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ObjectivesTo assess the beneficial and harmful effects of regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes.DesignSystematic review of randomised clinical trials with meta-analysis and trial sequential analysis.Data sourcesCENTRAL, MEDLINE, Embase, LILACS and other sources from inception to 30 January 2026.Study selectionRandomised clinical trials comparing regular human insulins versus rapid-acting insulin analogues (insulin aspart, lispro, glulisine) in children and adolescents with type 1 diabetes.AnalysesData were analysed using meta-analysis and trial sequential analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool, V.2, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Primary outcomesSevere hypoglycaemia, ketoacidosis and serious adverse events.Results10 trials randomising 1107 participants were included. The certainty of evidence was very low mainly due to high risk of bias and small sample sizes. Meta-analysis showed no evidence of a difference between regular human insulins and rapid-acting insulin analogues on severe hypoglycaemia (risk ratio (RR) 1.28, 95% CI 0.81 to 2.03; I2=0.0%; p=0.2851; nine trials), ketoacidosis (RR 0.88, 95% CI 0.26 to 2.93; I2=0.0%; p=0.8593; two trials) and serious adverse events (RR 1.00, 95% CI 0.44 to 2.25; I2=0.0%; p=0.9958; two trials). Trial sequential analysis showed that all meta-analyses of primary outcomes were underpowered.ConclusionsCurrent research shows no differential effects between regular human insulins and rapid-acting insulin analogues for children and adolescents with type 1 diabetes, but the evidence is very uncertain.PROSPERO registration numberCRD42024508625.

BackgroundIncretin-based drugs, including glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs, are increasingly used in the management of type 2 diabetes mellitus and obesity. While these agents have shown cardiovascular benefits, their effects on both cardiovascular outcomes and cardiac structure and function remain uncertain—particularly in patients with and without a history of heart failure (HF).Methods and analysisWe will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED) and Conference Proceedings Citation Index-Science (CPCI-S)), as well as clinical trial registries from their inception and onwards to identify relevant randomised trials. The literature search is scheduled for July 2025. Two review authors will independently extract data and assess risk of bias. We will include randomised controlled trials assessing the effects of cagrilintide/semaglutide, liraglutide, semaglutide and tirzepatide in patients with and without a history of HF. The primary outcome will be cardiovascular mortality. Secondary outcomes will include HF hospitalisation, myocardial infarction, stroke, heart rate, systolic blood pressure, N-terminal pro B-type natriuretic peptide, left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricular end-systolic volume. Data will be synthesised by aggregate data meta-analyses and trial sequential analysis. Risk of bias will be assessed with the Cochrane Risk of Bias tool, version 2, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE).Ethics and disseminationAs this study is a systematic review based on secondary analysis of published data, ethical approval is not required. Findings will be published in international peer-reviewed scientific journals.PROSPERO registration numberCRD420251003374.

BackgroundCardiovascular diseases, overweight, type 2 diabetes and chronic kidney disease increase the risk of cardiovascular events.Glucagon-like peptide-1 analogues are recommended by the European Society of Cardiology and the American College of Cardiology to lower the risk of death and progression of cardiovascular disease in patients with cardiovascular disease and type 2 diabetes. Semaglutide, tirzepatide and liraglutide are approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of type 2 diabetes mellitus and overweight. CagriSema is currently not approved, but several phase III trials are ongoing.No previous systematic review has investigated the effects of semaglutide, tirzepatide, CagriSema and liraglutide, which may not be disease-specific, on hard binary outcomes for all trial populations at increased risk of cardiovascular events.Methods and analysesWe will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index—Science) and clinical trial registries from their inception and onwards to identify relevant randomised trials. We expect to perform the literature search in December 2025. Two review authors will independently extract data and assess the risk of bias. We will include randomised trials assessing the effects of semaglutide, tirzepatide, CagriSema and/or liraglutide in participants with an increased risk of cardiovascular events. The primary outcome will be all-cause mortality. Secondary outcomes will be myocardial infarction, stroke and all-cause hospitalisation. Data will be synthesised by aggregate data meta-analyses, Trial Sequential Analyses and network meta-analysis, risk of bias will be assessed with Cochrane Risk of Bias tool V. 2, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations and the Confidence in Network Meta-Analysis approach.Ethics and disseminationThis protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration numberCRD42024623312.

