Safety and Efficacy of Highly Selective 5-Hydroxytryptamine Receptor 4 Agonists for Diabetic and Idiopathic Gastroparesis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Gastroparesis significantly affects quality of life and healthcare expenditure. Effective treatment options are limited, and the utility of current prokinetic agents is inhibited by serious adverse effects. There exists an unmet need for prokinetic agents demonstrating both efficacy and an acceptable adverse effect profile. Highly selective 5-Hydroxytryptamine receptor 4 (5-HT4) agonists have exhibited clinical efficacy and safety in randomized controlled trials (RCTs). Consequently, we conducted a meta-analysis to comprehensively assess the safety and efficacy of these highly selective agents. Multiple databases, including PubMed, Scopus, and Embase, were systematically screened from inception until September 2023. Only RCTs evaluating the efficacy and safety of highly selective 5-HT4 agonists for gastroparesis were included. Key outcomes of interest included the pooled rates of Gastroparesis Cardinal Symptom Index (GCSI) scores, gastric emptying time (GET), and adverse event rates in each group. We adhered to standard meta-analysis methodology utilizing the random-effects model, with heterogeneity assessed by I2 statistics. Our analysis identified six RCTs, comprising 570 patients with diabetic (48%) or idiopathic (51%) gastroparesis, with mean ages of 46 and 45.9 years in the intervention and placebo groups, respectively. In the meta-analysis, highly selective 5-HT4 agonists demonstrated significantly superior pooled GCSI scores compared to placebo (mean difference: 4.283, (1.380, 7.186), p<0.05). Pooled GET was also significantly improved with 5-HT4 agonists compared to placebo (mean difference: 2.534, (1.695, 3.373), p<0.05). Although pooled rates of total adverse events were higher with 5-HT4 agonists (mean difference: 6.975, (1.042, 46.684), p<0.05), rates of specific adverse events such as diarrhea, abdominal pain, and headaches were comparable. In conclusion, this meta-analysis underscores a statistically significant improvement in GET and GCSI scores among patients receiving highly selective 5-HT4 agonists (Velusetrag, Felcisetrag, Prucalopride) for both diabetic and idiopathic gastroparesis. While the overall adverse effect profile is deemed acceptable, larger studies with extended follow-up periods are needed to investigate rare and/or serious adverse events. Moreover, future high-quality RCTs comparing the efficacy and safety of these novel agents with currently available agents are essential to further validate these findings.