Background
Weight loss in response to the long‐acting GLP‐1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric‐emptying (GE). The aim of this pilot study was to assess whether ...specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short‐acting GLP‐1 agonist, exenatide.
Methods
We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 μg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks. Data were analyzed using the dominant genetic model and intention‐to‐treat analysis.
Key Results
There was a significant correlation between changes in weight and GE T1/2 (rs = −.382, P = .004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9 ± 27.5 SEM minutes and 128.9 ± 38.32 minutes) compared to GG genotype (95.8 ± 30.4 minutes and 61.4 ± 21.4 minutes, respectively; P = .11). There was a non‐significant difference in weight loss based on GLP1R rs6923761 genotype after 5 weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype.
Conclusions & Inferences
The minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.
The degree of weight loss is associated with greater delay in gastric‐emptying T1/2 in response to liraglutide and exenatide. The minor A allele of GLP1R (rs6923761) was associated with higher weight loss with liraglutide treatment. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.
Gastroparesis Camilleri, Michael; Chedid, Victor; Ford, Alexander C ...
Nature reviews. Disease primers,
11/2018, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Gastroparesis is a disorder characterized by delayed gastric emptying of solid food in the absence of a mechanical obstruction of the stomach, resulting in the cardinal symptoms of early satiety, ...postprandial fullness, nausea, vomiting, belching and bloating. Gastroparesis is now recognized as part of a broader spectrum of gastric neuromuscular dysfunction that includes impaired gastric accommodation. The overlap between upper gastrointestinal symptoms makes the distinction between gastroparesis and other disorders, such as functional dyspepsia, challenging. Thus, a confirmed diagnosis of gastroparesis requires measurement of delayed gastric emptying via an appropriate test, such as gastric scintigraphy or breath testing. Gastroparesis can have idiopathic, diabetic, iatrogenic, post-surgical or post-viral aetiologies. The management of gastroparesis involves: correcting fluid, electrolyte and nutritional deficiencies; identifying and treating the cause of delayed gastric emptying (for example, diabetes mellitus); and suppressing or eliminating symptoms with pharmacological agents as first-line therapies. Several novel pharmacologic agents and interventions are currently in the pipeline and show promise to help tailor individualized therapy for patients with gastroparesis.
Summary
Background
Tradipitant, an NK1 receptor antagonist, improved symptoms in patients with gastroparesis. It is unclear whether these effects are mediated centrally (e.g., vomiting centre) or on ...gastric functions. As a class, NK1 antagonists may retard gastric emptying (GE) or increase fasting and postprandial gastric volumes (GV).
Aim
To evaluate the effects of tradipitant relative to placebo on gastric motor functions, satiation, postprandial symptoms, and pharmacokinetics.
Methods
We conducted a randomised, double‐blind, placebo‐controlled, single‐centre study of tradipitant 85 mg or matching placebo b.i.d. for 9 consecutive days in 24 healthy volunteers. During the last 2 days of treatment, participants underwent scintigraphic measurements of GE of 320 kcal egg meal, fasting and postprandial GV by SPECT, and satiation by nutrient drink ingested to maximum tolerated volume (MTV) and symptoms 30 min later. Treatments were compared by Wilcoxon rank sum test. The study had 80% power to detect group differences of 23.6% in GV and 29.2% in GE T1/2.
Results
The two groups of healthy participants were well balanced based on demographic features, age, and BMI. There were nonsignificant positive correlations between blood levels of tradipitant and accommodation GV and GE at 4 h. There were no significant effects of tradipitant, 85 mg b.i.d. for 9 days compared to placebo on GE, GV, satiation, or symptoms 30 min after MTV.
Conclusion
Tradipitant, 85 mg b.i.d., does not significantly affect gastric motor functions (GV or GE). Importantly, there was no retardation of GE by tradipitant, which is important in relation to its potential use in patients with gastroparesis.
Clinic trials registry
ClinicalTrials.gov #NCT04849559.
Tradipitant, an NK1 receptor antagonist, has shown improvement in nausea and vomiting in patients with gastroparesis. NK1 receptors are located invomiting centre and myenteric neurons; an NK1 antagonist may inhibit GI motor functions. What is the effect of tradipitant on the motor functions of the human stomach?
Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to ...lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes.
Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a
Tc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T
) and percentage gastric retention at 1, 2 and 4 h.
Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids median GE T
ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal.
Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.
Background Gastric emptying (GE) is measured in pharmacodynamic and diagnostic studies. Our aim was to assess inter‐ and intra‐subject coefficients of variation (COV) of scintigraphic GE ...measurements in healthy subjects, and associations of GE with gender and body mass index (BMI).
Methods Data from participants with scintigraphic measurements of gastric emptying of solids were analyzed. Primary endpoints were gastric emptying T1/2 (GE T1/2) and GE at 1, 2, 3, and 4 h.
Key Results The patient cohort consisted of 105 males and 214 females; at least two studies were performed in 47 subjects 16 males (M), 32 females (F). Inter‐subject COV (COVinter) for GE T1/2 were similar in M and F: overall 24.5% (M 26.0%, F 22.5%); COV are predictably lowest for GE at 4 h (COVinter 9.6%). COVintra for T1/2 and GE at 4 h were overall 23.8% and 12.6%, and were similar to COVinter values. Gender (but not age or BMI) was significantly associated with GE T1/2 P < 0.001, F 127.6 ± 28.7 (SD) min; M 109.9 ± 28.6 min and with GE at 1 h and 2 h. Repeat GE T1/2 values in 47 participants were significantly correlated (r = 0.459, P < 0.001) with median difference of −6 min (mean −1.6, range −56 to 72 min). Bland–Altman plots showed Δ GE T1/2 similarly distributed across mean GE T1/2 100–155 min, and across studies conducted 90–600 days apart.
Conclusions & Inferences Inter‐subject variations in scintigraphic GE results are only slightly higher than the intra‐subject measurements, which are also reproducible over time in healthy volunteers. Gender, but not BMI, is significantly associated with GE results.
PDF
