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.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

A Retrospective Analysis of Glucagon-Like Peptide 1 Receptor Agonists in Treating Type 2 Diabetes Mellitus Complicated by Nonalcoholic Fatty Liver Disease

Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.

Activation of β_2-Adrenergic Receptor Induced by Three Catecholamine Agonists:a Docking and Molecular Dynamics Study

We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Glucagon-like-1 receptor agonists and sodium/glucose cotransporter-2 inhibitors combination—are we exploiting their full potential in a real life setting?

BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer’s disease therapy

Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients

BACKGROUND Currently,the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for glucose excursion is worth investigation.AIM To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes.METHODS Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis.All patients were treated with metformin.We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA(group A;n=33 and group B;n=37).RESULTS The degree of decrease in the levels of fasting blood glucose,mean blood glucose,mean amplitude of glycemic excursions,total cholesterol,triglycerides,tumor necrosis factor-α,interleukin-6,and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B(P<0.05),whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A(P<0.001).However,there were no statistically significant differences in the levels of glycated hemoglobin,standard deviation of blood glucose,coefficient of variation,absolute mean of daily differences,percentage of time with 3.9 mmol/L<glucose<10 mmol/L,and high-and low-density lipoproteins between the two groups(P>0.05).The incidence of adverse reactions was significantly lower in group A than in group B(P<0.05).CONCLUSION The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients,suppressing inflammation,and reducing adverse reactions was significantly higher than that of the daily preparations,which is worthy of clinical promotion.

达格列净联合胰高血糖素样肽-1受体激动剂对2型糖尿病的疗效研究

目的探讨达格列净联合胰高血糖素样肽-1受体激动剂(GLP-1 RAs)对2型糖尿病患者血液流变学及胰岛素抵抗的影响。方法将2020年11月—2022年10月泉州市中医院收治的102例2型糖尿病患者随机分为2组,每组51例。对照组给予达格列净治疗,研究组采用达格列净联合GLP-1 RAs(利拉鲁肽)的治疗方案。比较2组临床疗效、血糖指标[空腹血糖(FBG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbA1c)]、空腹胰岛素(FINS)及胰岛素抵抗[胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)]、血脂指标[总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]、血液流变学指标[红细胞聚集指数(EAI)、红细胞压积(HCT)、红细胞变形指数(EDI)、血浆黏度(PV)]和不良反应。结果研究组总有效率为94.12%,高于对照组的80.39%,差异有统计学意义(P<0.05)。研究组和对照组治疗后FBG、2 hPG、HbAlc、BMI均低于治疗前,且研究组治疗后FBG、2 hPG、HbAlc水平低于对照组,差异有统计学意义(P<0.05)。治疗后,研究组FINS、HOMA-β水平高于对照组,HOMA-IR水平低于对照组,差异有统计学意义(P<0.05)。研究组和对照组治疗后HDL-C均高于治疗前,TC、TG、LDL-C水平均低于治疗前;研究组治疗后HDL-C水平高于对照组,TC、TG、LDL-C水平低于对照组,差异均有统计学意义(P<0.05)。治疗后,研究组和对照组EAI、HCT、EDI、PV水平均低于治疗前,且研究组EAI、HCT、EDI、PV水平低于对照组,差异均有统计学意义(P<0.05)。研究组不良反应总发生率为11.76%,与对照组的9.80%比较,差异无统计学意义(P>0.05)。结论达格列净联合GLP-1 RAs(利拉鲁肽)治疗2型糖尿病的疗效确切,可有效调节患者血糖及血脂水平,缓解胰岛素抵抗,改善血液流变学指标。

