Risk Of Gastrointestinal Adverse Events Research Articles

A comprehensive assessment of the association between common drugs and psychiatric disorders using Mendelian randomization and real-world pharmacovigilance database

Medications prescribed for chronic diseases can lead to short-term neuropsychiatric symptoms, but their long-term effects on brain structures and psychiatric conditions remain unclear. We comprehensively analyzed the FDA Adverse Event Reporting System database and conducted drug target Mendelian Randomization (MR) studies on six categories of common drugs, 477 brain imaging-derived phenotypes (IDPs) and eight psychiatric disorders. Genetic instruments were extracted from expression quantitative trait loci (eQTLs) in blood, brain, and other target tissues, protein quantitative trait loci (pQTLs) in blood, and genome-wide association studies (GWAS) of hemoglobin and cholesterol. Summary statistics for brain IDPs, psychiatric disorders, and gut microbiome were obtained from the BIG40, Psychiatric Genomics Consortium, and MiBioGen. A two-step MR and mediation analysis were employed to screen possible mediators of drug-IDP effects from 119 gut microbiota genera and identify their mediation proportions. Among 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. We identified ten drug-psychiatric disorder associations, 202 drug-IDP associations, 16 drug-microbiota associations, and four drug-microbiota-IDP causal links. For example, PPARG activation mediated HbA1c reduction caused a higher risk of bipolar disorder (BD) II. Genetically proxied GLP-1R agonists were significantly associated with an increase in the volume of the CA3-head of the right hippocampus and the area of the left precuneus cortex, both of which have been shown to correlate with cognition in previous studies. Common drugs may affect brain structure and risk of psychiatric disorder. Oral medications in particular may exert some of these effects by influencing gut microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages drug repurposing. National Natural Science Foundation of China (grant No. 82330035, 82130043, 82172685, and 82001223), National Natural Science Foundation of Hunan Province (grant No. 2021SK1010), and the Science Foundation for Distinguished Young Scholars of Changsha (grant No. kq2209006).

Potential of phosphodiesterase 4B inhibitors in the treatment of interstitial lung disease associated with autoimmune diseases.

Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

Risk of gastrointestinal adverse events associated with chimeric antigen receptor T-cell therapy (CAR-T): A nationwide analysis.

e19505 Background: Chimeric antigen receptor T-cell therapy (CAR-T) has been successfully used and has improved outcomes in the treatment of B-cell hematological malignancies and multiple myeloma. There is evidence that unique serious adverse events like cytokine release syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS) are associated with CAR-T. Gastrointestinal adverse events (GI-AE) are commonly observed after CAR-T, although they are not well characterized. In the analysis, we summarized the incidence of gastrointestinal adverse events (GI-AE) and mortality associated with CAR-T with or without CRS. Methods: We conducted a retrospective cohort study using the 2020 Nationwide Inpatient Sample database, which is the largest nationally representative inpatient database in the United States. The dataset is weighted to obtain national estimates, and ICD-10 was utilized to identify admissions for CAR-T. The primary outcome is in-hospital mortality, and secondary outcomes are GI-AE associated with CAR-T with or without CRS and length of stay (LOS). Odds ratio (OR) and Mean difference (MD) were adjusted for confounders like comorbidities and sociodemographics using multivariate regression analysis. Results: There were 32 million weighted discharges in the 2020 NIS database; a total of 1950 cases were identified receiving CAR-T therapy with a mean age of 56.53, male 60.51%, and white race 74.8%. In our study, 40.25% had GI-AE, 15.38% had CRS and 13.8% had ICANS. The most common GI-AE was nausea and vomiting (23.84%). Other GI-AE were diarrhea (9.5%), colitis (8.2%), peptic ulcer disease (2.9%), hepatic failure (1.28%), and pancreatitis (2.2%). 68 (3.85%) patients died after receiving CAR-T. The results revealed that CAR-T with GI-AE was not significantly associated with in-hospital mortality (adjusted OR = 1.12, 95% CI: 0.29-4.24), and LOS (adjusted mean difference = 3.38, 95% CI: -0.91-7.67) compared to CAR-T without GI-AE. Liver failure is significantly associated with the highest mortality after CAR-T (OR = 46.62, 95% CI: 6.9-315). Conclusions: The national survey reveals that predominantly GI-AE are mild including nausea, vomiting, and diarrhea. GI-AE related with CAR-T had similar outcomes including mortality and LOS compared to CAR-T without GI-AE. The risk of mortality becomes higher when CAR-T complicated by hepatic failure. [Table: see text]

