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Metoclopramide as a prokinetic agent for diabetic gastroparesis: revisiting the risk of Parkinsonism.

ABSTRACT: Background:Metoclopramide is used to relieve gastrointestinal symptoms, however, it could cause adverse reactions of motor disorders. The aim of this study was to investigate whether metoclopramide treatment has a duration-response or dose-response effect and to estimate the risk of developing Parkinsonism following different and specific durations of treatment. Methods:A cohort study of newly diagnosed type 2 diabetes mellitus in 45- to 79-year-old patients, between 1999 and 2008, was selected using the Longitudinal Health Insurance Database 2005. A nested case-control study was conducted in the diabetes cohort in which all incident cases of Parkinsonism were identified. We randomly matched each case with up to 10 controls from the risk set. Conditional logistic regression was utilized to estimate odds ratio of Parkinsonism associated with metoclopramide use. Results:A total of 34,685 patients with diabetes were assembled as the cohort, and 541 incident Parkinsonism cases were identified. There were duration-response and dose-response effects on the risk of developing Parkinsonism. Compared with never-use patients, the adjusted odds ratios (ORs) of continuing therapy for 0-1 month, 1-2 months, 2-3 months, 3-5 months, and more than 5 months were 1.17 [95% confidence interval (CI) 0.93-1.45], 1.44 (95% CI 1.04-2.00), 1.74 (95% CI 1.14-2.65), 1.90 (95% CI 1.23-2.93), and 2.17 (95% CI 1.50-3.12), respectively. Conclusions:With metoclopramide treatment, regardless of less or more than 3 months of use, the risk of developing Parkinsonism in patients with newly diagnosed diabetes escalated with the duration of therapy. Therefore, we recommend close monitoring for the development of Parkinsonism in patients treated with metoclopramide, particularly (but not limited to) those with prolonged exposure.

SUBMITTER: Lai CH

PROVIDER: S-EPMC6587390 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Metoclopramide as a prokinetic agent for diabetic gastroparesis: revisiting the risk of Parkinsonism.

Lai Chien-Hsu CH Yeh Yi-Chun YC Chen Yen-Yu YY

Therapeutic advances in drug safety 20190620

<h4>Background</h4>Metoclopramide is used to relieve gastrointestinal symptoms, however, it could cause adverse reactions of motor disorders. The aim of this study was to investigate whether metoclopramide treatment has a duration-response or dose-response effect and to estimate the risk of developing Parkinsonism following different and specific durations of treatment.<h4>Methods</h4>A cohort study of newly diagnosed type 2 diabetes mellitus in 45- to 79-year-old patients, between 1999 and 2008 ...[more]

PMID: 31258887

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Project description:Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10-9; IG FDR = 6.3 × 10-12]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-? type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Project description:AIMS:We conducted a cohort study utilizing a nationwide health insurance database to assess the European Medicines Agency's restrictions on using metoclopramide and its association with the risk of parkinsonism. METHODS:New oral metoclopramide users aged ≥20 years, and age- and gender-matched non-users were recruited between 2001 and 2011. Users were divided into high-exposure (dose >30 mg day-1 and/or duration >5 days) and standard-exposure (dose ≤30 mg day-1 and duration ≤5 days) groups. The adjusted hazard ratio (aHR) with 95% confidence interval (CI) estimated the risk of parkinsonism. RESULTS:During a 1-year period, 122 of 218 931 (0.06%) users of metoclopramide vs. 56 of 218 931 (0.03%) non-users developed parkinsonism (P < 0.001). Among the 122 cases of parkinsonism in users, 64 (0.04%) were from 168 566 standard-exposure users and 58 (0.12%) from 50 365 high-exposure users. Compared with non-users, the risk of parkinsonism was higher in users (aHR 2.16; 95% CI 1.54, 3.02), including standard-exposure (aHR 1.73; 95% CI 1.11, 2.70), and high-exposure (aHR 3.15; 95% CI 1.78, 5.57) users. High-exposure users had a higher risk of parkinsonism than standard-exposure users (aHR 1.83; 95% CI 1.28, 2.63). Within the high-exposure group, 45 233 of 50 365 (89.81%) users and 55 of 58 (94.83%) parkinsonism were from long-duration exposure; 5 132 of 50 365 (10.19%) users and 3 of 58 (5.17%) parkinsonism were from high-dose exposure and long-duration + high-dose exposure. CONCLUSIONS:The risk of parkinsonism in metoclopramide users, although extremely low (0.06%), is 2.16-fold greater than in non-users. High-exposure users have a 1.83-fold higher risk than standard-exposure users. As users in high-exposure group had a higher risk of parkinsonism than in standard-exposure group, and the majority of users and parkinsonism in high-exposure group were from long-duration exposure; thus, physician are advised to avoid prescribing metoclopramide for >5 days, even if the daily dose is ≤30 mg.

Dataset Information

Metoclopramide as a prokinetic agent for diabetic gastroparesis: revisiting the risk of Parkinsonism.

Publications

Metoclopramide as a prokinetic agent for diabetic gastroparesis: revisiting the risk of Parkinsonism.

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