BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant rec...BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.展开更多
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to spe...Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to specific mutations affecting insulin synthesis,secretion and glucose regulation.Common traits across MODY subtypes include early-onset diabetes,a family history of autosomal dominant diabetes,lack of features of insulin resistance,and absent islet cell autoimmunity.Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus.Biomarkers and scoring systems can help identify candidates for genetic testing.GCK-MODY,a common subtype,manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy.In contrast,mutations in HNF4A,HNF1A,and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus.Neonatal diabetes mellitus(NDM)is a rare form of monogenic diabetes that usually presents within the first six months.Half of the cases are lifelong,while others experience transient remission.Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel(KCNJ11 or ABCC8)and can be transitioned to sulfonylurea after confirmation of diagnosis.Thus,in many cases,monogenic diabetes offers an opportunity to provide precision treatment.The scope has broadened with next-generation sequencing(NGS)technologies,replacing older methods like Sanger sequencing.NGS can be for targeted gene panels,whole-exome sequencing(WES),or whole-genome sequencing.Targeted gene panels offer specific information efficiently,while WES provides comprehensive data but comes with bioinformatic challenges.The surge in testing has also led to an increase in variants of unknown significance(VUS).Deciding whether VUS is disease-causing or benign can be challenging.Computational models,functional studies,and clinical knowledge help to determine pathogenicity.Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.展开更多
Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,im...Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.展开更多
BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)and type 2 diabetes mellitus(T2DM)are independent risk factors for the development of cardiovascular disease(CVD)and an exaggerated CVD risk is exp...BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)and type 2 diabetes mellitus(T2DM)are independent risk factors for the development of cardiovascular disease(CVD)and an exaggerated CVD risk is expected when both diseases co-exist.Therefore,thorough risk stratification is important to inform better clinical practice decisions based on good quality evidence for patient with MAFLD and T2DM.AIM To identify the CVD and cardiovascular event(CVE)risk in a systematic review when MAFLD and T2DM co-exist to inform better clinical practice decisions.METHODS A systematic review was performed by compiling data by searching PubMed,EMBASE and Cochrane Library databases.Quality appraisal of retrieved studies and the meta-analysis were performed using Joanna Briggs Institute(JBI)tool and RevMan 5.4 software respectively.The effect indicators for CVE and CVD risk were expressed as odds ratios(OR)and 95%CI with P-values<0.05 as significant.RESULTS Fourteen(5 cohort and 9 cross-sectional)studies with 370013 participants were included in this review.The metaanalysis of CVE showed that the risk of CVE in T2DM was higher in the MAFLD group when compared to the non-MAFLD group[OR 1.28(95%CI,1.04-1.56)P=0.02]with follow up duration ranging between 5-6 years.The prevalence of CVD in the metanalysis of cross-sectional studies was found to be higher[OR 1.47(95%CI,1.21-1.78)P=0.0001]in T2DM with MAFLD when compared to T2DM without MAFLD.Significant heterogeneity exists due to variations in study design,methodologies,and MAFLD diagnostic criteria,which may have influenced the study's findings.CONCLUSION The presence of MAFLD in T2DM increased the risk of CVE.The prevalence of CVD is higher in T2DM with MAFLD as compared to T2DM without MAFLD.Large well-designed multicentric long-term prospective studies are necessary to appropriately risk stratify the cardiovascular effect of the MAFLD in T2DM patients.展开更多
BACKGROUND The incidence of type 2 diabetes mellitus(T2DM)in children and adolescents is increasing,yet there is limited information on the available pharmacological interventions to combat T2DM and prevent associated...BACKGROUND The incidence of type 2 diabetes mellitus(T2DM)in children and adolescents is increasing,yet there is limited information on the available pharmacological interventions to combat T2DM and prevent associated comorbidities.AIM To assess the effectiveness of current pharmacological treatments in managing T2DM in children and adolescents.The protocol of the study was registered in PROSPERO(CRD42022382165).METHODS Searches were performed in PubMed,EMBASE,Scopus,and ClinicalTrials.gov for publications between 1990 to September 2024 without language restrictions.Randomized control trials(RCTs)of pharmacotherapy in children and adolescents with T2DM(aged<19 years)were included.The primary outcome was a change in glycated hemoglobin(HbA1c)from baseline to follow-up.Secondary outcomes were changes in body weight,body mass index(BMI),total cholesterol,triglycerides,high density lipoprotein,and low-density lipoprotein from baseline,and incidence of adverse events during study periods.Screening,full-text review,data extraction,and assessments of risk of bias were done by two reviewers.Conflicts on each step were resolved by a third reviewer.Data analysis was performed using Review Manager Version 6.5(RevMan 6.5)and‘R’software via RStudio,‘meta’and‘netmeta’.RESULTS A total of 12 studies having low to moderate risk of bias with 1658 participants,and follow-up duration 12-52 weeks were included.In our network meta-analysis,compared to control(s),the reduction of HbA1c was sig-nificantly larger for dulaglutide[mean difference(MD),95%confidence interval:-1.20,-2.12 to-0.28],followed by dapagliflozin(-0.94,-1.44 to-0.44),liraglutide(-0.91,-1.37 to-0.45),empagliflozin(-0.87,-1.40 to-0.34),exenatide(-0.59,-1.07 to-0.11)and linagliptin(-0.45,-0.87 to-0.02)while other drugs had little or no effect.While liraglutide was associated with a change in body weight[MD-2.41(-4.68,-0.14)kg],no other drug treatment was associated with significant changes in body weight,BMI,and lipids.Apart from level 1 hypoglycemia with liraglutide[risk difference(RD):0.20,0.04-0.37]and minor adverse events with dulaglutide(RD:0.24,0.08-0.40),no other treatment was associated with excess risk of hypoglycemia or minor or major adverse events.CONCLUSION Pharmacotherapy of T2DM with dulaglutide,dapagliflozin,liraglutide,empagliflozin,exenatide,and linagliptin in children is associated with modest reduction of HbA1c.Larger RCTs with longer follow-up durations are needed to guide better therapeutic decision making.展开更多
The advent of 6G wireless networks promises unprecedented connectivity,supporting ultra-high data rates,low latency,and massive device connectivity.However,these ambitious goals introduce significant challenges,partic...The advent of 6G wireless networks promises unprecedented connectivity,supporting ultra-high data rates,low latency,and massive device connectivity.However,these ambitious goals introduce significant challenges,particularly in channel estimation due to complex and dynamic propagation environments.This paper explores the concept of channel knowledge maps(CKMs)as a solution to these challenges.CKMs enable environment-aware communications by providing location-specific channel information,reducing reliance on real-time pilot measurements.We categorize CKM construction techniques into measurement-based,model-based,and hybrid methods,and examine their key applications in integrated sensing and communication(ISAC)systems,beamforming,trajectory optimization of unmanned aerial vehicles(UAVs),base station(BS)placement,and resource allocation.Furthermore,we discuss open challenges and propose future research directions to enhance the robustness,accuracy,and scalability of CKM-based systems in the evolving 6G landscape.展开更多
Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular(CV)disease.Glucagon-like polypeptide-1 receptor agonists(GLP1RA)and sodium-glucose cotransporter-2 inhibitors(SGLT2i)are two imp...Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular(CV)disease.Glucagon-like polypeptide-1 receptor agonists(GLP1RA)and sodium-glucose cotransporter-2 inhibitors(SGLT2i)are two important classes of drugs with CV benefits independent of their antihyperglycemic efficacy.The CV outcome trials of both GLP1RA and SGLT2i have demonstrated CV superiority/neutrality concerning major adverse CV events(MACE).While GLP1RAs have exhibited a significant reduction in ischemic stroke and myocardial infarction(MI),SGLT2i have demonstrated a uniformly significant reduction in hospitalization for heart failure(HF)as a class effect.The unique clinical benefits and the distinct but complementary mechanisms of action make the combination of these drugs a mechanistically sound one.Recent meta-analyses suggest an independent and additive benefit of combination therapy of GLP1RA/SGLT2i vs monotherapy.Zhu et al,in a recent issue of the World Journal of Diabetes,demonstrates a numerically lower hazard ratio(HR)for CV outcomes with combination therapy vs monotherapy with either agent,with a reduction in MACE compared to GLP1RA alone[HR=0.51,95%confidence interval(CI):0.16-1.65],or SGLT2i alone(HR=0.48,95%CI:0.15-1.54).The CV death rate was also lower with combination therapy compared to GLP1RA alone(HR=0.58,95%CI:0.08-3.39),or SGLT2i alone(HR=0.55,95%CI:0.07-3.25).Fatal and non-fatal MI and fatal and non-fatal stroke were reduced with combination therapy compared to GLP1RA alone(HR=0.45,95%CI:0.10-2.18 and HR=0.86,95%CI:0.12-6.23,respectively),or SGLT2i alone(HR=0.44,95%CI:0.09-2.10 and HR=0.74,95%CI:0.10-5.47,respectively).Hospitalization for HF was prevented with combination therapy compared to GLP1RA alone(HR=0.26,95%CI:0.03-1.88),or SGLT2i alone(HR=0.33,95%CI:0.04-2.53).They also demonstrated that GLP1RA or SGLT2i monotherapy may not provide significant improvement in CV death and recurrent MI in patients with prior MI or HF,proposing a role for combination therapy in this subgroup.Appropriate patient selection is vital to optimize CV risk reduction as well as the cost-effectiveness of this combination therapy.展开更多
Pancreatic neuroendocrine tumors(pNETs)are rare,presenting significant challenges in timely diagnosis and subsequent treatment.The clinical and pathobiological behavior of these tumors varies significantly,making foll...Pancreatic neuroendocrine tumors(pNETs)are rare,presenting significant challenges in timely diagnosis and subsequent treatment.The clinical and pathobiological behavior of these tumors varies significantly,making follow-up and therapeutic approaches challenging for clinicians.Although the majority of these neoplasms are hormonally inactive,some can be associated with endocrine dysfunction.Very rarely,a nonfunctional tumor can later become hormonally active,further complicating prognostication and management.Depending on the character of the disease,clinical picture and prognosis,different treatment modalities are instituted with varying effectivities.We recently came across a unique case of nonfunctioning malignant pNET at an advanced stage,metastatic disease upon diagnosis,managed medically with somatostatin analog therapy(Octreotide)and targeted therapy(Everolimus)with stable disease for 40 months that subsequently turned out to become functional(insulinoma).With the aid of this unique case,we update the current clinical,diagnostic and therapeutic approach to pNETs in this evidence-based review.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)is currently the leading cause of end-stage liver disease and liver cancer in the world because of the obesity pandemic.Insulin resistance resulting from abdo...Metabolic dysfunction-associated fatty liver disease(MAFLD)is currently the leading cause of end-stage liver disease and liver cancer in the world because of the obesity pandemic.Insulin resistance resulting from abdominal adiposity is the main cause of MAFLD and type 2 diabetes mellitus among these patients.Although very common,therapeutic options for MAFLD are currently limited.Metabolic and bariatric surgery is the best treatment option for weight loss that can also improve MAFLD in a very high proportion of patients.However,surgical interventions are expensive,technically challenging,and carry significant immediate and long-term postoperative risks.Duodenal mucosal ablation,a malabsorptive endoscopic bariatric intervention,has shown beneficial effects in the management of obesity with an improvement of insulin resistance.It alters the duodenal mucosal lining,which helps maintain cellular homeostasis and better intestinal endocrine function.This process helps reduce lipid deposition in the liver,maintain serum lipid levels,and promote weight loss,especially in patients with type 2 diabetes mellitus-related MAFLD.However,some of these effects were independent of weight loss and food intake.As a minimally invasive procedure,it is beneficial for patients who have not had success with drug therapy alone,though this approach needs to be tested and further developed in future clinical trials.A basic study by Yu et al in the recent issue of the World Journal of Gastroenterology on duodenal mucosal ablation using irreversible electroporation,when experimented on rats,has shown fewer complications compared to other metabolic surgeries.This editorial describes the minimally invasive endoscopic bariatric strategies for the management of obesity and MAFLD in light of this experimental study.展开更多
Acromegaly,characterized by persistent hypersecretion of growth hormone(GH),is most often caused by a pituitary neuroendocrine tumor(PitNET),though,less often,ectopic GH or GH-releasing hormone secretion from various ...Acromegaly,characterized by persistent hypersecretion of growth hormone(GH),is most often caused by a pituitary neuroendocrine tumor(PitNET),though,less often,ectopic GH or GH-releasing hormone secretion from various neoplasms outside the pituitary gland could cause it.Nearly 70%of somatotroph PitNETs are macroadenomas at diagnosis.Transsphenoidal surgery,the most effective treatment modality for acromegaly,could achieve remission in 73%.However,the remission rates could reach 87%if surgery is followed by medical therapy.Due to variable therapeutic responses to surgical and medical therapy,pre-treatment awareness regarding the best therapeutic modality based on clinical,biochemical,radiological,histopathological and genetic parameters would help in accurate pretreatment decision-making.Earlier studies have identified poor prognosis markers like tumor size,tumor invasion,T2-weighted hyperintensity,granulation,and pretreatment GH and/or insulin-like growth factor 1 levels.In a recent study,published by Alvarez et al identified that preoperative PitNET volume is a good predictor of control of acromegaly following surgical treatment and the likelihood of requiring more aggressive additional therapies after surgery.They found that PitNET volume exceeding 3697 mm³was associated with poorer disease control in patients with somatotroph PitNETs.展开更多
The ground-breaking development of the incretin agonists by manipulation of the incretin system,including the gut hormones glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP),as well as...The ground-breaking development of the incretin agonists by manipulation of the incretin system,including the gut hormones glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP),as well as the pancreatic hor-mone glucagon,has led to the emergence of promising pharmacotherapy for metabolic health.The GLP-1 receptor agonists(GLP-1RAs),namely liraglutide,dulaglutide,albiglutide,exenatide,and semaglutide,have been found to have beneficial effects on glycated hemoglobin,weight,lipid profile,and liver fat and thereby improving cardiometabolic health.Other drugs of the same group in development include Orforglipron,which has a high weight loss efficacy(-15%weight reduction).Long-acting GLP-1RAs in trials are Ecnoglutide,Efpeglenatide,TG103,and Visepegenatide.Many of these have cardiovascular benefits in terms of reduction in MACE(Non-fatal MI,Non-fatal stroke,and mortality).Tirzepatide is a dual GIP/GLP-1RA,the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists.The dual GLP-1/glucagon co-agonists cause tremendous weight loss due to the synergistic action.Most drugs in this class are long-acting and developed for once-weekly administration.The revolutionary triple agonists at the GLP-1,GIP,and Glucagon receptors have demonstrated the highest achievable weight loss with pharmaco-therapy.Retatrutide and Efocipegtrutide belong to this novel group of drugs.The newer drugs in the broad category of incretin co-agonists include the GLP-1/amylin receptor agonist like CagriSema and Amycretin,oral GLP-1 agonists other than semaglutide,and the peptide YY/GLP-1 receptor dual agonists.The profound bioche-mical and weight loss outcomes associated with incretin co-/poly-agonists are expected to translate into outstanding cardiometabolic benefits,the theme of this evidence review.展开更多
BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the ther...BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the therapeutic effects of beinaglutide in patients with overweight/obesity with/without type 2 diabetes.METHODS RCTs involving patients receiving beinaglutide in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The change from baseline in body weight was the primary outcome;secondary outcomes included changes in body mass index(BMI),waist circumference(WC),blood pressure,glycemic parameters,lipids,and adverse events(AEs).RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MDs),odds ratios(ORs),or risk ratios(RRs)with 95%confidence intervals(95%CIs).RESULTS Six RCTs(n=800)with mostly some concerns about the risk of bias were included.Over 12-24 weeks,beinaglutide 0.1-0.2 mg thrice daily was superior to the control group in reducing total(MD=-3.25 kg,95%CI:-4.52 to-1.98,I^(2)=84%,P<0.00001)and percent(MD=-4.13%,95%CI:-4.87 to-3.39,I^(2)=54%,P<0.00001)body weight reduction.Beinaglutide also outperformed the control group in achieving weight loss by 5%(OR 4.61)and 10%(OR=5.34).The superiority of beinaglutide vs the control group was also found in reducing BMI(MD=-1.22 kg/m^(2),95%CI:-1.67 to-0.77)and WC(MD=-2.47 cm,95%CI:-3.74 to-1.19]).Beinaglutide and the control group had comparable impacts on blood pressure,glycemic parameters,insulin resistance,hepatic transaminases,and lipid profile.Beinaglutide posed higher risks of treatment discontinuation due to AEs(RR=3.15),nausea(RR=4.51),vomiting(RR=8.19),palpitation(RR=3.95),headache(RR=2.87),and dizziness(RR=6.07)than the control.However,the two groups had identical risks of total and serious AEs,diarrhea,fatigue,and hypoglycemia.CONCLUSION Short-term data from RCTs suggested that beinaglutide causes modest benefits in reducing body weight,BMI,and WC,with no significant difference in glycemic and other metabolic endpoints compared to the control arm.Safety data were consistent with those of the other drugs in the glucagon-like polypeptide-1 receptor agonist class.Larger RCTs are warranted to prove the longer-term metabolic benefits of beinaglutide.展开更多
BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against o...BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.展开更多
Recent studies suggest per-and polyfluoroalkyl substances(PFAS)are ubiquitous in rivers worldwide.In the Asia-Pacific region,the frequency of PFAS detection in rivers is increasing.However,the overwhelming majority of...Recent studies suggest per-and polyfluoroalkyl substances(PFAS)are ubiquitous in rivers worldwide.In the Asia-Pacific region,the frequency of PFAS detection in rivers is increasing.However,the overwhelming majority of studies and data represent high population and urbanized river catchments.In this study,we investigate PFAS occurrence in major Philippines river systems characterized by both high and low population densities.In the Pasig Laguna de Bay River,which drains a major urban conurbation,we detected PFAS at concentrations typical of global rivers.Unexpectedly,we did not detect PFAS in river water or sediments in low population density river catchments,despite our instrument detection limits being lower than the vast majority of river concentrations reported worldwide.We hypothesize that septic tanks,as the dominant wastewater treatment practice in Philippines catchments,may control the release of PFAS into groundwater and rivers in the Philippines.However,no groundwater PFAS data currently exist to validate this supposition.More broadly,our findings highlight the need for more representative PFAS sampling and analysis in rivers to more accurately represent regional and global detection frequencies and trends.展开更多
BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effec...BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effectiveness of GLP-1RAs in these situations.AIM To evaluate the safety and efficacy of GLP-1RA in patients with T2DM fasting during Ramadan.METHODS Electronic databases were systematically searched for relevant studies that featured GLP-1RA in the intervention arm and other glucose-lowering medications in the control arm.The primary outcome was adverse events(AEs)during Ramadan for both groups;other outcomes included changes in glycemic and anthropometric measures during the peri-Ramadan period.RESULTS Four studies[three randomized-controlled trials with low risk of bias(RoB)and one prospective observational study with serious RoB]involving 754 subjects were analyzed.GLP-1RA group achieved greater glycated hemoglobin reduction than the non-GLP-1RA group[mean difference(MD):-0.31%,95%CI:-0.61 to-0.01,P=0.04,I2=77%]with a lower risk of documented symptomatic hypoglycemia(risk ratio=0.38,95%CI:0.16 to 0.88,P=0.02).Any AEs,serious AEs,or AEs that led to treatment discontinuation were comparable between the two groups.The GLP-1RA group experienced greater weight loss compared to the non-GLP-1RA group(MD:-2.0 kg,95%CI:-3.37 to-0.63,P=0.004,I2=95%).There were comparable changes in blood pressure and lipid profile between the two groups.GLP-1RA users experienced higher risks of gastrointestinal AEs,nausea,and vomiting;however,the risks of heartburn,abdominal pain,and diarrhea were similar in both groups.CONCLUSION Limited evidence suggests that GLP-1RAs are safe for T2DM management during Ramadan,offering modest benefits in blood sugar control and weight loss.Large multicenter trials are needed to confirm their safety and efficacy in at-risk populations,improving clinical practice decision-making.展开更多
BACKGROUND Despite therapeutic benefits,discontinuation of tirzepatide is common in randomized controlled trials(RCTs)due to adverse events(AEs)and other causes.No previous systematic reviews have explored the reasons...BACKGROUND Despite therapeutic benefits,discontinuation of tirzepatide is common in randomized controlled trials(RCTs)due to adverse events(AEs)and other causes.No previous systematic reviews have explored the reasons for discontinuing tirzepatide in the RCTs.AIM To explore the reasons for permanent discontinuation of tirzepatide vs controls[placebo,insulin,and glucagon-like peptide-1 receptor agonists(GLP-1Ras)]in RCTs.METHODS Relevant RCTs were systematically searched using related terms through multiple databases such as MEDLINE(via PubMed),Scopus,Cochrane Central Register,and ClinicalTrials.gov from their inception until June 20,2024.RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as risk ratios(RR)with 95%confidence intervals(CI).RESULTS Seventeen RCTs(n=14645),mostly having low risks of bias,were analyzed.Compared to placebo,the risk of permanent discontinuation of the study drug was substantially lower with tirzepatide 10 mg(RR:0.69,95%CI:0.51-0.93,P=0.02)and similar with tirzepatide 5 mg(RR:0.74,95%CI:0.47-1.17,P=0.20)and 15 mg(RR:0.94,95%CI:0.68-1.31,P=0.71).Tirzepatide had identical discontinuation risks when compared to insulin at 5 mg(RR:0.96,95%CI:0.75-1.24,P=0.77)and 10 mg(RR:1.19,95%CI:0.77-1.82,P=0.44)doses,whereas such risk was higher with tirzepatide 15 mg than insulin(RR:1.31,95%CI:1.03-1.67,P=0.03).Compared to GLP-1RA,the permanent discontinuation risk was similar with tirzepatide 5 mg(RR:0.98,95%CI:0.70-1.37,P=0.90)but was higher with tirzepatide 10 mg(RR:1.40,95%CI:1.03-1.90,P=0.03)and 15 mg(RR:1.70,95%CI:1.27-2.27,P=0.0004).Tirzepatide,at all doses,had higher risks of AE-related discontinuation than insulin;such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RA.Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin.Compared to the placebo,tirzepatide(all doses)conferred a lower risk of study drug discontinuation due to other causes not specifically mentioned.CONCLUSION The discontinuation risk is not higher in tirzepatide group than in the placebo arm.Many factors other than AEs led to drug discontinuation in the included RCTs.展开更多
BACKGROUND Efruxifermin(EFX),a fibroblast growth factor 21 analogue,has demonstrated the potential to improve liver fat and markers of liver injury,fibrosis,and key metabolic biomarkers in individuals with metabolic d...BACKGROUND Efruxifermin(EFX),a fibroblast growth factor 21 analogue,has demonstrated the potential to improve liver fat and markers of liver injury,fibrosis,and key metabolic biomarkers in individuals with metabolic dysfunction-associated steatohepatitis(MASH)in phase 2 clinical trials.AIM To summarize the safety and effectiveness of EFX in managing MASH.METHODS Electronic databases and registries were systematically searched from their inception to May 15,2025,for randomized-controlled trials(RCTs)that included EFX in the intervention arm and placebo in the control arm in individuals with MASH.The primary outcome was the safety of EFX,while additional outcomes included its efficacy in altering hepatic and metabolic parameters.Meta-analyses were conducted using the RevMan web computer program with the random-effects model.RESULTS Four phase 2 RCTs(five reports),mostly with low risk of bias,involving 450 subjects,were analyzed.Compared to the placebo,EFX 50 mg was associated with higher risks of treatment-emergent adverse events(TEAEs)[risk ratio(RR)=1.05],TEAEs leading to discontinuation(RR=3.05),nausea(RR=1.78),and diarrhea(RR=1.9).EFX 28 mg increased risks of vomiting(RR=2.17)and frequent bowel movements(RR=8.98).Both doses of EFX were associated with higher risks of drug-related TEAEs(28 mg:RR=1.45;50 mg:RR=1.67)and increased appetite(28 mg:RR=3.16;50 mg:RR=5.66).EFX(28 and 50 mg)and placebo exhibited identical risks for severe TEAEs,serious AEs,abdominal pain,fatigue,headache,injection site erythema,and injection site reactions.EFX(28 and 50 mg)was associated with improvements in hepatic safety outcomes,including liver enzymes and urate levels.EFX outperformed the placebo in both relative and absolute reductions in hepatic fat fraction.Reductions in enhanced liver fibrosis score,Pro-C3,and liver stiffness were also more robust with EFX.EFX was superior in terms of MASH resolution and improvement in fibrosis stage,MASH resolution and no worsening of the fibrosis stage,and fibrosis regression by≥1 stage and no worsening in steatohepatitis.Furthermore,EFX also improved metabolic parameters,including reductions in HbA1c and insulin resistance,as well as improvements in adiponectin and lipid parameters.CONCLUSION EFX demonstrates promising dual efficacy on liver histology and metabolic markers in MASH.However,gastrointestinal side effects and the need for parenteral administration require caution.Long-term data are still necessary to fully evaluate safety and long-term effectiveness.展开更多