A Systematic Review and Meta-analysis of Selective Cyclooxygenase-2 Inhibitors and Non-selective Non-steroidal Anti-inflammatory Drugs for Acute Gout

Background The term “gout” refers to a broad clinical spectrum of diseases, including common and complex forms of arthritis, that affect multiple joints in a patient due to an elevated serum urate concentration. Purpose The study aims to compare the efficacy and safety of selective cyclooxygenase-2 (COX-2) inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of acute gout, as well as to conduct a meta-analysis on safety. Methodology As of December 2021, the literature search was conducted using authorised electronic databases such as PubMed, Embase, Web of Science, and the Cochrane Library. Results There were seven investigations included in this study’s findings. Three COX-2 inhibitors, etoricoxib, celecoxib, and meloxicam, were reportedly compared to indomethacin or diclofenac. Four hours after the initial dose, 120 mg of etoricoxib reduces pain and inflammation by diminishing erythema. At higher dosages, celecoxib is more effective than at lower doses. Meloxicam has the same efficacy as NSAIDs. The subgroup analysis revealed that the risk of adverse events was 8.0% lower in the COX-2 inhibitors group than in the non-selective NSAIDs group (risk ratio = 0.92, 95% confidence interval = 0.60 to 0.40, p-value = 0.5). Conclusion Etoricoxib, a COX-2 inhibitor, has a more potent effect and may be more effective than non-selective NSAIDs. COX-2 inhibitors are more well tolerated and reduce the risk of adverse gastrointestinal events more effectively than non-selective NSAIDs. In the treatment of gout, non-selective NSAIDs may be a suitable alternative to COX-2 inhibitors.

Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m2. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.

Evaluating the impact of efpeglenatide on cardiometabolic and safety outcomes in individuals with diabetes: a systematic review and meta-analysis.

Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile. A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool. We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia. Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion. The online version contains supplementary material available at 10.1007/s40200-024-01409-3.

Efficacy and Safety of Pharmacist-Managed NSAIDs Deprescribing: A Jordanian Outpatient Study

Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage pain, including chronic pain conditions. However, their prolonged use is associated with significant risks, particularly gastrointestinal (GI) adverse events. This study aimed to evaluate the effectiveness and safety of a pharmacist-managed deprescribing program for NSAIDs in a Jordanian outpatient population. Methods. A convenience sample of 100 participants who had been using NSAIDs for pain management was recruited. Participants underwent a structured deprescribing intervention in collaboration with physicians. Various effectiveness and safety outcomes were assessed before and after deprescribing. Descriptive statistics and chi-square test were used for data analysis. Results. The majority of participants reported chronic pain conditions, with rheumatoid arthritis (24%) and osteoarthritis (22%) being the most prevalent. Ibuprofen (28%) and diclofenac (22%) were the most commonly used NSAIDs. The deprescribing program was associated with a significant reduction in heartburn, stomach ulcer, kidney problems and fluctuation in blood pressure readings (p&lt;0.05), and pain exacerbation. Notably, the reduction in pain exacerbation was evident (p=0.003) in the 4-month follow-up. Conclusion. A pharmacist-managed NSAIDs deprescribing program demonstrated effectiveness in reducing the risk of GI adverse events and fluctuation in blood pressure readings without causing harm during a short-term follow-up. These findings support the feasibility of implementing such programs in outpatient settings. Further long-term investigations are necessary to confirm these results.

