Gastrointestinal Adverse Events Research Articles

IGlarLixi for type 2 diabetes: a systematic review and meta-analysis.

To assess the efficacy and tolerability of iGlarLixi-a novel, fixed-ratio, soluble combination of insulin glargine and lixisenatide-for the treatment of type 2 diabetes (T2D). The PubMed, Embase, Cochrane Library and ClinicalTrials.gov databases were searched from inception to November 15, 2023 to identify randomized controlled trials (RCTs) comparing iGlarLixi with a placebo or any other antidiabetic agent in adults with T2D. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated to evaluate the outcomes. A total of 10 trials enrolling 6071 T2D patients were included. Compared with placebos or other antidiabetic agents, iGlarLixi exerted beneficial effects on changes in HbA1c, the percentage of patients who achieved an HbA1c < 7%, the percentage of patients who achieved an HbA1c < 6.5%, the percentage of patients who achieved an HbA1c < 7.0% without weight gain and/or without severe or blood glucose-confirmed hypoglycemic episodes, changes in fasting plasma glucose, and changes in self-measured plasma glucose. Regarding safety, iGlarLixi did not increase the incidence of severe hypoglycemia or serious adverse events but did increase the incidence of gastrointestinal adverse events, symptomatic hypoglycemia, and adverse events (e.g., nausea, vomiting, diarrhea). iGlarLixi showed improved efficacy and safety in patients with T2D. Additional large, multicenter RCTs are warranted to obtain deeper insights into the efficacy and safety of iGlarLixi, thereby providing guidance for clinical treatment decisions.

Nebulized inhalation of nintedanib-loaded biomimetic nano-liposomes attenuated bleomycin-induced interstitial lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial lung disease with a poor prognosis. However, there are currently few drugs available for its treatment. Nintedanib is clinically effective but is associated with gastrointestinal adverse effects and weight loss. Due to drug intolerance, the overall outcomes of nintedanib therapy are substantially compromised in quite a few patients. In the present study, we synthesized nintedanib-loaded biomimetic liposomes (Nin-lipo) to improve the antifibrotic efficacy and drug tolerance of nintedanib. It was observed that nebulized inhalation of small doses of Nin-lipo (2 mg/kg) resulted in greater delivery efficiency and higher drug concentrations in lung tissue than conventional oral doses of nintedanib (60 mg/kg). Furthermore, Nin-lipo significantly inhibited bleomycin (BLM)-induced pulmonary fibrosis and improved lung function in mice. The possible molecular mechanism of anti-fibrosis by Nin-lipo was investigated. Nin-lipo was found to act mechanistically on alveolar macrophages via alveolar surfactant proteins A and D (SP-A/D) by simulating pulmonary surfactants and inhibiting the polarization of M2 macrophages. These effects thereby reduced the secretion of transforming growth factor 1 (TGF-β1) in macrophages. Moreover, Nin-lipo demonstrated significant efficacy against weight loss and liver function abnormalities in a mouse model caused by nintedanib. Therefore, nebulized Nin-lipo could greatly improve the antifibrotic efficacy of nintedanib while maintaining an excellent safety profile. Nin-lipo could potentially be developed as a new therapy for IPF.

Study the Physiological and Biochemical Effects of Berberine Extract on Nonalcoholic Fatty Liver Disease (NAFLD) in Male Rabbits

Study the Physiological and Biochemical Effects of Berberine Extract on Nonalcoholic Fatty Liver Disease (NAFLD) in Male Rabbits