BACKGROUND Type 2 diabetes(T2D),as well as obesity,are risk factors for chronic kidney disease(CKD)and end-stage renal disease.The renal impacts of glucose-lowering and weight-lowering drugs and their potential benefi...BACKGROUND Type 2 diabetes(T2D),as well as obesity,are risk factors for chronic kidney disease(CKD)and end-stage renal disease.The renal impacts of glucose-lowering and weight-lowering drugs and their potential benefits in preventing CKD often guide clinicians in choosing them appropriately.Only limited data based on randomized controlled trials(RCTs)is currently available on the renal effects and safety profile of tirzepatide.AIM To explore the renal benefits and safety of tirzepatide vs controls.METHODS RCTs involving patients receiving tirzepatide for any indication in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The co-primary outcomes were percent change from baseline(CFB)in urine albumin-to-creatinine ratio(UACR)and absolute CFB in estimated glomerular filtration rate(eGFR;in mL/min/1.73 m^(2));the secondary outcome was tirzepatide’s renal safety profile.RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MD)or risk ratios with 95%confidence intervals.RESULTS Fifteen RCTs(n=14471)with mostly low risk of bias(RoB)were included.Over 26-72 weeks,tirzepatide 10 mg[MD-26.95%(-40.13,-13.76),P<0.0001]and 15 mg[MD-18.03%(-28.58,-7.47),P=0.0008]were superior to placebo in percent reductions of UACR.Tirzepatide,at all doses,outperformed insulin in percent reductions of UACR.Compared to the placebo,the percent UACR reduction was greater in subjects with T2D than those with obesity but without T2D(MD-33.25%vs-7.93%;P=0.001).The CFB in eGFR with all doses of tirzepatide was comparable[5 mg:MD 0.36(-1.41,2.14);10 mg:MD 1.17(-0.22,2.56);15 mg:MD 1.42(-0.04,2.88)];P>0.05 for all vs insulin.Tirzepatide(pooled and separate doses)did not increase the risks of adverse renal events,urinary tract infection,nephrolithiasis,acute kidney injury,and renal cancer compared to the placebo,insulin,and glucagon-like peptide-1 receptor agonists.CONCLUSION Short-term data from RCTs with low RoB suggests that tirzepatide positively impacts UACR without detrimental effects on eGFR in subjects with T2D and obesity without T2D,with a reassuring renal safety profile.Larger RCTs are warranted to prove the longer-term renal benefits of tirzepatide,which might also prevent eGFR decline and worsening of CKD.展开更多
BACKGROUND Automated insulin delivery(AID)systems have demonstrated benefits in managing patients with type 2 diabetes(T2D),but data are still limited.Moreover,the efficacy and safety of the AID systems in these patie...BACKGROUND Automated insulin delivery(AID)systems have demonstrated benefits in managing patients with type 2 diabetes(T2D),but data are still limited.Moreover,the efficacy and safety of the AID systems in these patients have been inadequately explored by systematic reviews and meta-analyses.AIM To provide a comprehensive understanding of the optimal use of AID in managing insulin-treated outpatients with T2D.METHODS A systematic search of multiple databases and registries,including MEDLINE,Scopus,Web of Science,Cochrane Library,and ClinicalTrials.gov,was conducted from inception to May 15,2025,to identify studies on AID use for outpatients with T2D.The co-primary outcomes were the change in glycated hemoglobin(HbA1c)and continuous glucose monitoring(CGM)metrics.Statistical analyses were conducted using Review Manager Web software with random-effects models and the inverse variance statistical method.The results were presented as mean differences(MDs)or risk ratios(RRs)with 95%CI.RESULTS A total of 15 studies with 28985 participants were identified,including 6 randomized trials(n=748;3 crossover and 3 parallel-group trials)and 9 single-arm studies.All included randomized trials raised some concerns,and the single-arm studies had serious risks of overall bias.Meta-analysis of randomized trials showed that AID is more effective than the control group in lowering HbA1c(MD:-0.89%,95%CI:-1.32 to-0.46,P<0.0001,I2=82%).Compared to control interventions,AID use was linked to a higher percentage of time in range(MD:19.25%,95%CI:11.43-27.06,P<0.00001,I2=74%)and a lower percentage of time above range>10 mmol/L(MD:-19.48%,95%CI:-27.14 to-11.82,P<0.00001,I2=73%);however,time below range remained similar between the two groups.The mean sensor glucose level was lower in the AID group;however,the coefficient of variation of glucose was the same in both groups.AID use also led to a reduction in insulin dose,but this is not a consistent finding across all study designs.The risks of serious adverse events(AEs)and severe hypoglycemia were similar in both groups;however,AID use raised the risk of device deficiency.Single-arm studies with participants using AID systems also demonstrated reductions in HbA1c(ranging from 0.7%to 2.07%)and improvements in CGM metrics,along with acceptable safety data.CONCLUSION Based on short-term study data,the use of AID systems in outpatients with T2D appears to improve glycemic outcomes and CGM metrics,with no significant AEs.Larger and longer-term randomized controlled trials involving diverse populations,along with a cost-benefit analysis,are needed to guide more informed clinical practice decisions.展开更多
BACKGROUND Cotadutide(MEDI0382)is a twincretin that acts as an agonist for both the glucagon-like peptide-1 and glucagon receptors.Several randomized controlled trials(RCTs)have been published evaluating the use of co...BACKGROUND Cotadutide(MEDI0382)is a twincretin that acts as an agonist for both the glucagon-like peptide-1 and glucagon receptors.Several randomized controlled trials(RCTs)have been published evaluating the use of cotadutide in individuals with type 2 diabetes(T2D),showing promising results.However,the efficacy and safety of the drug use have been inadequately explored by systematic reviews and meta-analyses.AIM To assess the clinical efficacy and safety of cotadutide in individuals with T2D having overweight or obesity.METHODS The systematic reviews and meta-analyses have been registered with International Prospective Register of Systematic Reviews(CRD42024511703),and the protocol summary can be accessed online.Several databases and registries,including MEDLINE(via PubMed),Scopus,Web of Science,the Cochrane Central Register of Controlled Trials,and ClinicalTrials.gov,were systematically searched using related terms from their inception to May 15,2025,for RCTs involving individuals with T2D receiving cotadutide in the intervention group.Review Manager web was used to conduct meta-analysis using random-effects models.The co-primary outcomes of interest were the changes in glycated hemoglobin(HbA1c)and the percent changes in body weight from baseline.The results of the outcomes were expressed as mean differences(MDs)or risk ratios(RRs)with 95%confidence intervals(CIs).The analysis of outcomes was stratified according to whether the control group received a placebo,denoted as the placebo control group(PCG),or an active comparator,referred to as the active control group(ACG).RESULTS Nine RCTs(mostly phase 2 RCTs,n=1525)with study durations varying from 28 days to 54 weeks that met all the inclusion criteria were analyzed;five studies had a low overall risk of bias,while the other four had some concerns.Compared to the PCG,greater reductions in HbA1c were achieved with cotadutide 100μg(MD-0.77%,95%CI:-1.06 to-0.47),200μg(MD-0.68%,95%CI:-1.12 to-0.23),300μg(MD-0.67%,95%CI:-0.79 to-0.56),and 600μg(MD-0.69%,95%CI:-0.97 to-0.41).Cotadutide 100μg(MD-1.74%,95%CI:-3.23 to-0.25),200μg(MD-2.56%,95%CI:-3.37 to-1.75),300μg(MD-3.49%,95%CI:-4.14 to-2.84),and 600μg(MD-5.45%,95%CI:-7.17 to-3.73)achieved greater percent reductions in body weight from baseline.However,the certainty of evidence for HbA1c and percent body weight reductions was very low to low.Cotadutide,at all doses,also outperformed PCG in reducing fasting plasma glucose and absolute body weight.The changes in HbA1c,percent body weight,fasting plasma glucose,and absolute body weight were similar between the cotadutide group and the ACG.Compared to PCG,pooled doses of cotadutide increased the risks of treatment-emergent adverse events(AEs),treatment-related AEs,and discontinuation of the study drug due to AEs,but not for serious AEs.More subjects experienced overall gastrointestinal AEs,dyspepsia,nausea,vomiting,constipation,and decreased appetite with cotadutide than with PCG.Compared to the ACG,none of the AEs showed increased risk in the cotadutide group.CONCLUSION Cotadutide demonstrated glycemic control and weight-loss benefits in short-term,small RCTs(mostly phase 2).However,small sample sizes,very low to low certainty of evidence,and the absence of data on long-term cardiovascular and renal outcomes highlight substantial uncertainties,warranting cautious interpretation and further investigation in larger,longer-term trials to establish its safety and efficacy profile.展开更多
文摘BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.
