SGLT2 Inhibitor–Induced Sympathoinhibition

Herat, Lakshini Y.; Magno, Aaron L.; Rudnicka, Caroline; Hricova, Jana; Carnagarin, Revathy; Ward, Natalie C.; Arcambal, Angélique; Kiuchi, Márcio Galindo; Head, Geoffrey A.; Schlaich, Markus P.; Matthews, Vance B.

doi:10.1016/j.jacbts.2019.11.007

Cited by 182 publications

(107 citation statements)

References 32 publications

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“…With these lines of evidence in mind, our present findings further support the contention that cardiac sympatho-inhibitory 5-HT5A receptors could establish a novel therapeutic strategy targeting certain cardiac disorders associated with T1D. Consistent with these results, dapagliflozin has recently been shown to induce a reduction in sympathetic activity that contributes to the renal-and cardio-protective effects of this drug for the treatment of diabetes [56]. Admittedly: (i) further in vivo studies will be necessary to explore whether selective activation of 5-HT5A receptors is effective in the treatment of CAN or other cardiac disturbances present in T1D; and (ii) one possible limitation of our study may be that we did not measure the expression of the 5-HT1B, 5-HT1D and 5-HT5A receptors in the central nervous system.…”

Section: Potential Clinical Perspectives In T1dsupporting

confidence: 87%

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

García-Pedraza

Hernández-Abreu

Morán

et al. 2020

Preprint

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Abstract Background: In normoglycaemic pithed rats, cardiac sympathetic control is modulated by serotonin (5-hydroxytryptamine; 5‑HT), which inhibits the cardioaccelerator sympathetic outflow via the activation of 5-HT 1B , 5-HT 1D and 5-HT 5A receptors. Notwithstanding, type 1 diabetes impairs the functionality of the cardiac sympathetic innervation and leads to cardiovascular complications including cardiac autonomic neuropathy. On this basis, the present study investigated whether the influence of 5-HT on cardiac noradrenergic neurotransmission is altered in type 1 diabetic rats, by analysing the profile of the 5-HT receptors involved and their peripheral expression. Methods: Type 1 diabetes was induced in male Wistar rats with a single injection of streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by either electrical preganglionic stimulation (C 7 ‑T 1 ) of the cardioaccelerator sympathetic outflow or i.v. bolus injections of exogenous noradrenaline. Immunohistochemistry analyses were performed to study the expression of 5‑HT 1B , 5-HT 1D and 5-HT 5A receptors in the stellate (sympathetic) ganglion obtained from normoglycaemic and diabetic rats. Results: The increases in heart rate evoked by both cardiac sympathetic stimulation and exogenous noradrenaline were not modified after saline in diabetic rats. Moreover, i.v. continuous infusions of 5‑HT induced a cardiac sympatho-inhibition that was mimicked by the 5‑HT 1/5A receptor agonist 5‑carboxamidotryptamine, but not by the agonists indorenate (5-HT 1A ), CP 93,129 (5‑HT 1B ), PNU 142633 (5-HT 1D ), or LY344864 (5‑HT 1F ) in the diabetic group. In contrast, the above agonists at 5-HT 1B , 5-HT 1D and 5-HT 1/5A receptors mimicked 5-HT-induced sympatho-inhibition in normoglycaemic rats. In diabetic animals, i.v. administration of SB 699551 (1 mg/kg; 5‑HT 5A receptor antagonist) abolished 5‑CT-induced cardiac sympatho-inhibition. Finally, the immunohistochemistry analysis in the stellate ganglion showed that, as compared to normoglycaemic rats, in diabetic rats (P<0.05): (i) the expression of 5-HT 1B receptors was slightly higher, whereas that of 5-HT 1D receptors was slightly lower; and (ii) there was a clear overexpression of 5-HT 5A receptors. Conclusions: Taken together, these results show the prominent role of the peripheral overexpression of prejunctional 5-HT 5A receptors in the inhibition of the cardiac sympathetic drive in type 1 diabetic rats. These findings may represent a new pharmacological strategy for the treatment of diabetes-related cardiac abnormalities.

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Section: Potential Clinical Perspectives In T1dsupporting

confidence: 87%

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

García-Pedraza

Hernández-Abreu

Morán

et al. 2020

Preprint

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“…Another compartment that could influence extracellular volume and blood pressure is the endothelial surface layer or glycocalyx ( 34 , 35 ). Damage to the endothelial glycocalyx has been observed in patients with type 2 diabetes, and SGLT2 inhibition has been shown to restore the structural integrity of the glycocalyx in vitro and in vivo ( 35 – 37 ).…”

Section: Resultsmentioning

confidence: 99%

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

et al. 2020

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OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2–4), end of treatment (ET) (days 12–14), and follow-up (FU) (days 15–18). RESULTS Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: −7.0 mmol/24-h [95% CI −22.4, 8.4]; change at ET: 2.1 mmol/24-h [−28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (−6.1 mmHg [−9.1, −3.1]; P < 0.001) and ET (−7.2 mmHg [−10.0, −4.3]; P < 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (−0.7 L [−1.3, −0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure–lowering effects.

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“…Previous studies have indicated that SGLT2 inhibitors decrease BP without a compensatory increase or notable changes in heart rates, 41 implying the sympathoinhibitory effects of SGLT2 inhibitors. 42 , 43 SGLT2 inhibitor-induced reduction of sympathetic activity may be an important reason why SGLT2 inhibitors do not increase the risk of OH in patients with T2DM.…”

Section: Discussionmentioning

confidence: 99%

Risk of orthostatic hypotension associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials

Rong

Gou

et al. 2020

Diabetes and Vascular Disease Research

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Objective: The aim of this study was to assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of orthostatic hypotension (OH) in patients with type 2 diabetes mellitus (T2DM). Method: A systematic literature retrieval was performed using PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception up to 16 October 2019. Data for study characteristics and outcomes of interest were extracted from each eligible study. Pooled risk ratios (RRs) with 95% confidence intervals (CI) for OH were calculated using a random-effects model. Result: A total of 16 studies ( n = 12,749) were included in our meta-analysis, with a result of 44 incident OH cases (29 in the SGLT2 inhibitor group, and 15 in the control group). The pooled RR was 1.17 (95% CI: 0.65–2.09). There was no evidence that receiving SGLT2 inhibitors increased the risk of OH, when stratified by age, duration of T2DM, or placebo-control or active-control and baseline blood pressure. Conclusion: This meta-analysis suggested that, in general, SGLPT2 inhibitors did not increase the risk of OH in patients with T2DM. The possibility of OH should be, therefore, considered on an individual basis, especially in patients with a history of OH, long duration of T2DM, or comorbidities.

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SGLT2 Inhibitor–Induced Sympathoinhibition

Cited by 182 publications

References 32 publications

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

Risk of orthostatic hypotension associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials

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