桂田 健一

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to suppress cardiovascular events and are widely used for treating diabetes, chronic heart failure and chronic kidney disease. Although the underlying mechanisms by which SGLT2 inhibitors suppress cardiovascular events are not entirely clear, several mechanisms have been proposed to explain the cardiorenal protective effects of SGLT2 inhibitors. One of these involves sympathoinhibition. In vitro, SGLT2 expression is upregulated by norepinephrine, and SGLT2 inhibitors have been shown to attenuate SGLT2 expression and normalize the diuretic response to volume expansion with isotonic saline in rats with heart failure. These findings suggest that inhibition of renal sympathetic nerve activity is the mechanism underlying the beneficial effects of SGLT2 inhibitors on heart failure. Increased resting afferent renal nerve activity has been observed in several disease models, including models of hypertension, heart failure, and kidney disease, and might induce augmented sympathetic outflow via the central nervous system. SGLT2 inhibitors may suppress afferent renal nerve activity via intrarenal environmental modifications such as renal tissue hypoxia, inflammation, oxidative stress, mitochondrial function, and congestion, thereby inhibiting sympathetic outflow to the peripheral organs, including the heart and kidneys. On the other hand, SGLT2 is also expressed in the brain, and electrophysiological techniques in rats have shown that SGLT2 inhibitors suppress the activities of the rostral ventrolateral medulla neurons which project to the sympathetic preganglionic nuclei of the spinal cord to control sympathetic outflow, suggesting decreased sympathetic nerve activities. This mini review focuses on the bidirectional interaction between SGLT2 and the sympathetic nervous system and introduces recent related findings from Hypertension Research and other journals.

We conducted a systematic review and meta-analysis to evaluate the effects of intensive versus standard antihypertensive therapy on cardiovascular outcomes in adult patients with hypertension. The primary endpoints were composite cardiovascular events, all-cause death, cardiovascular death, and serious adverse events. The secondary endpoints included cognitive impairment, hypotension, syncope, acute kidney injury, and composite renal outcomes. Eight trials classifying a systolic blood pressure (SBP) target of <130 mmHg as intensive control was adopted in the primary analysis. The intensive blood pressure (BP) control significantly reduced the relative risk (RR) for cardiovascular events and cardiovascular death compared to standard BP control (RR 0.83 [95% confidence interval, 0.76-0.90] and 0.74 [0.56-0.97], respectively). The intensive BP control tended to reduce the RR for all-cause death, but not significant (0.89 [0.78-1.02]). On the other hand, the intensive BP control significantly increased the RR for serious adverse events, hypotension, and syncope (1.59 [1.19-2.12], 1.96 [1.04-3.70], and 2.36 [1.95-2.85], respectively). The intensive BP control significantly increased the RR for acute kidney injury (2.65 [1.78-3.95]), but did not affect for composite renal outcomes (1.38 [0.83-2.31]). For cognitive impairment, no significant increase or decrease in risk was observed (0.93 [0.68-1.26]). Based on these findings, we recommend the intensive BP control targeting SBP below 130 mmHg to achieve significant reductions in cardiovascular events and cardiovascular death, accompanied by careful monitoring for potential adverse events including acute kidney injury, hypotension, syncope related with the intensive BP control.

The efficacy of renal denervation (RDN) has been controversial, but recent randomized sham-controlled trials demonstrated significant blood pressure reductions after RDN in patients with hypertension. We conducted a systematic review and updated meta-analysis to evaluate the effects of RDN on ambulatory and office blood pressures in patients with hypertension. Databases were searched up to 15 November 2023 to identify randomized, sham-controlled trials of RDN. The primary endpoint was change in 24 h ambulatory systolic blood pressure (SBP) with RDN versus sham control. The secondary endpoints were changes in 24 h ambulatory diastolic blood pressure, daytime and nighttime blood pressure (BP), office BP, and home BP. A sub-analysis determined outcomes by medication, procedure, and device. From twelve trials, 2222 patients with hypertension were randomized to undergo RDN (n = 1295) or a sham procedure (n = 927). At 2-6 months after treatment, RDN significantly reduced 24 h ambulatory SBP by 2.81 mmHg (95% confidence interval: -4.09, -1.53; p < 0.001) compared with the sham procedure. RDN also reduced daytime SBP by 3.17 mmHg (- 4.75, - 1.58; p < 0.001), nighttime SBP by 3.41 mmHg (- 4.69, - 2.13; p < 0.001), office SBP by 4.95 mmHg (- 6.37, - 3.54; p < 0.001), and home SBP by 4.64 mmHg (- 7.44, - 1.84; p = 0.001) versus the sham control group. There were no significant differences in the magnitude of BP reduction between first- and second-generation trials, between devices, or between with or without medication. These data from randomized sham-controlled trials showed that RDN significantly reduced all blood pressure metrics in medicated or unmedicated patients with hypertension, including resistant/uncontrolled hypertension.