Abstract PO3-04-12: SUMIT-BC: Phase 2 randomized study of fulvestrant with or without the cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. In an initial single-arm evaluation samuraciclib (CT7001), a once daily (QD) oral CDK7 inhibitor has demonstrated a favourable safety profile and clinical activity in combination with fulvestrant, a selective estrogen receptor degrader (SERD), in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor. There was evidence of enhanced benefit in patients with no detectable TP53 mutation from baseline circulating tumor DNA (ctDNA) analysis and in patients without baseline liver metastases [1]. Samuraciclib is associated with low grade gastrointestinal (GI) adverse events such as nausea, vomiting and diarrhea managed with simple prophylaxis and patient counselling. An instant release capsule formulation was used in the initial clinical evaluation of samuraciclib requiring patients to take multiple capsules designed to rapidly release a large amount of material high in the GI tract. In this study a novel single tablet formulation will be administered which may enhance GI tolerability (2). This Phase 2 open-label randomised study will evaluate the efficacy, safety, pharmacokinetics and Quality of Life (QoL) impact of samuraciclib in combination with fulvestrant in comparison to a fulvestrant monotherapy control arm. Consistent with the principles of the current Project OPTIMUS initiative, 2 dose levels of samuraciclib will be evaluated [3]. All patients will undergo baseline ctDNA evaluation of TP53 mutation status to permit a prospective evaluation of its patient selection biomarker potential. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. All patients will undergo baseline Guardant360 ctDNA analysis to establish their TP53 mutation status among others. 60 patients will be enrolled and will all receive fulvestrant 500mg IM administered on days 1, 15 and 29 and then monthly thereafter. Patients will be randomized 1:1:1 to fulvestrant alone, fulvestrant and samuraciclib 240mg QD or fulvestrant and samuraciclib 360mg QD. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. The pharmacokinetics of samuraciclib and fulvestrant will be studied though the first 6 months of the study, with highest intensity during month 1. To evaluate Quality of Life (QoL) The Functional Assessment of Cancer Therapy -Breast questionnaire (FACT-B) will be completed. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and the pharmacokinetics of fulvestrant and samuraciclib. QoL and correlations between ctDNA detectable TP53 mutations and efficacy/safety finding in this patient population will be reported. The study opened for recruitment in June 2023.

Treatment Related Acute Toxicities Between Treatment with 3D-CRT and IMRT in Localised Prostate Cancer.

To compare the acute toxicities of two radiation treatment techniques, intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (3D-CRT) in localised prostate adenocarcinoma. Descriptive study. Place and Duration of the Study:Department of Oncology, Dr. Ziauddin Hospital, Karachi, Pakistan, from July 2016 to June 2022. Patients with localised prostate adenocarcinoma who underwent treatment using two different advanced radiotherapy techniques i.e., IMRT and 3D-CRT were recruited during the study period. They were followed up for six months for acute gastrointestinal (GI) and genitourinary (GU) adverse events (acute toxicities) related to both treatment modalities according to Modified radiation therapy oncology group (RTOG) criteria. The acute toxicities were assessed at the 2nd, 4th, and 6th week during treatment and at the 3rd and 6th month after treatment. There were 78 patients, with 39 patients in each group. The mean age was 68 ± 10 years in the 3D-CRT and 68 ± 07 years in the IMRT group. Patients in the IMRT group exhibited markedly lower treatment-related acute GI and GU effects at the end of 4th and 6th weeks for anorectal pain (p = 0.04) and (p = 0.01) and burning micturition (p = 0.003) and (p = 0.01), respectively. Furthermore, at 3 months anorectal pain (p = 0.02), loose stools (p = 0.005), and burning micturition (p = 0.01) were present and at 6 months anorectal pain was (p = 0.01) still present. Radiation therapy modalities 3D-CRT and IMRT both showed acceptable toxicity profile in the management of localised prostate cancer, while IMRT group exhibited significantly lower treatment-related acute GI and GU effects. 3D-CRT (3-Dimensional Conformal Radiation Therapy), IMRT (Intensity-Modulated Radiation Therapy), Radiation toxicity.

P044 Janus Kinase Inhibitors-a retrospective study on side effects and discontinuation reasons

Abstract Background/Aims In light of drug safety warnings for Janus kinase inhibitors (JAKi), we aimed to evaluate the occurrence of adverse events and identify reasons for discontinuation of JAKi in clinical practice. Methods Medical records of all patients prescribed JAKi in NHS Grampian from January 2021 to January 2023 for rheumatic diseases were retrospectively reviewed. Patient demographics, co-morbidities, reasons for treatment discontinuation and occurrence of adverse events (including cardiovascular events) were recorded. Results 160 patients were prescribed JAKi. 131 (81.8%) patients had rheumatoid arthritis, 16 (10%) psoriatic arthritis, five (3%) axial spondyloarthritis, three (2%) juvenile idiopathic arthritis (in adulthood), 3 (2%) undifferentiated inflammatory arthritis, one (0.6%) granulomatous polyangiitis (GPA), one (0.6%) enteropathic arthritis. Mean duration of treatment was 9.9±12 months with 34.4% on treatment for &amp;gt;12 months. 47.5% discontinued JAKi after an average of 7.0 ± 5.1 months. Patients discontinuing treatment were significantly older than patients who continued treatment 60.1yrs ± 11.0 vs 55.9yrs ± 12.5 respectively, p = 0.03. There were no differences between discontinuing and continuing treatment groups with respect to BMI, smoking, diabetes, cardiovascular disease, hypertension or statin use. Discontinuation rates were 66.7 % tofacitinib, 44.4 % filgotinib and 34.4 % upadacitinib. Discontinuation reasons were inefficacy (37.9 %), headache (9.2 %), infections (9.2 %) and gastrointestinal adverse effects (8.0 %). One patient discontinued JAKi due to an arterial embolism (DVT in the context of undiagnosed patent foramen ovale), three developed new onset hypertension. Common infections leading to discontinuation were urinary tract (37.5 %) and chest (25.0 %), with one case of tuberculosis. No herpes zoster infections led to JAKi discontinuation. In patients who continued treatment infections occurred in 27.1% (30% chest, 21.7%, Covid-19, 13% UTIs, 8.7% herpes zoster 8.7% otitis media). Other adverse events such as fatigue and nausea were reported in &amp;lt; 4 % of all patients. No malignancies were recorded. Conclusion Older patients are more likely to discontinue JAKi due to infections. Upadacitinib patients were least likely to discontinue. Treatment inefficacy, urine and chest infections were the commonest reasons for discontinuation. Disclosure J. Klein: None. J. Alexander: None. L. Robertson: Other; LR has received funding for conference attendance from UCB. R. Hollick: None.