Efficacy and Safety of Colchicine for the Prevention of Postoperative Atrial Fibrillation Among Patients Undergoing Major Cardiothoracic Surgery: A Meta-analysis and Meta-regression of Randomized Controlled Trials.

The role of colchicine for the prevention of postoperative atrial fibrillation (POAF) after cardiothoracic surgery is not well-established. We aimed to evaluate its potential in preventing POAF using data from randomized controlled trials (RCTs). A literature search was performed to identify studies reporting POAF as an outcome after cardiac or thoracic surgery in adult patients randomized to either colchicine or placebo. Primary outcome measured was incidence of POAF. Secondary outcomes included gastrointestinal (GI) adverse effects, sepsis, and length of stay. Subgroup analyses based on treatment durations and type of surgery were also performed, as well as regression analyses to control for covariates. We identified a total of 5377 patients (colchicine = 2,689, placebo = 2688). Although colchicine use was associated with a significantly reduced risk of POAF, risk of GI adverse effects were significantly higher. The rates of infection and length of stay were similar across the groups. Subgroup analyses showed that colchicine was effective for POAF prevention in cardiac surgery, but not in thoracic surgery. Prevention of POAF and incidence of GI adverse effects were similar in short-term and long-term colchicine treatment. Colchicine significantly reduces the incidence of POAF in patients undergoing cardiac surgery, but not in thoracic surgery.

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.

Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis.

The authors used a meta-analysis to evaluate the risks of gastrointestinal adverse events in the cotreatment of malignant tumors with nivolumab and ipilimumab. The meta-analysis revealed that the most common gastrointestinal adverse event at all grades was diarrhea, followed by nausea, decreased appetite, vomiting, constipation, colitis and abdominal pain. The most common severe gastrointestinal adverse events were colitis and diarrhea. Different administration schemes differ in the risk of such events, and thus these events may be minimized by modulating the administration scheme of the cotreatment.

Efficacy and safety of inhibiting the NLRP3/IL-1β/IL-6 pathway in patients with ST-elevation myocardial infarction: A meta-analysis.

The NLRP3/IL-1β/IL-6 pathway plays a key role in mediating inflammatory responses after ST-elevation myocardial infarction (STEMI). However, the clinical benefits of inhibiting this pathway in STEMI are uncertain. We aimed to evaluate the efficacy and safety of inhibiting the NLRP3/IL-1β/IL-6 pathway in STEMI patients. This study followed PRISMA guidelines. PubMed, Embase, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) of inhibiting the NLRP3/IL-1β/IL-6 pathway in STEMI patients within 7 days of symptom onset. The efficacy outcomes included all-cause death, cardiovascular death, recurrent MI, new-onset or worsening heart failure (HF) and stroke. The safety outcomes were serious infection, gastrointestinal adverse events and injection site reactions. Of 316 screened records, nine trials with 1211 patients were included in the meta-analysis. Colchicine reduced the risk of recurrent MI (RR 0.28, 95% CI 0.10-0.74; I2 = 0.0%). Anakinra was associated with reduced risk of new-onset or worsening HF (RR 0.32, 95% CI 0.13-0.77; I2 = 0.0%) and decreased C-reactive protein levels (SMD -1.34, 95% CI -2.04 to -0.65; I2 = 0.0%). Colchicine and anakinra increased the risk of gastrointestinal adverse events (RR 4.43, 95% CI 2.75-7.13; I2 = 38.1%) and injection site reactions (RR 4.52, 95% CI 1.32-15.49; I2 = 0.8%), respectively. None of the three medications affected the risks of all-cause death, cardiovascular death, stroke and serious infection. There is still no large-scale RCT evidence on the efficacy and safety of inhibiting the NLRP3/IL-1β/IL-6 pathway for the treatment of STEMI. Preliminary results from the available RCTs suggest colchicine and anakinra may respectively reduce the risks of recurrent MI and new-onset or worsening HF. The available RCTs in this meta-analysis lack power to determine any differences on mortality.

