt + empagliflozin (one-way analysis of variance followed by Tukey's multiple comparison test), †P < 0.0001 vs. high-salt + empagliflozin dark period (2-way analysis), #P < 0.0001 vs. high-salt light period (t-test), *P < 0.05 vs. high-salt (t-test).

Figure 2

Effects of empagliflozin treatment on low frequency (LF) of systolic blood pressure (SBP), and on circadian rhythm of LF of SBP, in Otsuka Long Evans Tokushima Fatty (OLETF) rats. (A) 24-h LF of SBP. (B) Average of 24-h LF of SBP. (C) LF of SBP in dark and light period. (D) Differences between dark and light period in LF of SBP. OLETF rats were treated with vehicle (vehicle, n = 7), 1% NaCl drinking water (high-salt, n = 5), or 1% NaCl drinking water and empagliflozin (high-salt + empagliflozin, n = 8), for 5 weeks. Values are mean ± SEM. †P < 0.001 vs. high-salt + empagliflozin dark period (2-way analysis), #P < 0.001 vs. high-salt light period (t-test), *P < 0.05 vs. vehicle (one-way analysis of variance followed by Tukey's multiple comparison test).

Figure 3

Possible mechanisms for reducing sympathetic nervous activity (SNA) through use of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Recent studies have suggested that SGLT2 inhibitors elicit a reduction in SNA by decreasing insulin, leptin (59, 60) and blood glucose levels; and by improving insulin resistance and hyperinsulinemia, which could reduce the activation of carotid body (CB) (57); as well as by reducing sodium volume, which inhibits the activation of organum vasculosum laminae terminalis (OVLT) (58). Importantly, there are likely to be other mechanisms that have not been described.