文摘Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to specific mutations affecting insulin synthesis,secretion and glucose regulation.Common traits across MODY subtypes include early-onset diabetes,a family history of autosomal dominant diabetes,lack of features of insulin resistance,and absent islet cell autoimmunity.Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus.Biomarkers and scoring systems can help identify candidates for genetic testing.GCK-MODY,a common subtype,manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy.In contrast,mutations in HNF4A,HNF1A,and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus.Neonatal diabetes mellitus(NDM)is a rare form of monogenic diabetes that usually presents within the first six months.Half of the cases are lifelong,while others experience transient remission.Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel(KCNJ11 or ABCC8)and can be transitioned to sulfonylurea after confirmation of diagnosis.Thus,in many cases,monogenic diabetes offers an opportunity to provide precision treatment.The scope has broadened with next-generation sequencing(NGS)technologies,replacing older methods like Sanger sequencing.NGS can be for targeted gene panels,whole-exome sequencing(WES),or whole-genome sequencing.Targeted gene panels offer specific information efficiently,while WES provides comprehensive data but comes with bioinformatic challenges.The surge in testing has also led to an increase in variants of unknown significance(VUS).Deciding whether VUS is disease-causing or benign can be challenging.Computational models,functional studies,and clinical knowledge help to determine pathogenicity.Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
文摘Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.
文摘BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)and type 2 diabetes mellitus(T2DM)are independent risk factors for the development of cardiovascular disease(CVD)and an exaggerated CVD risk is expected when both diseases co-exist.Therefore,thorough risk stratification is important to inform better clinical practice decisions based on good quality evidence for patient with MAFLD and T2DM.AIM To identify the CVD and cardiovascular event(CVE)risk in a systematic review when MAFLD and T2DM co-exist to inform better clinical practice decisions.METHODS A systematic review was performed by compiling data by searching PubMed,EMBASE and Cochrane Library databases.Quality appraisal of retrieved studies and the meta-analysis were performed using Joanna Briggs Institute(JBI)tool and RevMan 5.4 software respectively.The effect indicators for CVE and CVD risk were expressed as odds ratios(OR)and 95%CI with P-values<0.05 as significant.RESULTS Fourteen(5 cohort and 9 cross-sectional)studies with 370013 participants were included in this review.The metaanalysis of CVE showed that the risk of CVE in T2DM was higher in the MAFLD group when compared to the non-MAFLD group[OR 1.28(95%CI,1.04-1.56)P=0.02]with follow up duration ranging between 5-6 years.The prevalence of CVD in the metanalysis of cross-sectional studies was found to be higher[OR 1.47(95%CI,1.21-1.78)P=0.0001]in T2DM with MAFLD when compared to T2DM without MAFLD.Significant heterogeneity exists due to variations in study design,methodologies,and MAFLD diagnostic criteria,which may have influenced the study's findings.CONCLUSION The presence of MAFLD in T2DM increased the risk of CVE.The prevalence of CVD is higher in T2DM with MAFLD as compared to T2DM without MAFLD.Large well-designed multicentric long-term prospective studies are necessary to appropriately risk stratify the cardiovascular effect of the MAFLD in T2DM patients.
文摘BACKGROUND The incidence of type 2 diabetes mellitus(T2DM)in children and adolescents is increasing,yet there is limited information on the available pharmacological interventions to combat T2DM and prevent associated comorbidities.AIM To assess the effectiveness of current pharmacological treatments in managing T2DM in children and adolescents.The protocol of the study was registered in PROSPERO(CRD42022382165).METHODS Searches were performed in PubMed,EMBASE,Scopus,and ClinicalTrials.gov for publications between 1990 to September 2024 without language restrictions.Randomized control trials(RCTs)of pharmacotherapy in children and adolescents with T2DM(aged<19 years)were included.The primary outcome was a change in glycated hemoglobin(HbA1c)from baseline to follow-up.Secondary outcomes were changes in body weight,body mass index(BMI),total cholesterol,triglycerides,high density lipoprotein,and low-density lipoprotein from baseline,and incidence of adverse events during study periods.Screening,full-text review,data extraction,and assessments of risk of bias were done by two reviewers.Conflicts on each step were resolved by a third reviewer.Data analysis was performed using Review Manager Version 6.5(RevMan 6.5)and‘R’software via RStudio,‘meta’and‘netmeta’.RESULTS A total of 12 studies having low to moderate risk of bias with 1658 participants,and follow-up duration 12-52 weeks were included.In our network meta-analysis,compared to control(s),the reduction of HbA1c was sig-nificantly larger for dulaglutide[mean difference(MD),95%confidence interval:-1.20,-2.12 to-0.28],followed by dapagliflozin(-0.94,-1.44 to-0.44),liraglutide(-0.91,-1.37 to-0.45),empagliflozin(-0.87,-1.40 to-0.34),exenatide(-0.59,-1.07 to-0.11)and linagliptin(-0.45,-0.87 to-0.02)while other drugs had little or no effect.While liraglutide was associated with a change in body weight[MD-2.41(-4.68,-0.14)kg],no other drug treatment was associated with significant changes in body weight,BMI,and lipids.Apart from level 1 hypoglycemia with liraglutide[risk difference(RD):0.20,0.04-0.37]and minor adverse events with dulaglutide(RD:0.24,0.08-0.40),no other treatment was associated with excess risk of hypoglycemia or minor or major adverse events.CONCLUSION Pharmacotherapy of T2DM with dulaglutide,dapagliflozin,liraglutide,empagliflozin,exenatide,and linagliptin in children is associated with modest reduction of HbA1c.Larger RCTs with longer follow-up durations are needed to guide better therapeutic decision making.
基金supported by the National Natural Science Foundation of China under Grants Nos.62431014 and 62271310the Fundamental Research Funds for the Central Universities of China。
文摘The advent of 6G wireless networks promises unprecedented connectivity,supporting ultra-high data rates,low latency,and massive device connectivity.However,these ambitious goals introduce significant challenges,particularly in channel estimation due to complex and dynamic propagation environments.This paper explores the concept of channel knowledge maps(CKMs)as a solution to these challenges.CKMs enable environment-aware communications by providing location-specific channel information,reducing reliance on real-time pilot measurements.We categorize CKM construction techniques into measurement-based,model-based,and hybrid methods,and examine their key applications in integrated sensing and communication(ISAC)systems,beamforming,trajectory optimization of unmanned aerial vehicles(UAVs),base station(BS)placement,and resource allocation.Furthermore,we discuss open challenges and propose future research directions to enhance the robustness,accuracy,and scalability of CKM-based systems in the evolving 6G landscape.