IntroductionParkinson’s disease is a neurological disease with a rising incidence and prevalence. Patients with Parkinson’s disease may receive antipsychotics, for example, due to Parkinson’s disease psychosis. Parkinson’s disease psychosis is characterised by visual hallucinations and other psychotic symptoms. To date, no systematic review has evaluated the effects of antipsychotics in patients with Parkinson’s disease. Therefore, this review aims to assess the beneficial and harmful effects of antipsychotics for Parkinson’s disease.Methods and analysisThis is a protocol for a systematic review. A search specialist will perform a search in major medical databases (eg, MEDLINE (Medical Literature Analysis and Retrieval System Online), EMBASE (Excerpta Medica database), CENTRAL (Cochrane Central Register of Controlled Trials)) and clinical trial registries. Published and unpublished randomised clinical trials comparing antipsychotics to any control (placebo, standard care or other antipsychotics) in patients with Parkinson’s disease will be included. Two review authors will independently extract data and conduct risk of bias assessments with the Cochrane Risk of Bias tool—V.2. Primary outcomes will be all-cause mortality, serious adverse events and significant falls. Secondary outcomes will be hospitalisations, non-serious adverse events, Unified Parkinson’s Disease Rating Scale total score and psychotic symptoms using any valid symptom scale. Data will be synthesised by aggregate meta-analysis, trial sequential analysis and network meta-analysis. Several subgroup analyses are planned. An eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by GRADE (Grading of Recommendations Assessment, Development and Evaluations) and CiNeMA (Confidence in Network Meta-Analysis) approach.Ethics and disseminationThis protocol does not include results, and ethics approval is not required for the project. The findings from the systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration numberPROSPERO ID: CRD42025633985. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD42025633985.

Background Tirzepatide is a dual-acting glucagon-like peptide-1 analog and a glucose-dependent insulinotropic polypeptide analog. The disease-specific weight-reducing effects associated with tirzepatide use are well established, but its adverse effects have not been systematically assessed and may not be disease-specific. This systematic review aimed to assess the adverse effects associated with tirzepatide use compared with placebo in patients at increased risk of cardiovascular events. Methods We searched six electronic databases and other sources from inception to June 16, 2025. Randomized clinical trials comparing tirzepatide with placebo in patients at increased risk of cardiovascular events were eligible for inclusion. The literature search identified 8866 records after removal of duplicates. Two review authors screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with Cochrane Risk of Bias tool – version 2; an eight-step procedure was used to assess whether thresholds for statistical significance were crossed, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included non-serious adverse events (nsAEs). Results The analysis included 21 trials, randomizing 8043 participants to tirzepatide versus placebo. Beta-binomial regression showed no evidence of a difference when assessing all-cause mortality (odds ratio 1.02, 95% CI 0.57 to 1.81; p  = 0.95; 21 trials; TSA: underpowered meta-analysis; very low certainty of evidence) or SAEs (odds ratio 0.98, 95% CI 0.82 to 1.17; p  = 0.80; 21 trials; TSA: sufficiently powered meta-analysis; moderate certainty of evidence). Meta-analysis showed that tirzepatide increased the risk of several nsAEs, primarily gastrointestinal nsAEs such as nausea, diarrhea, decreased appetite, and vomiting. Conclusions Current evidence indicates that tirzepatide does not appear to influence the risk of serious adverse events. A meta-analysis of all-cause mortality showed no evidence of a difference; however, this finding was based on sparse data and is associated with very low certainty. Tirzepatide use is associated with an increased risk of several gastrointestinal nsAEs. Further trials designed for investigating the effects of tirzepatide compared with placebo on all-cause mortality are needed. Trial registration PROSPERO, CRD42024599035.

Background Mirtazapine is used to treat depression worldwide, and the effects of mirtazapine on depression rating scales are well-known. Our primary objective was to assess the risks of adverse events with mirtazapine for major depressive disorder. Methods We searched relevant sources from inception to 7 March 2024 for randomised clinical trials comparing mirtazapine versus placebo in adults with major depressive disorder. The primary outcomes were suicides or suicide attempts, serious adverse events, and non-serious adverse events. Data were synthesised using meta-analysis and Trial Sequential Analysis. Results We included 17 trials randomising 2,131 participants to mirtazapine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. The included trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to determine the effects of mirtazapine on the risks of suicides or suicide attempts and serious adverse events. Meta-analyses showed that mirtazapine increased the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite but decreased the risk of headaches. Conclusions There is a lack of evidence on the effects of mirtazapine on suicides and serious adverse events. Mirtazapine increases the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite. Mirtazapine might decrease the risk of headaches. The long-term effects of mirtazapine are unknown. Prospero id CRD42022315395.