Safety and efficacy of colchicine for the prevention of post-operative atrial fibrillation in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

Colchicine is an anti-inflammatory drug that may prevent post-operative atrial fibrillation (POAF). The effect of this drug has been inconsistently shown in previous clinical trials. We aimed to compare the efficacy and safety of colchicine vs. placebo to prevent POAF in patients undergoing cardiac surgery. A systematic search of EMBASE, MEDLINE, SCOPUS, ClinicalTrials.gov, and the Cochrane Library for randomized controlled trials (RCTs) was conducted from inception till April 2023. The primary outcome was the incidence of POAF after any cardiac surgery. The secondary outcome was the rate of drug discontinuation due to adverse events and adverse gastrointestinal events. Risk ratios (RR) were reported using the Mantel Haenszel method. A total of eight RCTs comprising 1885 patients were included. There was a statistically significant lower risk of developing POAF with colchicine vs. placebo (RR: 0.70; 95% CI: 0.59-0.82; P < 0.01, I2 = 0%), and this effect persisted across different subgroups. There was a significantly higher risk of adverse gastrointestinal events (RR: 2.20; 95% CI: 1.38-3.51; P < 0.01, I2 = 55%) with no difference in the risk of drug discontinuation in patients receiving colchicine vs. placebo (RR: 1.33; 95% CI: 0.93-1.89; P = 0.11, I2 = 0%). This meta-analysis of eight RCTs shows that colchicine is effective at preventing POAF, with a significantly higher risk of adverse gastrointestinal events but no difference in the rate of drug discontinuation. Future studies are required to define the optimal duration and dose of colchicine for the prevention of POAF.

#3775 PHOSPHATE BINDERS FOR PATIENTS WITH CHRONIC KIDNEY DISEASE UNDERGOING DIALYSIS: A NETWORK META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS

Abstract Background and Aims Phosphate binders (PBs) are essential for proper serum phosphorus control in patients with chronic kidney disease (CKD) requiring dialysis along with adequate dialysis and phosphorus restriction. To evaluate the clinical efficacy and safety of each PBs, we conducted a systematic review (SR) using a network meta-analysis (NMA) of randomised controlled trials (RCTs). Method We searched published RCTs in MEDLINE, EMBASE, the Cochrane Register of Controlled Trials (CENTRAL), and Clinical trial.gov databases using the search terms and text words relevant to this SR. We included RCTs involving adults (18 years and older) with at least 8 weeks of follow-up. Interventions and controls were the following: sevelamer-, bixalomer-, tenapanor-, iron- (ferric citrate, sucroferric oxyhydroxide), calcium-, magnesium-, lanthanum-, aluminium-, nicotinic acid-, and standard treatment or placebo). The outcomes were all-cause mortality, gastrointestinal adverse events (AEs), coronary artery calcium score (CACS), and serum calcium, phosphorus, and bicarbonate concentrations. Summary estimates were expressed as relative risk (RR) for binary outcomes and mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, respectively, with 95% confidence intervals (CI). The protocol of this study is registered in PROSPERO: CRD42022328388. Results All-cause mortality was identified and analysed in 29 trials involving 12,622 participants. Compared with calcium-containing PBs, sevelamer reduced the risk of all-cause mortality (RR 0.65, 95%CI 0.45 to 0.96). The risk of gastrointestinal AEs was higher for nicotinic acid (RR 3.79, 95%CI 1.29 to 11.12), sucroferric oxyhydroxide (RR 1.96, 95%CI 1.47 to 2.63), sevelamer (RR 1.47, 95%CI 1.14 to 1.88), and lanthanum (RR 1.36, 95%CI 1.14 to 1.64) than calcium-containing PBs. Lanthanum had an inhibitory effect on CACS progression compared to calcium-containing PBs (SMD -0.63, 95% CI -1.05 to -0.22). Serum calcium was lower than calcium-containing PBs in the following order: magnesium (MD -0.67, 95% CI -1.12 to -0.22), placebo (MD -0.64, 95% CI -1.22 to -0.67), nicotinic acid (MD -0.56, 95% CI -1.11 to -0.005), sevelamer (MD -0.35, 95% CI -0.47 to -0.23), and lanthanum (MD -0.24, 95% CI -0.38 to -0.095). No significant difference was observed in serum phosphorus decrease between any PBs and calcium-containing PBs. Serum bicarbonate concentration increased with ferric citrate (MD 1.16, 95% CI 0.36 to 1.96) and sucroferric oxyhydroxide (MD 1.06, 95% CI 0.29 to 1.82) but decreased with sevelamer (MD -1.24, 95% CI -1.71 to -0.77). Conclusion Our findings from SR based on NMA suggest that lanthanum may attenuate CACS and sevelamer may reduce the risk of all-cause mortality compared to calcium-containing PBs in patients with CKD requiring dialysis.