文摘Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular(CV)disease.Glucagon-like polypeptide-1 receptor agonists(GLP1RA)and sodium-glucose cotransporter-2 inhibitors(SGLT2i)are two important classes of drugs with CV benefits independent of their antihyperglycemic efficacy.The CV outcome trials of both GLP1RA and SGLT2i have demonstrated CV superiority/neutrality concerning major adverse CV events(MACE).While GLP1RAs have exhibited a significant reduction in ischemic stroke and myocardial infarction(MI),SGLT2i have demonstrated a uniformly significant reduction in hospitalization for heart failure(HF)as a class effect.The unique clinical benefits and the distinct but complementary mechanisms of action make the combination of these drugs a mechanistically sound one.Recent meta-analyses suggest an independent and additive benefit of combination therapy of GLP1RA/SGLT2i vs monotherapy.Zhu et al,in a recent issue of the World Journal of Diabetes,demonstrates a numerically lower hazard ratio(HR)for CV outcomes with combination therapy vs monotherapy with either agent,with a reduction in MACE compared to GLP1RA alone[HR=0.51,95%confidence interval(CI):0.16-1.65],or SGLT2i alone(HR=0.48,95%CI:0.15-1.54).The CV death rate was also lower with combination therapy compared to GLP1RA alone(HR=0.58,95%CI:0.08-3.39),or SGLT2i alone(HR=0.55,95%CI:0.07-3.25).Fatal and non-fatal MI and fatal and non-fatal stroke were reduced with combination therapy compared to GLP1RA alone(HR=0.45,95%CI:0.10-2.18 and HR=0.86,95%CI:0.12-6.23,respectively),or SGLT2i alone(HR=0.44,95%CI:0.09-2.10 and HR=0.74,95%CI:0.10-5.47,respectively).Hospitalization for HF was prevented with combination therapy compared to GLP1RA alone(HR=0.26,95%CI:0.03-1.88),or SGLT2i alone(HR=0.33,95%CI:0.04-2.53).They also demonstrated that GLP1RA or SGLT2i monotherapy may not provide significant improvement in CV death and recurrent MI in patients with prior MI or HF,proposing a role for combination therapy in this subgroup.Appropriate patient selection is vital to optimize CV risk reduction as well as the cost-effectiveness of this combination therapy.
文摘Pancreatic neuroendocrine tumors(pNETs)are rare,presenting significant challenges in timely diagnosis and subsequent treatment.The clinical and pathobiological behavior of these tumors varies significantly,making follow-up and therapeutic approaches challenging for clinicians.Although the majority of these neoplasms are hormonally inactive,some can be associated with endocrine dysfunction.Very rarely,a nonfunctional tumor can later become hormonally active,further complicating prognostication and management.Depending on the character of the disease,clinical picture and prognosis,different treatment modalities are instituted with varying effectivities.We recently came across a unique case of nonfunctioning malignant pNET at an advanced stage,metastatic disease upon diagnosis,managed medically with somatostatin analog therapy(Octreotide)and targeted therapy(Everolimus)with stable disease for 40 months that subsequently turned out to become functional(insulinoma).With the aid of this unique case,we update the current clinical,diagnostic and therapeutic approach to pNETs in this evidence-based review.
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)is currently the leading cause of end-stage liver disease and liver cancer in the world because of the obesity pandemic.Insulin resistance resulting from abdominal adiposity is the main cause of MAFLD and type 2 diabetes mellitus among these patients.Although very common,therapeutic options for MAFLD are currently limited.Metabolic and bariatric surgery is the best treatment option for weight loss that can also improve MAFLD in a very high proportion of patients.However,surgical interventions are expensive,technically challenging,and carry significant immediate and long-term postoperative risks.Duodenal mucosal ablation,a malabsorptive endoscopic bariatric intervention,has shown beneficial effects in the management of obesity with an improvement of insulin resistance.It alters the duodenal mucosal lining,which helps maintain cellular homeostasis and better intestinal endocrine function.This process helps reduce lipid deposition in the liver,maintain serum lipid levels,and promote weight loss,especially in patients with type 2 diabetes mellitus-related MAFLD.However,some of these effects were independent of weight loss and food intake.As a minimally invasive procedure,it is beneficial for patients who have not had success with drug therapy alone,though this approach needs to be tested and further developed in future clinical trials.A basic study by Yu et al in the recent issue of the World Journal of Gastroenterology on duodenal mucosal ablation using irreversible electroporation,when experimented on rats,has shown fewer complications compared to other metabolic surgeries.This editorial describes the minimally invasive endoscopic bariatric strategies for the management of obesity and MAFLD in light of this experimental study.
文摘Acromegaly,characterized by persistent hypersecretion of growth hormone(GH),is most often caused by a pituitary neuroendocrine tumor(PitNET),though,less often,ectopic GH or GH-releasing hormone secretion from various neoplasms outside the pituitary gland could cause it.Nearly 70%of somatotroph PitNETs are macroadenomas at diagnosis.Transsphenoidal surgery,the most effective treatment modality for acromegaly,could achieve remission in 73%.However,the remission rates could reach 87%if surgery is followed by medical therapy.Due to variable therapeutic responses to surgical and medical therapy,pre-treatment awareness regarding the best therapeutic modality based on clinical,biochemical,radiological,histopathological and genetic parameters would help in accurate pretreatment decision-making.Earlier studies have identified poor prognosis markers like tumor size,tumor invasion,T2-weighted hyperintensity,granulation,and pretreatment GH and/or insulin-like growth factor 1 levels.In a recent study,published by Alvarez et al identified that preoperative PitNET volume is a good predictor of control of acromegaly following surgical treatment and the likelihood of requiring more aggressive additional therapies after surgery.They found that PitNET volume exceeding 3697 mm³was associated with poorer disease control in patients with somatotroph PitNETs.
文摘The ground-breaking development of the incretin agonists by manipulation of the incretin system,including the gut hormones glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP),as well as the pancreatic hor-mone glucagon,has led to the emergence of promising pharmacotherapy for metabolic health.The GLP-1 receptor agonists(GLP-1RAs),namely liraglutide,dulaglutide,albiglutide,exenatide,and semaglutide,have been found to have beneficial effects on glycated hemoglobin,weight,lipid profile,and liver fat and thereby improving cardiometabolic health.Other drugs of the same group in development include Orforglipron,which has a high weight loss efficacy(-15%weight reduction).Long-acting GLP-1RAs in trials are Ecnoglutide,Efpeglenatide,TG103,and Visepegenatide.Many of these have cardiovascular benefits in terms of reduction in MACE(Non-fatal MI,Non-fatal stroke,and mortality).Tirzepatide is a dual GIP/GLP-1RA,the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists.The dual GLP-1/glucagon co-agonists cause tremendous weight loss due to the synergistic action.Most drugs in this class are long-acting and developed for once-weekly administration.The revolutionary triple agonists at the GLP-1,GIP,and Glucagon receptors have demonstrated the highest achievable weight loss with pharmaco-therapy.Retatrutide and Efocipegtrutide belong to this novel group of drugs.The newer drugs in the broad category of incretin co-agonists include the GLP-1/amylin receptor agonist like CagriSema and Amycretin,oral GLP-1 agonists other than semaglutide,and the peptide YY/GLP-1 receptor dual agonists.The profound bioche-mical and weight loss outcomes associated with incretin co-/poly-agonists are expected to translate into outstanding cardiometabolic benefits,the theme of this evidence review.
文摘BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the therapeutic effects of beinaglutide in patients with overweight/obesity with/without type 2 diabetes.METHODS RCTs involving patients receiving beinaglutide in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The change from baseline in body weight was the primary outcome;secondary outcomes included changes in body mass index(BMI),waist circumference(WC),blood pressure,glycemic parameters,lipids,and adverse events(AEs).RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MDs),odds ratios(ORs),or risk ratios(RRs)with 95%confidence intervals(95%CIs).RESULTS Six RCTs(n=800)with mostly some concerns about the risk of bias were included.Over 12-24 weeks,beinaglutide 0.1-0.2 mg thrice daily was superior to the control group in reducing total(MD=-3.25 kg,95%CI:-4.52 to-1.98,I^(2)=84%,P<0.00001)and percent(MD=-4.13%,95%CI:-4.87 to-3.39,I^(2)=54%,P<0.00001)body weight reduction.Beinaglutide also outperformed the control group in achieving weight loss by 5%(OR 4.61)and 10%(OR=5.34).The superiority of beinaglutide vs the control group was also found in reducing BMI(MD=-1.22 kg/m^(2),95%CI:-1.67 to-0.77)and WC(MD=-2.47 cm,95%CI:-3.74 to-1.19]).Beinaglutide and the control group had comparable impacts on blood pressure,glycemic parameters,insulin resistance,hepatic transaminases,and lipid profile.Beinaglutide posed higher risks of treatment discontinuation due to AEs(RR=3.15),nausea(RR=4.51),vomiting(RR=8.19),palpitation(RR=3.95),headache(RR=2.87),and dizziness(RR=6.07)than the control.However,the two groups had identical risks of total and serious AEs,diarrhea,fatigue,and hypoglycemia.CONCLUSION Short-term data from RCTs suggested that beinaglutide causes modest benefits in reducing body weight,BMI,and WC,with no significant difference in glycemic and other metabolic endpoints compared to the control arm.Safety data were consistent with those of the other drugs in the glucagon-like polypeptide-1 receptor agonist class.Larger RCTs are warranted to prove the longer-term metabolic benefits of beinaglutide.