Background Semaglutide’s disease-specific weight-reducing effects are well established, but its adverse effects, which may not be disease-specific, have not been systematically assessed. The aim of this review was to assess the adverse effects associated with semaglutide use compared with placebo in patients at increased risk of cardiovascular events. Methods We searched six electronic databases and other sources from inception to 31/03/2025. Randomized trials comparing semaglutide (oral or subcutaneous) with placebo in patients at increased risk of cardiovascular events were eligible. The search identified 8370 records. Two review authors independently screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with the Cochrane Risk of Bias tool – version 2; our eight-step procedure was used to assess if the thresholds for statistical significance were crossed, and the certainty of the evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included myocardial infarction and non-serious adverse events (AEs). Results The analysis included 50 trials, with a total of 54,972 participants randomized. Nineteen (38%) enrolled participants with type 2 diabetes (T2DM), 17 (34%) with overweight, 5 (10%) with T2DM and chronic kidney disease, 5 (10%) with T2DM and overweight, and 4 (8%) involved other patient populations. Meta-analysis and TSA showed evidence of beneficial effects of semaglutide on all-cause mortality (relative risk (RR) 0.85; 95% CI 0.79 to 0.91; I 2  = 0.0%; p  < 0.01) and myocardial infarction (RR 0.77, 95% CI 0.69 to 0.85; I 2  = 0.0%; p  < 0.01). None of these analyses showed signs of heterogeneity, and the evidence was of high certainty. Meta-analysis showed that semaglutide decreased the risk of SAEs (RR 0.93, 95% CI 0.88 to 0.98; I 2  = 24.1%; p  < 0.01), but increased the risk of several non-serious gastrointestinal AEs including nausea (RR 3.00, 95% CI 2.63 to 3.42), vomiting (RR 4.12, 95% CI 3.47 to 4.90), and diarrhea (RR 1.88, 95% CI 1.68 to 2.11). Conclusions In patients at increased risk of cardiovascular events, semaglutide reduced the risk of mortality, SAEs, and myocardial infarction but increased the risk of several non-serious gastrointestinal AEs. Registration PROSPERO, CRD42024499511.

IntroductionCardiovascular diseases remain the leading cause of mortality worldwide. Tirzepatide is approved for the treatment of type 2 diabetes mellitus and overweight and is increasingly used. The adverse effects with tirzepatide may not be disease-specific and have not been assessed previously.Methods and analysisWe will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index—Science (CPCI-S)) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in January 2025. Two review authors will independently extract data and perform risk of bias assessments. We will include randomised clinical trials comparing tirzepatide versus placebo or no intervention in all patient groups with an increased risk of cardiovascular events. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and Trial Sequential Analysis, risk of bias will be assessed with the Cochrane Risk of Bias tool—version 2. We will systematically assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations.Ethics and disseminationThis protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration numberCRD42024599035.

IntroductionSemaglutide is increasingly used for the treatment of type 2 diabetes mellitus, overweight and other conditions. It is well known that semaglutide lowers blood glucose levels and leads to significant weight loss. Still, a systematic review has yet to investigate the adverse effects with semaglutide for all patient groups.Methods and analysisWe will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medline, Embase, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index—Science) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in July 2024. Two review authors will independently extract data and perform risk-of-bias assessments. We will include randomised clinical trials comparing oral or subcutaneous semaglutide versus placebo. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and trial sequential analysis; risk of bias will be assessed with Cochrane Risk of Bias tool—version 2, an eight-step procedure will be used to assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations.Ethics and disseminationThis protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration numberCRD42024499511.

IntroductionAfter resuscitation from out of hospital cardiac arrest (OHCA), mechanical ventilation (MV) and respiratory management are fundamental to support patients in the intensive care unit (ICU) and to minimise secondary brain injury. Best practices for MV and association with clinical outcomes in patients with OHCA remain unclear.Methods and analysisThis protocol describes a pre-planned respiratory-focused series of sub-analyses within the Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) trial, an ongoing interventional study evaluating 6-month mortality after randomisation in patients admitted to ICUs following OHCA. The primary aim is to describe real-world ventilator settings and gas-exchange targets during the first 72 hours after ICU admission in patients receiving invasive mechanical ventilation after OHCA. Secondary aims include to estimate the incidence of respiratory complications during ICU stay (eg, ventilator-associated pneumonia, acute respiratory distress syndrome, barotrauma); and to explore the association between early ventilator settings/gas-exchange parameters and 6-month outcomes (mortality and neurological status). Exploratory aim is to characterise weaning and extubation practices, including timing and failure rates.Eligible patients will include adult STEPCARE participants receiving invasive MV after return of spontaneous circulation with available respiratory data recorded within the STEPCARE database.Data collected in the STEPCARE trial that will be analysed include patients’ prehospital characteristics; clinical examination at hospital admission and at ICU admission; ventilator settings and arterial blood gases recorded at predefined time points during ICU stay. In particular: MV setting (mode, tidal volume, positive end-expiratory pressure, fraction of inspired oxygen, tidal volume, mechanical power, plateau/driving pressures), gas-exchange values (arterial partial pressure of oxygen and carbon dioxide, pH, arterial saturation of oxygen), timing of measurements and the occurrence/timing of respiratory complications and weaning outcomes.Ethics and disseminationThe STEPCARE study has been approved by the regional ethics committee at Lund University (Dnr 2022-02425-01, Approved IRB on 2022-06-18) and by all ethics boards in the participating countries. No additional ethical approval is required for this predefined secondary analysis, as no further data collection or interventions will be performed. Findings will be disseminated through publication in peer-reviewed journals and, where appropriate, conference abstracts and presentations. Patients and the public were not involved.ClinicalTrials.govNCT05564754.