Adverse Gastrointestinal Events With Sodium Polystyrene Sulfonate Use in Patients on Maintenance Hemodialysis: An International Cohort Study

Background: There are concerns regarding the gastrointestinal (GI) safety of sodium polystyrene sulfonate (SPS), a medication commonly used in the management of hyperkalemia. Objective: To compare the risk of GI adverse events among users versus non-users of SPS in patients on maintenance hemodialysis. Design: International prospective cohort study. Setting: Seventeen countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018). Patients: 50 147 adults on maintenance hemodialysis. Measurements: An adverse GI event defined by a GI hospitalization or GI fatality with SPS prescription compared with no SPS prescription. Methods: Overlap propensity score–weighted Cox models. Results: Sodium polystyrene sulfonate prescription was present in 13.4% of patients and ranged from 0.42% (Turkey) to 20.6% (Sweden) with 12.5% use in Canada. A total of 935 (1.9%) adverse GI events (140 [2.1%] with SPS, 795 [1.9%] with no SPS; absolute risk difference 0.2%) occurred. The weighted hazard ratio (HR) of a GI event was not elevated with SPS use compared with non-use (HR = 0.93, 95% confidence interval = 0.83-1.6). The results were consistent when examining fatal GI events and/or GI hospitalization separately. Limitations: Sodium polystyrene sulfonate dose and duration were unknown. Conclusions: Sodium polystyrene sulfonate use in patients on hemodialysis was not associated with a higher risk of an adverse GI event. Our findings suggest that SPS use is safe in an international cohort of maintenance hemodialysis patients.

Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.

The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes. A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model. The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis. Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. However, risk of gastrointestinal adverse events, discontinuation of treatment and serious adverse events were higher in the semaglutide group versus placebo.

Risk of major adverse events associated with gabapentinoid and opioid combination therapy: A systematic review and meta-analysis.

