-
BMJ (Clinical Research Ed.) Jan 2024To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.
OBJECTIVE
To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible.
RESULTS
76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration.
CONCLUSIONS
GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42022342845.
Topics: Adult; Humans; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-1 Receptor Agonists; Glycated Hemoglobin; Glycemic Control; Hypoglycemic Agents; Network Meta-Analysis; Weight Loss; Lipid Metabolism
PubMed: 38286487
DOI: 10.1136/bmj-2023-076410 -
Molecular Psychiatry Aug 2023The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin... (Meta-Analysis)
Meta-Analysis
The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
Topics: Humans; Depression; Serotonin; Receptor, Serotonin, 5-HT1A; Tryptophan; Hydroxyindoleacetic Acid; Antidepressive Agents; Serotonin Plasma Membrane Transport Proteins
PubMed: 35854107
DOI: 10.1038/s41380-022-01661-0 -
Cureus Dec 2023Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory,... (Review)
Review
Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory, axial, and limb muscles exhibiting a typical fatigable weakening due to the development of antibodies against the acetylcholine receptor (AChR). Infections, stress, surgeries, thymus gland anomalies, and pharmaceutical side effects can also cause it. Ocular symptoms are initially experienced by most of the sufferers. The majority of the sufferers will go through at least one episode of symptom exacerbation during their illness. The immune system in MG interferes with nerve-muscle communication, causing muscles to become weak and tired quickly. The actual cause is not yet known, but a problem in the thymus gland may be the cause. In a person suffering from this disease, the size of the thymus becomes larger than normal, which is also called thymic hyperplasia. It is more common for women to have early-onset MG (EOMG) than for males to have late-onset MG (LOMG). Merely clinical evidence, encompassing the patients' medical history and physical indications of fluctuating muscle weakness in a specific region, is utilized to diagnose MG. Complementary diagnostic procedures and lab techniques aid in confirming the synaptic dysfunction and characterizing its kind and degree. Early diagnosis and the availability of effective treatments have reduced the burden of severe impairment and high mortality previously associated with MG. Current immunomodulation-based therapies come with side effects brought on by persistent immune suppression. Improved knowledge of this relatively uncommon but curable condition is required among primary carers. The objective of this review is to provide information about MG and to help people recognize its symptoms and start treatment without panic so that the progression of this disease can be stopped and complications can be avoided.
PubMed: 38186498
DOI: 10.7759/cureus.50017 -
Clinical Breast Cancer Dec 2023Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a... (Meta-Analysis)
Meta-Analysis Review
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a systematic review to evaluate the efficacy and safety of T-DXd in treating breast cancer, based on clinical trials. A systematic search of the literature was conducted to identify clinical trials investigating the efficacy and safety of T-DXd in breast cancer. Clinical trials of any phase were included. Outcome measures were any adverse events and survival. Meta-analysis was conducted where possible. Pooled prevalence for each adverse event of any grade and grade 3 or greater were estimated. Progression-free survival (PFS), overall survival (OS) and objective response rates (ORRs) were also reported to evaluate the efficacy of T-DXd in breast cancer. A total of 1593 patients from 6 clinical trials were included. Common adverse events of any grade were nausea, anemia, neutropenia, vomiting, fatigue, constipation and diarrhea, occurring in greater than 30% of cases. In terms of adverse events of grade 3 or more, only anemia and neutropenia occurred at a relatively high rate. Median PFS ranged from 11.1 to 22.1 months. There was evidence of a benefit of T-DXd compared to controls in terms of both PFS (OR: 0.38; 95% CI: 0.32, 0.45) and OS (OR: 0.61; 95% CI: 0.48, 0.78). ORRs ranged from 37% to 79.9%. The present systematic review shows evidence that T-DXd is a safe and effective agent in the treatment of breast cancer based on currently available data. The most common adverse events affected the blood, lymphatic and gastrointestinal systems. Interstitial lung disease (ILD) is a notable and potentially serious adverse event.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Camptothecin; Neutropenia; Anemia; Receptor, ErbB-2
PubMed: 37775347
DOI: 10.1016/j.clbc.2023.09.005 -
Journal of Thoracic Oncology : Official... Dec 2023Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations.
METHODS
A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models.
RESULTS
A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17).
CONCLUSIONS
Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance.
