The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity:A Meta-Analysis

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Real-world effectiveness of early insulin therapy on the incidence of cardiovascular events in newly diagnosed type 2 diabetes

Early insulin therapy is capable to achieve glycemic control and restoreβ-cell function in newly diagnosed type 2 diabetes(T2D),but its effect on cardiovascular outcomes in these patients remains unclear.In this nationwide real-world study,we analyzed electronic health record data from 19 medical centers across China between 1 January 2000,and 26 May 2022.We included 5424 eligible patients(mean age 56 years,2176 women/3248 men)who were diagnosed T2D within six months and did not have prior cardiovascular disease.Multivariable Cox regression models were used to estimate the associations of early insulin therapy(defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients)with the incidence of major cardiovascular events including coronary heart disease(CHD),stroke,and hospitalization for heart failure(HF).During 17,158 persons years of observation,we documented 834 incident CHD cases,719 stroke cases,and 230 hospitalized cases for HF.Newly diagnosed T2D patients who received early insulin therapy,compared with those who did not receive such treatment,had 31%lower risk of incident stroke,and 28%lower risk of hospitalization for HF.No significant difference in the risk of CHD was observed.We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models.These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.

Chiglitazar monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomized,double-blind,phase 3 trial(CMAS)

Chiglitazar(Carfloglitazar)is a novel peroxisome proliferator-activated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes.In this randomized phase 3 trial,we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen.Eligible patients were randomized(1:1:1)to receive chiglitazar 32 mg(n=245),chiglitazar 48 mg(n=246),or sitagliptin 100 mg(n=248)once daily for 24 weeks.The primary endpoint was the change in glycosylated hemoglobin A_(1C)(HbA_(1c))from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin.Both chiglitazar and sitagliptin significantly reduced HbA1c at week 24 with values of-1.40%,-1.47%,and-1.39%for chiglitazar 32 mg,chiglitazar 48 mg,and sitagliptin 100 mg,respectively.Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg,with mean differences of-0.04%(95%confidential interval(Cl)-0.22 to 0.15)and-0.08%(95%Cl-0.27 to 0.10),respectively.Compared with sitagliptin,greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar.Overall adverse event rates were similar between the groups.A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported.The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Efficacy and safety of chiglitazar,a novel peroxisome proliferatoractivated receptor pan-agonist,in patients with type 2 diabetes:a randomized,double-blind,placebo-controlled,phase 3 trial(CMAP)

Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies.This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone.Eligible patients were randomly assigned to receive chiglitazar 32 mg(n=167),chiglitazar 48 mg(n=166),or placebo(n=202)once daily.The primary endpoint was the change in glycosylated hemoglobin A_(1c)(HbA_(1c))at week 24 with superiority of chiglitazar over placebo.The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA_(1c),and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were-0.87%(95%confidential interval(CI):-1.10 to-0.65;P<0.0001)and-1.05%(95%CI:-1.29 to-0.81;P<0.0001),respectively.Secondary efficacy parameters including glycemic control,insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups.The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups.Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups.The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Negative association of time in range and urinary albumin excretion rate in patients with type 2 diabetes mellitus:a retrospective study of inpatients

Background:Time in range(TIR)refers to the time an individual spends within their target glucose range,which now has been popularized as an important metric to classify glycemic management and also recognized as an important outcome of current diabetes therapies.This study aimed to investigate the association between TIR and the severity of the urinary albumin excretion rate(UAER)in patients with type 2 diabetes mellitus(T2DM).Methods:We retrospectively analyzed the data of 1014 inpatients with T2DM at the Department of Endocrinology and Metabolism of Peking University International Hospital,China.TIR was defined as the percentage of blood glucose within the target range of 3.90-10.00 mmol/L.Urine samples for assessment of UAER were collected for 3 consecutive days from the start of hospitalization.Results:The TIR values for patients with normal urine levels of albumin,microalbuminuria,and macroalbuminuria were 70%±20%,50%±20%,and 30%±20%,respectively(allP<0.001).The patients were stratified according to quartiles of TIR as follows:quartile(Q)1,<55%;Q2,55%-72%;Q3,73%-83%;and Q4,>83%.The incidences of microalbuminuria in Q1,Q2,Q3,and Q4 were 41.1%,21.6%,7.1%,and 5.5%(allP<0.001),respectively.The respective incidences of macroalbuminuria were 24.2%,1.1%,1.4%,and 0%(allP<0.001).In multinomial logistic regression analyses,TIR was significantly correlated with microalbuminuria(odds ratio[OR]0.58,95%confidence interval[CI]:0.52-0.65,P<0.001)and macroalbuminuria(OR 0.26,95%CI:0.18-0.38,P<0.001)after adjusting for age,sex,body mass index,diabetes duration,systolic blood pressure,and levels of triglycerides,glycosylated hemoglobin A1c,and creatinine.Conclusion:The proportion of blood glucose in TIR is closely related to the severity of UAER in patients with T2DM.

