Gastroparesis is a serious and well-recognized disorder that can occur acutely in response to surgery or medications, chronically as a well-known complication of diabetes mellitus (DM), in an idiopathic form, or following surgery that damaged the vagal nerve. Patients with chronic gastroparesis may be asymptomatic or they may display a variety of symptoms including abdominal distension/bloating, persistent fullness, early satiety, anorexia and nausea with or without vomiting.
Treatment for gastroparesis has involved prokinetic agents that enhance and coordinate gastrointestinal (GI) motility and transit of material in the GI tract (e.g. cisapride, domperidone, metoclopramide and erythromycin).1 Infusion of motilin, an endogenous peptide hormone present in the duodenum, has been shown to accelerate gastric emptying (GE) in patients with diabetic gastroparesis.2 As motilin is a peptide hormone that cannot be administered orally, research has focused on finding motilin receptor agonists that can be administered orally. Erythromycin, one of the macrolide antibiotics, is known as a motilin receptor agonist,3 and studies have shown that erythromycin, administered either intravenously or orally, is capable of accelerating GE in patients with diabetic gastroparesis.4, 5 However, erythromycin has a number of drawbacks—it is not acid stable, its antibacterial properties can disrupt the intestinal bacterial flora and promote resistance in bacterial strains, and it can induce cardiac arrhythmias.6
Other macrolide analogues that possess motilin agonist properties were expected to show improvement in gastroparesis symptoms, but have not consistently done so. The motilin agonist ABT-229 showed lack of efficacy in relieving the symptoms of gastroparesis and functional dyspepsia in patients with or without delayed-GE.7, 8 It has been postulated that a long half life, leading to tachyphylaxis, could have contributed to the lack of therapeutic benefit.9
A macrolide analogue currently in clinical development is mitemcinal,10 which accelerates GE in animals and humans and hence has the potential to clarify whether a motilin agonist can ameliorate gastroparesis symptoms.10, 11 We investigated in a double-blind study if mitemcinal can be efficacious in DM patients with symptoms of gastroparesis, as well as identifying whether various factors [body mass index (BMI), haemoglobin A1c (HbA1c), sex, diabetes type and age] affected the response (symptoms of gastroparesis) to mitemcinal or to placebo. Because obesity12 and poor glycaemic control13 are thought to be independent risk factors for upper GI symptoms, we also examined the efficacy of mitemcinal in the subgroup of patients with BMI < 35 kg/m2 and HbA1c < 10%.