基金Supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number(PNURSP2025R381),Princess Nourah bint Abdulrahman University,Riyadh,Saudi Arabia.
文摘BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.
基金Natural Environment Research Council,Grant/Award Number:NE/W006871/1。
文摘Recent studies suggest per-and polyfluoroalkyl substances(PFAS)are ubiquitous in rivers worldwide.In the Asia-Pacific region,the frequency of PFAS detection in rivers is increasing.However,the overwhelming majority of studies and data represent high population and urbanized river catchments.In this study,we investigate PFAS occurrence in major Philippines river systems characterized by both high and low population densities.In the Pasig Laguna de Bay River,which drains a major urban conurbation,we detected PFAS at concentrations typical of global rivers.Unexpectedly,we did not detect PFAS in river water or sediments in low population density river catchments,despite our instrument detection limits being lower than the vast majority of river concentrations reported worldwide.We hypothesize that septic tanks,as the dominant wastewater treatment practice in Philippines catchments,may control the release of PFAS into groundwater and rivers in the Philippines.However,no groundwater PFAS data currently exist to validate this supposition.More broadly,our findings highlight the need for more representative PFAS sampling and analysis in rivers to more accurately represent regional and global detection frequencies and trends.
基金thankful to Dr.Marina George Kudiyirickal MSc,MJDF-RCS,PhD for providing us the audio core tip of this article.
文摘BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effectiveness of GLP-1RAs in these situations.AIM To evaluate the safety and efficacy of GLP-1RA in patients with T2DM fasting during Ramadan.METHODS Electronic databases were systematically searched for relevant studies that featured GLP-1RA in the intervention arm and other glucose-lowering medications in the control arm.The primary outcome was adverse events(AEs)during Ramadan for both groups;other outcomes included changes in glycemic and anthropometric measures during the peri-Ramadan period.RESULTS Four studies[three randomized-controlled trials with low risk of bias(RoB)and one prospective observational study with serious RoB]involving 754 subjects were analyzed.GLP-1RA group achieved greater glycated hemoglobin reduction than the non-GLP-1RA group[mean difference(MD):-0.31%,95%CI:-0.61 to-0.01,P=0.04,I2=77%]with a lower risk of documented symptomatic hypoglycemia(risk ratio=0.38,95%CI:0.16 to 0.88,P=0.02).Any AEs,serious AEs,or AEs that led to treatment discontinuation were comparable between the two groups.The GLP-1RA group experienced greater weight loss compared to the non-GLP-1RA group(MD:-2.0 kg,95%CI:-3.37 to-0.63,P=0.004,I2=95%).There were comparable changes in blood pressure and lipid profile between the two groups.GLP-1RA users experienced higher risks of gastrointestinal AEs,nausea,and vomiting;however,the risks of heartburn,abdominal pain,and diarrhea were similar in both groups.CONCLUSION Limited evidence suggests that GLP-1RAs are safe for T2DM management during Ramadan,offering modest benefits in blood sugar control and weight loss.Large multicenter trials are needed to confirm their safety and efficacy in at-risk populations,improving clinical practice decision-making.
文摘BACKGROUND Despite therapeutic benefits,discontinuation of tirzepatide is common in randomized controlled trials(RCTs)due to adverse events(AEs)and other causes.No previous systematic reviews have explored the reasons for discontinuing tirzepatide in the RCTs.AIM To explore the reasons for permanent discontinuation of tirzepatide vs controls[placebo,insulin,and glucagon-like peptide-1 receptor agonists(GLP-1Ras)]in RCTs.METHODS Relevant RCTs were systematically searched using related terms through multiple databases such as MEDLINE(via PubMed),Scopus,Cochrane Central Register,and ClinicalTrials.gov from their inception until June 20,2024.RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as risk ratios(RR)with 95%confidence intervals(CI).RESULTS Seventeen RCTs(n=14645),mostly having low risks of bias,were analyzed.Compared to placebo,the risk of permanent discontinuation of the study drug was substantially lower with tirzepatide 10 mg(RR:0.69,95%CI:0.51-0.93,P=0.02)and similar with tirzepatide 5 mg(RR:0.74,95%CI:0.47-1.17,P=0.20)and 15 mg(RR:0.94,95%CI:0.68-1.31,P=0.71).Tirzepatide had identical discontinuation risks when compared to insulin at 5 mg(RR:0.96,95%CI:0.75-1.24,P=0.77)and 10 mg(RR:1.19,95%CI:0.77-1.82,P=0.44)doses,whereas such risk was higher with tirzepatide 15 mg than insulin(RR:1.31,95%CI:1.03-1.67,P=0.03).Compared to GLP-1RA,the permanent discontinuation risk was similar with tirzepatide 5 mg(RR:0.98,95%CI:0.70-1.37,P=0.90)but was higher with tirzepatide 10 mg(RR:1.40,95%CI:1.03-1.90,P=0.03)and 15 mg(RR:1.70,95%CI:1.27-2.27,P=0.0004).Tirzepatide,at all doses,had higher risks of AE-related discontinuation than insulin;such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RA.Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin.Compared to the placebo,tirzepatide(all doses)conferred a lower risk of study drug discontinuation due to other causes not specifically mentioned.CONCLUSION The discontinuation risk is not higher in tirzepatide group than in the placebo arm.Many factors other than AEs led to drug discontinuation in the included RCTs.
文摘BACKGROUND Efruxifermin(EFX),a fibroblast growth factor 21 analogue,has demonstrated the potential to improve liver fat and markers of liver injury,fibrosis,and key metabolic biomarkers in individuals with metabolic dysfunction-associated steatohepatitis(MASH)in phase 2 clinical trials.AIM To summarize the safety and effectiveness of EFX in managing MASH.METHODS Electronic databases and registries were systematically searched from their inception to May 15,2025,for randomized-controlled trials(RCTs)that included EFX in the intervention arm and placebo in the control arm in individuals with MASH.The primary outcome was the safety of EFX,while additional outcomes included its efficacy in altering hepatic and metabolic parameters.Meta-analyses were conducted using the RevMan web computer program with the random-effects model.RESULTS Four phase 2 RCTs(five reports),mostly with low risk of bias,involving 450 subjects,were analyzed.Compared to the placebo,EFX 50 mg was associated with higher risks of treatment-emergent adverse events(TEAEs)[risk ratio(RR)=1.05],TEAEs leading to discontinuation(RR=3.05),nausea(RR=1.78),and diarrhea(RR=1.9).EFX 28 mg increased risks of vomiting(RR=2.17)and frequent bowel movements(RR=8.98).Both doses of EFX were associated with higher risks of drug-related TEAEs(28 mg:RR=1.45;50 mg:RR=1.67)and increased appetite(28 mg:RR=3.16;50 mg:RR=5.66).EFX(28 and 50 mg)and placebo exhibited identical risks for severe TEAEs,serious AEs,abdominal pain,fatigue,headache,injection site erythema,and injection site reactions.EFX(28 and 50 mg)was associated with improvements in hepatic safety outcomes,including liver enzymes and urate levels.EFX outperformed the placebo in both relative and absolute reductions in hepatic fat fraction.Reductions in enhanced liver fibrosis score,Pro-C3,and liver stiffness were also more robust with EFX.EFX was superior in terms of MASH resolution and improvement in fibrosis stage,MASH resolution and no worsening of the fibrosis stage,and fibrosis regression by≥1 stage and no worsening in steatohepatitis.Furthermore,EFX also improved metabolic parameters,including reductions in HbA1c and insulin resistance,as well as improvements in adiponectin and lipid parameters.CONCLUSION EFX demonstrates promising dual efficacy on liver histology and metabolic markers in MASH.However,gastrointestinal side effects and the need for parenteral administration require caution.Long-term data are still necessary to fully evaluate safety and long-term effectiveness.
