Efficacy and Safety of Ghrelin Agonists in Patients with Diabetic Gastroparesis: A Systematic Review and Meta-Analysis

Abstract

Background/Aims: Ghrelin agonists are emerging prokinetic agents for treating gastroparesis. Although recent clinical trials have demonstrated their efficacy in patients with diabetic gastroparesis (DG), the impact of such agents on symptoms and gastric dysmotility remains unclear. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of ghrelin agonists in patients with DG. Methods: A search of common electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) was preformed, using keyword combinations that referenced ghrelin and DG and retrieving all eligible randomized controlled trials (RCTs) of ghrelin agonists versus placebo in patients with DG. The primary outcome measure was the change in patient-reported overall gastroparesis symptom scores. Secondary outcomes included the change in gastric emptying time, specific symptoms related to gastroparesis, and adverse events. A random-effects model was applied to all study outcomes. Heterogeneity among studies was determined by the chi-square test and I 2 statistics. Results: We selected six RCTs of patients with DG (n=557) for meta-analysis. Ghrelin agonist administration (vs placebo) significantly improved overall gastroparesis symptoms (standardized mean difference,-0.34; 95% confidence interval,-0.56 to-0.13) and significantly improved symptoms related to gastroparesis, including nausea, vomiting, early satiety, and abdominal pain. Adverse events recorded for ghrelin agonists and placebo did not differ significantly. There was no significant heterogeneity among eligible studies. Conclusions: Compared with placebo, ghrelin agonists are effective and well-tolerated for the treatment of DG.

Ghrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward

“…Patients treated with cisplatin also present lower concentrations of circulating ghrelin [ 156 ] and GHSR agonism alleviates nausea and vomiting induced by chemotherapy [ 157 , 158 , 159 , 160 ]. In addition, GHSR agonists can provide relief to diabetic individuals experiencing nausea and vomiting as a result of gastroparesis [ 161 , 162 , 163 , 164 ]. Thus, ghrelin signaling may promote food reward-motivated behaviors in humans, in part, by minimizing GI discomfort.…”

Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

“…Despite the latter promising studies, the long-term metabolic effects of AG are questionable. Generally, as concluded by a recent meta-analysis in diabetic patients suffering from gastropareses, the long-term clinical use of AG seems to be safe and is well-tolerated, even in metabolically susceptible populations (Hong et al, 2019 ). However, clinical studies in healthy, non-obese subjects have shown that the infusion of AG impairs the glucose-stimulated secretion of insulin, diminishes glucose tolerance and worsens insulin sensitivity (Gauna et al, 2004 ; Vestergaard et al, 2007 ; Tong et al, 2010 , 2014 ).…”

“…In the vast majority of PD patients, relamorelin potentiated the frequency of incomplete bowel movements to a degree that the prolonged participation of the patients was impossible (Parkinson Study Group, 2017 ). As such, while AG can evidently improve gastrointestinal dysfunction (Hong et al, 2019 ), the occurrence of unwanted gastrointestinal side-effects in some PD patients may restrict the administration of ghrelin agonists in the long-term.…”

Normal and disordered gastric emptying in diabetes: recent insights into (patho)physiology, management and impact on glycaemic control

“…Sepiapterin, an essential cofactor of NOS, has been reported to improve gastric accommodation, but not symptoms, in women with diabetic gastroparesis [ 78 ]. Relamorelin, a ghrelin agonist, led to both symptomatic improvement and acceleration of gastric emptying in three studies, but the subsequent phase 3 trial was terminated prematurely, apparently for commercial reasons [ 79 ].…”