Gastrointestinal effects of caffeine in preterm infants: a systematic review and Bayesian meta-analysis.

Caffeine is widely used in preterm infants to prevent or treat apnoea of prematurity. Adverse gastrointestinal effects of caffeine have not been thoroughly researched in preterm infants. With this systematic review and meta-analysis, we aim to summarise the results of trials on the gastrointestinal effects of caffeine in preterm infants. We searched MEDLINE, Web of Science, Scopus and ClinicalTrials.gov up to 21 April 2023. We included randomised controlled trials assessing caffeine versus placebo in preterm neonates and reporting gastrointestinal side effects. Risk of bias was assessed using the Cochrane Risk of Bias tool. A Bayesian meta-analysis was performed to estimate the pooled OR of gastrointestinal side effects. Nine trials involving 2746 preterm infants were analysed. Seven trials assessing necrotising enterocolitis and four trials assessing feeding intolerance in our meta-analysis found no differences between caffeine and placebo (OR=1.007 (95% credible interval 0.021, 5.462), I2=97.4%, and OR=1.266 (95% credible interval 0.064, 28.326), I2=84.8%, respectively). Four trials assessed the outcomes spontaneous intestinal perforation, constipation, gastrointestinal disorder (composite outcome: gastro-oesophageal regurgitation or dilated bowel loops), age at oral feeding and cholestasis syndrome and found no differences between groups. One trial assessed the outcomes gastro-oesophageal symptoms and duration of tube feeding and found that caffeine was associated with a reduced burden of gastro-oesophageal reflux symptoms at 2 weeks (p<0.05), but not at term. According to this systematic review and meta-analysis, the use of caffeine at usual doses in preterm infants does not seem to be associated with significant gastrointestinal adverse effects.

Rectal Spacer Reduces Gastrointestinal Side Effects of Radiation Post Radical Prostatectomy

Objectives: Our objective was to assess the rate of complications and gastrointestinal adverse effects of rectal spacer insertion for salvage post prostatectomy radiation therapy. Methods: A retrospective observational study was performed. Between September 2018 and March 2022, 64 post-radical prostatectomy patients who were planned for salvage radiation therapy received a rectal spacer. The selected patients were those who had nerve-sparing prostatectomy with intrafascial or interfascial dissections (where Denonvillier’s fascia is retained). Radiation dose to the rectal wall and gastrointestinal symptoms were assessed. Symptoms were graded using the National Cancer Center Institute Common Terminology Criteria for Adverse Events v4.0 grading scheme. A total of 39 patients had pre-spacer planning computer tomography (CT) scans, and the rectal dose before and after the spacer insertion was calculated. Comparisons were made using the Student’s t-test, with a p-value &lt; 0.05 representing statistical significance. Finally, clinicians were surveyed to rate the ease of the procedure using a 5-point Likert scale of 1 to 5 (1: very difficult, 2: difficult, 3: moderate, 4: easy, 5: very easy). Results: A total of 64 patients successfully underwent rectal spacer insertion. The mean age was 64.4 years (standard deviation: 5.7 years). After a median of 14 months’ (range 6 to 35) follow up, acute grade 1 and above gastrointestinal (GI) toxicities were seen in 28% of patients (grade 2 in 1.5%), and late grade 1 and above GI toxicities were seen in 12% of patients (grade 2 in 1.5%). Amongst the 39 patients with pre-spacer planning CT images, the volume of the rectum receiving 60%, 70%, 80%, 90%, and 100% of the prescribed radiation dose was reduced by 25.9%, 34.2%, 35.4%, 43.7%, and 61.7%, respectively. All dose reductions were statistically significant. The procedure was rated as “easy” or “very easy” to perform in 56% of cases. Conclusions: The insertion of a rectal spacer in selected patients undergoing PPRT is feasible and safe and significantly improves rectal wall radiation dosimetry in salvage post prostatectomy radiation therapy. It was accomplished in &gt;95% of patients, increasing vesico-rectal separation from ‘immediate vicinity’ to 11 mm without any post-operative complications in experienced hands. In addition, it achieved significant reduction in rectal radiation doses, leading to low rates of acute and late grade 2 toxicity.

Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. PROSPERO registration no. CRD42022382594.

Impact of Anti Tubercular Drugs on Biochemical Changes in Newly Diagnosed Tuberculosis Patients

Background: The disease tuberculosis (TB) continues to be a major global health concern, with high rates of morbidity and mortality, particularly in developing nations. It affects multiple organs and has the ability to alter metabolic processes. The purpose of this study was to ascertain how patients' serum biochemical markers were affected by tuberculosis and the medications used to treat it. Objective: The aim of this study is to evaluate impact of anti-tubercular drugs on biochemical changes in newly diagnosed tuberculosis patients. Methods: The cross-sectional observational study was conducted in Netrokona Medical College Hospital, Netrokona, from 1st January 2022 to 31st December 2023. A total of 120 newly diagnosed cases of pulmonary tuberculosis were enrolled and analyzed in this study. The questionnaire was pretested, corrected and finalized. Data were collected by face-to-face interview and analyzed by appropriate computer based programmed software Statistical Package for the Social Sciences (SPSS), version 24. Results: In this study, majority 48 (40.0%) of the patients were in 31 - 40 years age group and 28 (23.3%) patients were in 41 - 50 years age group, Mean±SD of age was 36.13±11.03 years. Most of the patients 69 (57.50%) were male and 51 (42.50%) patients were female. Most of the patients 87 (72.5%) were in normal range (18.5 – 29.9 kg/m2), 15 (11.7%) of the patients were underweight (&lt;18.5) and 19 (15.8%) of the patients were overweight (&gt;30). Serum Glutamic Oxaloacetic Transaminase and Serum Glutamic Pyruvic Transaminase level were 18.00 (4.01), 21.04 (3.16) before treatment but after treatment the level became 20.10 (3.52), 22.57 (4.41). Urea and Creatinine level were 18.20 (2.31), 0.63 (0.15) before treatment but after treatment 20.01 (5.34) and 0.53 (0.13). After treatment by anti-tubercular drug gastrointestinal adverse drug effects were nausea 3 (2.5%), vomiting 6 (5.0%), diarrhea 3 (2.5%) and abdominal pain 5 (4.2%), followed by itching ......

Lipid clinic experience with bempedoic acid in 3 UK centres

Objective: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. Methods: This study audited bempedoic acid therapy in 216 consecutive patients from 3 hospital centres – a university hospital (n = 77) and 2 district general hospitals (n = 106 & 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. Results: The population was aged 65.9 ± 11.0 years, 42% male, 25% has type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44mmol/L (20%), LDL-C by 1.37 ± 1.31mmol/L (27%), 0.22mmol/L (2%) in triglycerides and 0.06mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C < 2.5mmol/L was achieved in 40% and <2mmol/L in 20%. Efficacy (r2=0.33) was predicted by baseline LDL-C (β = 0.54; p < 0.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (β = 1.60; p = 0.009) was a contributing factor to discontinuation. Conclusion: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalisable to all lipid-lowering drug therapies in susceptible individuals.

Efficacy and safety of once-weekly subcutaneous semaglutide in adults with overweight or obesity: systematic review with meta-analysis.