文摘BACKGROUND Type 2 diabetes(T2D),as well as obesity,are risk factors for chronic kidney disease(CKD)and end-stage renal disease.The renal impacts of glucose-lowering and weight-lowering drugs and their potential benefits in preventing CKD often guide clinicians in choosing them appropriately.Only limited data based on randomized controlled trials(RCTs)is currently available on the renal effects and safety profile of tirzepatide.AIM To explore the renal benefits and safety of tirzepatide vs controls.METHODS RCTs involving patients receiving tirzepatide for any indication in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The co-primary outcomes were percent change from baseline(CFB)in urine albumin-to-creatinine ratio(UACR)and absolute CFB in estimated glomerular filtration rate(eGFR;in mL/min/1.73 m^(2));the secondary outcome was tirzepatide’s renal safety profile.RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MD)or risk ratios with 95%confidence intervals.RESULTS Fifteen RCTs(n=14471)with mostly low risk of bias(RoB)were included.Over 26-72 weeks,tirzepatide 10 mg[MD-26.95%(-40.13,-13.76),P<0.0001]and 15 mg[MD-18.03%(-28.58,-7.47),P=0.0008]were superior to placebo in percent reductions of UACR.Tirzepatide,at all doses,outperformed insulin in percent reductions of UACR.Compared to the placebo,the percent UACR reduction was greater in subjects with T2D than those with obesity but without T2D(MD-33.25%vs-7.93%;P=0.001).The CFB in eGFR with all doses of tirzepatide was comparable[5 mg:MD 0.36(-1.41,2.14);10 mg:MD 1.17(-0.22,2.56);15 mg:MD 1.42(-0.04,2.88)];P>0.05 for all vs insulin.Tirzepatide(pooled and separate doses)did not increase the risks of adverse renal events,urinary tract infection,nephrolithiasis,acute kidney injury,and renal cancer compared to the placebo,insulin,and glucagon-like peptide-1 receptor agonists.CONCLUSION Short-term data from RCTs with low RoB suggests that tirzepatide positively impacts UACR without detrimental effects on eGFR in subjects with T2D and obesity without T2D,with a reassuring renal safety profile.Larger RCTs are warranted to prove the longer-term renal benefits of tirzepatide,which might also prevent eGFR decline and worsening of CKD.
文摘BACKGROUND Automated insulin delivery(AID)systems have demonstrated benefits in managing patients with type 2 diabetes(T2D),but data are still limited.Moreover,the efficacy and safety of the AID systems in these patients have been inadequately explored by systematic reviews and meta-analyses.AIM To provide a comprehensive understanding of the optimal use of AID in managing insulin-treated outpatients with T2D.METHODS A systematic search of multiple databases and registries,including MEDLINE,Scopus,Web of Science,Cochrane Library,and ClinicalTrials.gov,was conducted from inception to May 15,2025,to identify studies on AID use for outpatients with T2D.The co-primary outcomes were the change in glycated hemoglobin(HbA1c)and continuous glucose monitoring(CGM)metrics.Statistical analyses were conducted using Review Manager Web software with random-effects models and the inverse variance statistical method.The results were presented as mean differences(MDs)or risk ratios(RRs)with 95%CI.RESULTS A total of 15 studies with 28985 participants were identified,including 6 randomized trials(n=748;3 crossover and 3 parallel-group trials)and 9 single-arm studies.All included randomized trials raised some concerns,and the single-arm studies had serious risks of overall bias.Meta-analysis of randomized trials showed that AID is more effective than the control group in lowering HbA1c(MD:-0.89%,95%CI:-1.32 to-0.46,P<0.0001,I2=82%).Compared to control interventions,AID use was linked to a higher percentage of time in range(MD:19.25%,95%CI:11.43-27.06,P<0.00001,I2=74%)and a lower percentage of time above range>10 mmol/L(MD:-19.48%,95%CI:-27.14 to-11.82,P<0.00001,I2=73%);however,time below range remained similar between the two groups.The mean sensor glucose level was lower in the AID group;however,the coefficient of variation of glucose was the same in both groups.AID use also led to a reduction in insulin dose,but this is not a consistent finding across all study designs.The risks of serious adverse events(AEs)and severe hypoglycemia were similar in both groups;however,AID use raised the risk of device deficiency.Single-arm studies with participants using AID systems also demonstrated reductions in HbA1c(ranging from 0.7%to 2.07%)and improvements in CGM metrics,along with acceptable safety data.CONCLUSION Based on short-term study data,the use of AID systems in outpatients with T2D appears to improve glycemic outcomes and CGM metrics,with no significant AEs.Larger and longer-term randomized controlled trials involving diverse populations,along with a cost-benefit analysis,are needed to guide more informed clinical practice decisions.
文摘BACKGROUND Cotadutide(MEDI0382)is a twincretin that acts as an agonist for both the glucagon-like peptide-1 and glucagon receptors.Several randomized controlled trials(RCTs)have been published evaluating the use of cotadutide in individuals with type 2 diabetes(T2D),showing promising results.However,the efficacy and safety of the drug use have been inadequately explored by systematic reviews and meta-analyses.AIM To assess the clinical efficacy and safety of cotadutide in individuals with T2D having overweight or obesity.METHODS The systematic reviews and meta-analyses have been registered with International Prospective Register of Systematic Reviews(CRD42024511703),and the protocol summary can be accessed online.Several databases and registries,including MEDLINE(via PubMed),Scopus,Web of Science,the Cochrane Central Register of Controlled Trials,and ClinicalTrials.gov,were systematically searched using related terms from their inception to May 15,2025,for RCTs involving individuals with T2D receiving cotadutide in the intervention group.Review Manager web was used to conduct meta-analysis using random-effects models.The co-primary outcomes of interest were the changes in glycated hemoglobin(HbA1c)and the percent changes in body weight from baseline.The results of the outcomes were expressed as mean differences(MDs)or risk ratios(RRs)with 95%confidence intervals(CIs).The analysis of outcomes was stratified according to whether the control group received a placebo,denoted as the placebo control group(PCG),or an active comparator,referred to as the active control group(ACG).RESULTS Nine RCTs(mostly phase 2 RCTs,n=1525)with study durations varying from 28 days to 54 weeks that met all the inclusion criteria were analyzed;five studies had a low overall risk of bias,while the other four had some concerns.Compared to the PCG,greater reductions in HbA1c were achieved with cotadutide 100μg(MD-0.77%,95%CI:-1.06 to-0.47),200μg(MD-0.68%,95%CI:-1.12 to-0.23),300μg(MD-0.67%,95%CI:-0.79 to-0.56),and 600μg(MD-0.69%,95%CI:-0.97 to-0.41).Cotadutide 100μg(MD-1.74%,95%CI:-3.23 to-0.25),200μg(MD-2.56%,95%CI:-3.37 to-1.75),300μg(MD-3.49%,95%CI:-4.14 to-2.84),and 600μg(MD-5.45%,95%CI:-7.17 to-3.73)achieved greater percent reductions in body weight from baseline.However,the certainty of evidence for HbA1c and percent body weight reductions was very low to low.Cotadutide,at all doses,also outperformed PCG in reducing fasting plasma glucose and absolute body weight.The changes in HbA1c,percent body weight,fasting plasma glucose,and absolute body weight were similar between the cotadutide group and the ACG.Compared to PCG,pooled doses of cotadutide increased the risks of treatment-emergent adverse events(AEs),treatment-related AEs,and discontinuation of the study drug due to AEs,but not for serious AEs.More subjects experienced overall gastrointestinal AEs,dyspepsia,nausea,vomiting,constipation,and decreased appetite with cotadutide than with PCG.Compared to the ACG,none of the AEs showed increased risk in the cotadutide group.CONCLUSION Cotadutide demonstrated glycemic control and weight-loss benefits in short-term,small RCTs(mostly phase 2).However,small sample sizes,very low to low certainty of evidence,and the absence of data on long-term cardiovascular and renal outcomes highlight substantial uncertainties,warranting cautious interpretation and further investigation in larger,longer-term trials to establish its safety and efficacy profile.