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy(STRATEGY):a multicenter,randomized,controlled,non-inferiority clinical trial

Despite the current guideline's recommendation of a timely stepwise intensification therapy,the "clinical inertia",termed as the delayed treatment intensification,commonly exists in the real world,which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy.In this clinical trial performed in 237 centers in China,5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks.The patients who did not reach the glycated hemoglobin A1c(HbA1c) goal were then further randomized into glimepiride,gliclazide,repaglinide,or acarbose group for an additional 24-week triple therapy.A mean HbAlc reduction of 0.85%was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks.Further HbAlc reductions in the 24-week triple therapy stage were 0.65%in glimepiride group,0.70%in gliclazide group,0.61%in repaglinide group,and 0.45%in acarbose group.The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide,but not for acarbose,compared with glimepiride,when added to metformin/sitagliptin dual therapy.The incidences of adverse events(AEs) were 29.2%in the dual therapy stage and30.3%in the triple therapy stage.Metformin/sitagliptin as baseline therapy,with the addition of a third oral antihyperglycemic agent,including glimepiride,gliclazide,repaglinide,or acarbose,was effective,safe and well-tolerated for achieving an HbAlc<7.0%goal in type 2 diabetic patients inadequately controlled with previous therapies.The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Estimation of atherosclerotic cardiovascular disease risk in type 2 diabetes

To the Editor:The global prevalence of diabetes is increasing dramatically.[1]To prevent and treat diabetes and its cardiovascular complications,clinical practice guidelines recommend to assess the prevalent nonmodifiable risk factors in people with diabetes.The prediction for atherosclerotic cardiovascular disease(ASCVD)risk in China(China-PAR)model was specifically developed to predict the 10-year risk for ASCVD in China.

Lipid control in adult Chinese patients with type 2 diabetes:a retrospective analysis of time trends and geographic regional differences

To the Editor:Patients with type 2 diabetes have a higher risk of cardiovascular diseases(CVD),relative to people without diabetes.Patients with diabetes always exhibit lipid abnormalities.Rapid economic development and accelerated urbanization have also led to lifestyle changes that may have an influence on the lipid parameters of Chinese patients with diabetes.Given the significant differences in socioeconomic status in China,geographical variations were also observed in the prevalence,awareness,treatment,and control of dyslipidemia among individuals who were≥45 years old in the general Chinese population.[1]There is a lack of large-scale studies regarding time trends and geographical variations in lipid concentrations and lipid control among Chinese adults with type 2 diabetes.Therefore,we conducted a study on time trends and geographical variations in lipid concentrations and lipid control in this population using the China National HbA1c Surveillance System(CNHSS)database of adult Chinese outpatients with type 2 diabetes during 2009 to 2013.The Ethics Committee of the Chinese People Liberation Army General Hospital approved the study protocol.Informed consent was obtained from all the patients before they were interviewed and data collected.

662 A/G gene variation in human tumor necrosis factor receptor superfamily,member 9(TNFRSF9)

The aim of this paper is to report a new coding variance of the TNFRSF9 gene,a candidate for auto-immune diseases.We found the variation in two families with type 2 diabetes mellitus by D-HPLC mutation screening method and confirmed our results by direct sequencing and PCR-RFLP.Although without changing the amino acid coding,the variance may have an effect on codon usage and play a role in disease development,such as type 2 diabetes mellitus.However,we cannot define the role of this variance because the frequency of the minor allele is low in the Chinese population and no homozygote of the variance was found.More research in multiple populations will be necessary to define the role of this variance.

Trends and regional differences in glycemic control of patients with type 2 diabetes in China, 2009–2013

To the Editor:According to the International Diabetes Federation,China has been ranked first worldwide in terms of the prevalence of diabetes among people aged 20 to 79 years.[1]As a cornerstone in the management of patients with type 2 diabetes mellitus(T2DM),the level of glycemic control has changed considerably over the past decades.A multicenter observational study in North China showed that 45.82%of patients with T2DM met the glycated hemoglobin(HbA1c)control standard in 2017.[2]With the largest population of residents with T2DM,China is also faced with significant regional discrepancies in the rates of adequate glycemic control(HbA1c<7%),ranging from 25.9%in Shaanxi province[3]to 56.1%in Jiangsu province.[4]Indeed,previous studies in China were conducted for short periods of time,in a limited number of areas,and with relatively small sample sizes.Based on the data of the China National HbA1c Surveillance System study(CNHSS),this analysis aimed to investigate temporal trends and regional variations in glycemic control in T2DM patients in China from 2009 to 2013.

Cardiovascular risk profile and clinical characteristics of diabetic patients:a cross-sectional study in China

Background:Cardiovascular(CV)disease is the leading cause of morbidity and mortality in adults with type 2 diabetes(T2D).The aim of this study was to determine the CV risk in Chinese patients with T2D based on the 2019 European Society of Cardiology(ESC)and the European Association for the Study of Diabetes(EASD)guidelines on diabetes,pre-diabetes,and CV diseases.Methods:A total of 25,411 patients with T2D,who participated in the study of China Cardiometabolic Registries 3B study,were included in our analysis.We assessed the proportions of patients in each CV risk category according to 2019 ESC/EASD guidelines.Results:Based on the 2019 ESC/EASD guidelines,16,663(65.6%),1895(7.5%),and 152(0.6%)of patients were included in"very high risk,""high risk,"and"moderate risk"categories,respectively.The proportions of patients in each category varied based on age,sex,body mass index,and duration.While 58.7%(9786/16,663)of elderly patients were classified to"very high risk"group,89.6%(3732/4165)of patients with obesity were divided into"very high risk"group.Almost all patients with a duration of diabetes>10 years had"very high risk"or"high risk."However,6701(26.4%)of Chinese T2D patients,who had shorter duration,and one or two risk factors,could not be included in any category(the"unclear risk"category).Conclusions:In China,most patients with T2D have"very high"or"high"CV risk based on 2019 ESC/EASD guidelines.However,the risk of patients in"unclear risk"group needs to be further classified.