Topics: Humans; Lung Neoplasms; Incidence; Protein-Tyrosine Kinases; Proto-Oncogene Proteins p21(ras); Proto-Oncogene Proteins; Carcinoma, Non-Small-Cell Lung; Genomics; Brain Neoplasms; Receptor Protein-Tyrosine Kinases; ErbB Receptors
PubMed: 37392903
DOI: 10.1016/j.jtho.2023.06.017 -
The American Journal of Geriatric... Jan 2024Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may exert positive effects in patients with depression. Our aim was to conduct a... (Meta-Analysis)
Meta-Analysis Review
AIM/HYPOTHESIS
Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may exert positive effects in patients with depression. Our aim was to conduct a systematic review and meta-analysis to examine the antidepressant effects of GLP-1RAs.
METHODS
Randomized controlled trials and prospective cohort studies investigating the effects of GLP-1RAs versus placebo or other antidiabetic therapies on depressive symptoms were searched for using multiple electronic sources (CENTRAL, PubMed, EMBASE, PsycINFO, World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, China Network Knowledge Infrastructure, China Biomedical Database, Wan Fang data, and Chinese Scientific Journals Database) from inception to February 16, 2023. We utilized a random effects model to analyze standardized mean differences for the change in depression rating scales comparing GLP-1RA treated groups with control treated groups.
RESULTS
The meta-analysis comprising 2,071 participants included 5 randomized controlled trials and 1 prospective cohort study. The meta-analysis indicated that the change from baseline in depression rating scale scores decreased significantly when patients received treatment with GLP-1RAs compared to control treatments (SMD = -0.12, 95% CI [-0.21, -0.03], p <0.01, I = 0%, p = 0.52). The subgroup analysis showed that the effects of GLP-1RAs on depressive symptoms were consistent in patients with Type 2 diabetes mellitus (SMD = -0.12, 95% CI [-0.21, -0.03], p <0.01, I = 2%, p = 0.40).
CONCLUSIONS
Adults treated with GLP-1RAs showed significant reductions in the depression rating scale scores compared to those treated with control substances. Our findings suggest that GLP-1RAs may be a potential treatment for alleviating depressive symptoms in humans.
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor Agonists; Prospective Studies; Hypoglycemic Agents; Antidepressive Agents
PubMed: 37684186
DOI: 10.1016/j.jagp.2023.08.010 -
Reviews in Endocrine & Metabolic... Aug 2023Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological... (Review)
Review
Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological complications such as stroke, cognitive impairment, and peripheral neuropathy. We performed a systematic review to examine the evidence concerning the effects of GLP-1 RAs on neurological complications of diabetes. The databases used were Pubmed, Scopus and Cochrane. We selected clinical trials which analysed the effect of GLP-1 RAs on stroke, cognitive impairment, and peripheral neuropathy. We found a total of 19 studies: 8 studies include stroke or major cardiovascular events, 7 involve cognitive impairment and 4 include peripheral neuropathy. Semaglutide subcutaneous and dulaglutide reduced stroke cases. Liraglutide, albiglutide, oral semaglutide and efpeglenatide, were not shown to reduce the number of strokes but did reduce major cardiovascular events. Exenatide, dulaglutide and liraglutide improved general cognition but no significant effect on diabetic peripheral neuropathy has been reported with GLP-1 RAs. GLP-1 RAs are promising drugs that seem to be useful in the reduction of some neurological complications of diabetes. However, more studies are needed.
Topics: Humans; Hypoglycemic Agents; Liraglutide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Cardiovascular Diseases; Stroke; Diabetes Complications
PubMed: 37231200
DOI: 10.1007/s11154-023-09807-3 -
Molecular Psychiatry Aug 2023Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic... (Meta-Analysis)
Meta-Analysis
Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D receptor (DR) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The DR occupancy curves showed that the risk increased substantially when DR occupancy exceeded 75-85%, except for DR partial agonists that had smaller ORs albeit high DR occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current DR therapeutic window for EPS.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Haloperidol; Clozapine; Receptors, Dopamine D2; Drug-Related Side Effects and Adverse Reactions
PubMed: 37537284
DOI: 10.1038/s41380-023-02203-y -
Phytomedicine : International Journal... Jul 2023Every day the skin is constantly exposed to several harmful factors that induce oxidative stress. When the cells are incapable to maintain the balance between... (Review)
Review
BACKGROUND
Every day the skin is constantly exposed to several harmful factors that induce oxidative stress. When the cells are incapable to maintain the balance between antioxidant defenses and reactive oxygen species, the skin no longer can keep its integrity and homeostasis. Chronic inflammation, premature skin aging, tissue damage, and immunosuppression are possible consequences induced by sustained exposure to environmental and endogenous reactive oxygen species. Skin immune and non-immune cells together with the microbiome are essential to efficiently trigger skin immune responses to stress. For this reason, an ever-increasing demand for novel molecules capable of modulating immune functions in the skin has risen the level of their development, particularly in the field of natural product-derived molecules.