Background: The use of opioid–gabapentinoid combinations has increased, raising several safety concerns. However, meta-analysis studies focusing on this issue are limited. Objective: To evaluate the risk of central nervous system (CNS) depression, gastrointestinal (GI) adverse events, and mortality of combination therapy compared with those of opioid therapy and to explore the differences in the results according to study design and indications. Methods: Relevant studies were selected (published before 30 January 2022) by searching the MEDLINE, Embase, and CENTRAL databases. The pooled odds ratios (OR) with 95% confidence intervals (CI) of the outcomes were estimated using the Mantel–Haenszel method. Subgroup and meta-regression analyses were performed according to study characteristics. Quality assessment was conducted using the Risk of Bias 2 tool for randomized controlled trials (RCTs) and Cochrane Collaboration’s Risk of Bias in non-RCTs tool for non-randomized trials. Results: Adverse events were reported in 26 RCTs and 7 non-RCTs, and mortality was reported in 10 non-RCTs. Compared to opioid therapy, dizziness, cognitive dysfunction, and respiratory depression in combination therapy significantly increased in non-RCTs (OR 3.26, 95% CI 1.82–5.85; OR 3.13, 95% CI 1.51–6.50; OR 1.71, 95% CI 1.31–2.24, respectively), and a similar trend for dizziness and cognitive dysfunction was also identified in the RCT analysis, although the difference was not significant. Combination therapy for cancer pain was associated with the highest risk of sedation in subgroup analysis. Combination therapy significantly decreased the risk of GI adverse events, including nausea, vomiting, and constipation. The mortality risk associated with combination therapy was higher than that associated with opioid therapy (OR 2.76, 95% CI 1.26–6.05). Conclusion: Opioid-gabapentinoid combination therapy could be associated with an increased risk of CNS depression and mortality, despite tolerable GI adverse events. These data suggest that combination therapy requires close monitoring of CNS depression, especially in cancer patients. Caution is needed in interpreting the clinical meanings owing to the lack of risk difference in respiratory depression in the RCT-only analysis and the absence of RCT or prospective studies investigating mortality.

Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials.

IntroductionMetformin is the first choice drug in the treatment of type 2 diabetes mellitus but its administration may be linked to gastrointestinal adverse events limiting its use.ObjectivesThe objective of this systematic review and meta-analysis was to assess the risk of gastrointestinal adverse events related to metformin use in patients with type 2 diabetes treated with metformin.MethodsPUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 08.11.2020 for articles in English and randomized controlled trials related to patients with type 2 diabetes treated with metformin were included.ResultsFrom 5315 publications, we identified 199 potentially eligible full-text articles. Finally, 71 randomized controlled trials were included in the meta-analysis. In these studies, metformin use was associated with higher risk of abdominal pain, diarrhea and nausea comparing to control. The risks of abdominal pain and nausea were highest comparing to placebo. Bloating risk was only elevated when metformin treatment was compared to DPP4i.ConclusionsThe risk of gastrointestinal adverse events such as abdominal pain, nausea and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs. There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended release formulation.Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975.

Life threatening gastrointestinal tract complications in a patient of rheumatoid arthritis. Is it drug or disease related?

Introduction: Gastrointestinal (GI) complications are very frequent and sometimes fatal in patients with Rheumatoid Arthritis (RA). Gastrointestinal perforation is a rare but serious event, most frequently involving the lower GIT, which has been observed in patients with RA.&#x0D; Case Presentation: We present here an Adverse Drug Reaction (ADR) which is small bowel ischemia with perforation in a 61-year-old RA patient, who was taking a tablet of Prednisolone and tablet Hydroxychloroquine.&#x0D; Discussion: Several studies indicated that RA patients may be at a higher risk of GI perforation. This could be attributed to the disease pathophysiology or the use of drugs for treatment like Glucocorticoids and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Rheumatologists must be vigilant for GI complications while prescribing anti-rheumatoid drugs.&#x0D; Conclusion: GI perforations are rare events in RA patients, but cause significant morbidity and mortality. Increasing age and other comorbid conditions also increase the risk of adverse GI events.

The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Patients Without Diabetes: A Systematic Review and Meta-Analysis.

Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=-5.39, 95% CI (-6.82, -3.96)] and metformin [WMD=-5.46, 95% CI (-5.87, -5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.

Patient preferences for the treatment of systemic sclerosis-associated interstitial lung disease: a discrete choice experiment.

ObjectivesTreatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes.MethodsSeven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated.ResultsOverall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6–12 monthly infusions. Patients’ choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions’ frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections.ConclusionsThis is the first study to quantitatively elicit patients’ preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.