To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide treatment in overweight or obese patients without type 2 diabetes. Randomized clinical trials that accessed the impact of once-weekly semaglutide on body weight and safety outcomes in overweight or obese patients were retrieved from Pubmed, EMBASE, and Lilacs up to November 2023. Risk of bias was assessed with RoB 2.0, and certainty of evidence (CoE) with GRADE. We conducted a random-effects meta-analysis. We included ten publications with 22.155 patients. Semaglutide decreased relative body weight (MD: -11.80; 95%CI: -13.53 to -10.07; CoE: High), absolute body weight (MD: -11.58; 95%CI: -13.25 to -9.90; CoE: High) and BMI (MD: -4.15; 95%CI: -4.85 to -3.45; CoE: High). Semaglutide also increased the proportion of patients who achieved 5%, 10% and 15% of weight loss ([weight loss ≥5%: RR 2.29, 95% CI: 1.88 to 2.80; CoE: High]; [weight loss ≥10%: RR 4.54, 95% CI: 3.45 to 5.98; CoE: High]; [weight loss ≥15%: RR 8.29, 95%CI: 5.54 to 12.39; CoE: High]). Semaglutide leads to small risk to adverse events (RR: 1.03; 95%CI: 1 to 1.06; CoE: High), no difference in the serious adverse events (RR: 1.07; 95%CI: 0.70 - 1.62; CoE: Low), but increases in the risk to discontinued treatment (RR: 2.03; 95%CI: 1.87 - 2.20; CoE: High) and gastrointestinal adverse events (RR: 3.26; 95%CI: 1.99 - 5.34; CoE: Moderate). This up-to-date systematic review highlights that once-weekly semaglutide treatment resulted in clinically important weight loss, becoming a promising adjuvant therapy to treat obesity.

Janus kinase inhibitors and tumour necrosis factor inhibitors show a favourable safety profile and similar persistence in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: real-world data from the BIOBADASER registry

ObjectivesTo compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).MethodsWe...

Androgen deprivation alone versus combined with pelvic radiation for adverse events and quality of life in clinically node-positive prostate cancer

The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.

The first MASH drug therapy on the horizon: Current perspectives of resmetirom.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.

Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

Vincristine-induced adverse events related to body weight in dogs treated for lymphoma.

Traditional dosing of chemotherapy drugs based on body surface area may overdose small dogs, leading to an increased frequency of adverse events (AEs). Evaluate the frequency of hematologic and gastrointestinal AEs in dogs with newly diagnosed lymphoma treated with vincristine weighing ≤15 kg in comparison to dogs weighing >15 kg. We hypothesized that dogs weighing ≤15 kg would experience a higher frequency of AEs. One hundred and thirty-eight dogs with newly diagnosed lymphoma were treated with vincristine. A multicenter retrospective study reviewing hematologic data and medical record information. Complete blood counts were performed no more than 24 hours before vincristine administration and then between 4 and 8 days post-administration. Data were evaluated using logistic regression or ordinal logistic regression. Thirty-eight dogs weighing ≤15 kg and 100 dogs weighing >15 kg were included. The median vincristine dose for both groups was 0.6 mg/m2. Seventeen (12.3%) instances of neutropenia occurred with no significant difference in overall frequency or grade between groups. Thirty initially asymptomatic substage A dogs (29.4%) experienced gastrointestinal AEs. Because of the widespread use of gastrointestinal supportive care medications, statistical comparison between groups could not be performed. Seven instances of hospitalization occurred (5.0%) and the risk of hospitalization did not differ significantly between groups (P = .37). Vincristine dosed at ≤0.6 mg/m2 does not increase the risk of hematologic AEs in dogs weighing ≤15 kg.

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

Gastrointestinal infections and gastrointestinal haemorrhage are underestimated but serious adverse events in chimeric antigen receptor T-cell recipients: A real-world study.

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved durable response in patients with hematological malignancies, however, therapy-associated multisystem toxicities are commonly observed. Here, we systematically analyzed CAR-T-related gastrointestinal adverse events (GAEs) using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC). Among 105,087,611 reports in FAERS, 1518 CAR-T-related GAEs reports were identified. 23 GAEs (n = 281, 18.51%) were significantly overreported following CAR-T therapy compared with the full database, of which 11 GAEs (n = 156, 10.28%) were associated with gastrointestinal infections (GI), such as clostridium difficile colitis (n = 44 [2.90%], ROR = 5.55), enterovirus infection (n = 23 [1.52%], ROR = 20.02), and mucormycosis (n = 15 [0.99%], ROR = 3.09). Overall, the fatality rate of 11 GI-related AEs was 29.49%, especially mucormycosis causing substantial mortality with 60%. In addition, 4 of 23 overreported GAEs were related to haemorrhage and the mortality of gastrointestinal haemorrhage was 73.17%. Lastly, 29 death-related GAEs were identified. These findings could help clinicians early alert those rarely reported but lethal GAEs, thus reducing the risk of severe toxicities.