siponimod and Hypertension

All agents engaging sphongosine-1-phospate receptors (S1PRs) will have some cardiovascular effect. This study aimed to elucidate the risk of cardiovascular adverse events (AEs) in patients with multiple sclerosis (MS) treated with S1PR modulators (S1PRMs).. We systematically searched the PubMed, EMBASE, and Cochrane Library databases for randomised controlled trials (RCTs) published through January 5, 2021. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity analyses and meta-regression were performed.. Seventeen RCTs (12 for fingolimod; 3 for ozanimod; 2 for siponimod) involving 13,295 patients were included. Compared with the control treatment, S1PRMs significantly increased the risk of cardiovascular AEs (RR, 2.21; 95% CI, 1.58-3.10; I. S1PRM use increased the risk of cardiovascular AEs by 1.21 times in patients with MS, and increased risks for bradyarrhythmia and hypertension were at 2.92- and 2.00-fold, respectively. These findings can help clinicians assess the risk of cardiovascular AEs in patients treated with S1PRMs.. The PROSPERO ID is CRD42020183215.

Topics: Azetidines; Benzyl Compounds; Bradycardia; Drug-Related Side Effects and Adverse Reactions; Fingolimod Hydrochloride; Humans; Hypertension; Indans; Multiple Sclerosis; Oxadiazoles; Randomized Controlled Trials as Topic; Risk; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors

Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.

Topics: Animals; Azetidines; Benzyl Compounds; Bradycardia; Cells, Cultured; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Humans; Hypertension; Immunosuppressive Agents; Male; Propylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Substrate Specificity