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

Ningning Wan¹, Asadur Rahman¹, Hirofumi Hitomi¹

¹Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Frontiers in Endocrinology

|August 11, 2018

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.

Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in type 2 diabetes. These drugs lower blood pressure by normalizing circadian rhythms of blood pressure and sympathetic nervous activity, potentially explaining their cardiovascular benefits.

Area of Science:

Cardiovascular research
Diabetes mellitus
Pharmacology

Background:

Sodium-glucose cotransporter 2 (SGLT2) inhibitors like empagliflozin and canagliflozin show cardiovascular benefits in type 2 diabetes.
The exact mechanism behind these cardiovascular protective effects remains unclear.
Previous studies suggest potential sympathoinhibitory effects due to blood pressure reduction without compensatory heart rate changes.

Purpose of the Study:

To investigate the effects of SGLT2 inhibitors on blood pressure (BP) and sympathetic nervous activity (SNA).
To explore the role of circadian rhythms in BP and SNA regulation by SGLT2 inhibitors.
To elucidate the mechanism underlying the cardiovascular protective effects of SGLT2 inhibitors.

Main Methods:

Utilized salt-treated obese rats with metabolic syndrome, exhibiting non-dipper hypertension and absent SNA circadian rhythm.
Administered SGLT2 inhibitors to assess changes in BP, heart rate (HR), and SNA.
Monitored urinary sodium excretion to evaluate the drug's effect on sodium balance.

Main Results:

SGLT2 inhibitor treatment significantly decreased BP in the study rats.
The treatment normalized the circadian rhythms of both BP and SNA.
Heart rate (HR) remained unchanged, and urinary sodium excretion increased.

Conclusions:

SGLT2 inhibitors decrease BP by normalizing circadian rhythms of BP and SNA.
This normalization of BP and SNA circadian rhythms may contribute to the beneficial cardiovascular outcomes observed in type 2 diabetes patients.
SGLT2 inhibitors offer a potential therapeutic strategy for managing hypertension and cardiovascular risk in this population.

Read full analysis

Keywords:

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

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