PURPOSE
In this review, we explore different classes of molecules that showed evidence in modulate skin immune responses, as well as their target receptors and signaling pathways. Moreover, we describe the role of polyphenols, polysaccharides, fatty acids, peptides, and probiotics as possible treatments for skin conditions, including wound healing, infection, inflammation, allergies, and premature skin aging.
METHODS
Literature was searched, analyzed, and collected using databases, including PubMed, Science Direct, and Google Scholar. The search terms used included "Skin", "wound healing", "natural products", "skin microbiome", "immunomodulation", "anti-inflammatory", "antioxidant", "infection", "UV radiation", "polyphenols", "polysaccharides", "fatty acids", "plant oils", "peptides", "antimicrobial peptides", "probiotics", "atopic dermatitis", "psoriasis", "auto-immunity", "dry skin", "aging", etc., and several combinations of these keywords.
RESULTS
Natural products offer different solutions as possible treatments for several skin conditions. Significant antioxidant and anti-inflammatory activities were reported, followed by the ability to modulate immune functions in the skin. Several membrane-bound immune receptors in the skin recognize diverse types of natural-derived molecules, promoting different immune responses that can improve skin conditions.
CONCLUSION
Despite the increasing progress in drug discovery, several limiting factors need future clarification. Understanding the safety, biological activities, and precise mechanisms of action is a priority as well as the characterization of the active compounds responsible for that. This review provides directions for future studies in the development of new molecules with important pharmaceutical and cosmeceutical value.
Topics: Humans; Skin Aging; Reactive Oxygen Species; Biological Products; Antioxidants; Inflammation; Anti-Inflammatory Agents; Polyphenols; Peptides; Polysaccharides
PubMed: 37119762
DOI: 10.1016/j.phymed.2023.154824 -
Clinical Cardiology Aug 2023This study aimed to evaluate the efficacy of single-pill combination (SPC) antihypertensive drugs in patients with uncontrolled essential hypertension. Through Searching... (Meta-Analysis)
Meta-Analysis Review
This study aimed to evaluate the efficacy of single-pill combination (SPC) antihypertensive drugs in patients with uncontrolled essential hypertension. Through Searching Pubmed, EMBASE, the Cochrane Library, and Web of Science collected only randomized controlled trials on the efficacy of single-pill combination antihypertensive drugs in people with uncontrolled essential hypertension. The search period is from the establishment of the database to July 2022. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias Assessment, and statistical analyses were performed using Review Manage 5.3 and Stata 15.1 software. This review ultimately included 32 references involving 16 273 patients with uncontrolled essential hypertension. The results of the network meta-analysis showed that a total of 11 single-pill combination antihypertensive drugs were included, namely: Amlodipine/valsartan, Telmisartan/amlodipine, Losartan/HCTZ, Candesartan/HCTZ, Amlodipine/benazepril, Telmisartan/HCTZ, Valsartan/HCTZ, Irbesartan/amlodipine, Amlodipine/losartan, Irbesartan/HCTZ, and Perindopril/amlodipine. According to SUCRA, Irbesartan/amlodipine may rank first in reducing systolic blood pressure (SUCRA: 92.2%); Amlodipine/losartan may rank first in reducing diastolic blood pressure (SUCRA: 95.1%); Telmisartan/amlodipine may rank first in blood pressure control rates (SUCRA: 83.5%); Amlodipine/losartan probably ranks first in diastolic response rate (SUCRA: 84.5%). Based on Ranking Plot of the Network, we can conclude that single-pill combination antihypertensive drugs are superior to monotherapy, and ARB/CCB combination has better advantages than other SPC in terms of systolic blood pressure, diastolic blood pressure, blood pressure control rate, and diastolic response rate. However, due to the small number of some drug studies, the lack of relevant studies has led to not being included in this study, which may impact the results, and readers should interpret the results with caution.
Topics: Humans; Antihypertensive Agents; Losartan; Hypertension; Telmisartan; Irbesartan; Angiotensin Receptor Antagonists; Network Meta-Analysis; Hydrochlorothiazide; Valine; Drug Therapy, Combination; Angiotensin-Converting Enzyme Inhibitors; Amlodipine; Valsartan; Tetrazoles; Blood Pressure; Essential Hypertension
PubMed: 37432701
DOI: 10.1002/clc.24082