司美格鲁肽对2型糖尿病合并超重及肥胖患者的胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响

目的探讨司美格鲁肽对2型糖尿病(T2DM)合并超重及肥胖患者的血糖控制、胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响。方法采用单中心、前瞻性、临床病例对照试验的方法,选取2021年10月至2022年10月在金华市中心医院诊断为T2DM合并超重(BMI 25~<28 kg/m^(2))及肥胖(BMI≥28 kg/m^(2))的86例患者为研究对象,均接受稳定剂量的二甲双胍单药或联合口服用药至少3个月,糖化血红蛋白(HbA1C)为6.5%~8.0%。采用随机数字表法将患者分为对照组和观察组,各43例。对照组继续原方案口服降糖,观察组在原方案的基础上联合司美格鲁肽(起始剂量0.25 mg,4周后增加至0.5 mg并稳定,1次/周,皮下注射)。两组均干预24周。比较两组患者血糖(FPG、餐后2 h血糖和HbA1C)、血脂(TC、TG、LDL-C、HDL-C)、BMI、腰围、胰岛细胞功能[空腹胰岛素(FINS)、胰岛β细胞功能指数(HOMA-β)和胰岛素抵抗指数(HOMA-IR)]。通过非对称回波的最小二乘估算法迭代水脂分离序列测量胰头、胰体和胰尾的胰腺脂肪分数(PFF),计算平均PFF并进行组间比较;测量肝脏右上、右下和左叶的肝脏脂肪分数(HFF),计算平均HFF并进行组间比较。结果对照组39例和观察组40例随访至研究结束。治疗后观察组患者FPG、餐后2 h血糖、HbA1C、BMI、FINS、HOMA-IR、平均PFF和平均HFF均低于对照组,而HOMA-β高于对照组,差异均有统计学意义(均P<0.01)。结论司美格鲁肽应用方便,对T2DM合并超重及肥胖患者能够在常规降糖药的基础上进一步改善胰岛素和胰岛β细胞功能,降低血糖水平、胰腺和肝脏脂肪含量,同时可产生额外的减重获益。

GLP-1RA与DPP-4i治疗2型糖尿病的疗效及对患者并发症的影响

目的探讨胰高糖素样肽1受体激动剂(GLP-1RA)与二肽基肽酶4抑制剂(DPP-4i)治疗2型糖尿病(T2MD)的疗效及对患者并发症的影响。方法选取2020年6月至2022年6月邯郸市第一医院收治的110例T2MD随机分为GLP-1RA组和DPP-4i组,每组55例,GLP-1RA组采用利拉鲁肽或艾塞那肽治疗,DPP-4i组采用西格列汀或利格列汀治疗。对比2组临床疗效,治疗前后糖脂代谢指标[空腹血糖(FPG)、糖化血红蛋白(HbA1c)、总胆固醇、三酰甘油]、炎症指标[白介素-6(IL-6)、C反应蛋白(CRP)、中性粒细胞/淋巴细胞(NLR)]、肾功能[尿素氮、肌酐、胱抑素C];观察并统计2组并发症及不良反应。结果2组总有效率、并发症总发生率比较差异均无统计学意义(P>0.05)。治疗18周后,2组FPG、HbA1c、三酰甘油、总胆固醇水平低于治疗前,且GLP-1RA组低于DPP-4i组(P<0.05)。治疗18周后,2组IL-6、CRP、NLR水平低于治疗前(P<0.05),但2组间差异无统计学意义(P>0.05)。2组治疗前和治疗18周后尿素氮、肌酐、胱抑素C水平比较差异均无统计学意义(P>0.05)。GLP-1RA组不良反应总发生率高于DPP-4i组(P<0.05)。结论GLP-1RA与DPP-4i均能改善T2MD患者糖脂水平,减轻炎性反应,保护肾功能,预防并发症发生,但GLP-1RA在控制血糖、调脂方面优于DPP-4i,而DPP-4i耐受性更好。

Review on the Effect of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease（NAFLD） is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus（T2DM）, dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1（GLP-1） analogues and dipeptidyl peptidase-4（DPP-4） inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor（GLP-1R） is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride（TG） content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

Is there a role for glucagon-like peptide-1 receptor agonists in the management of diabetic nephropathy?

Chronic kidney disease constitutes a major microvascular complication of diabetes mellitus.Accumulating data suggest that glucagon-like peptide-1 receptor agonists(GLP-1 RAs)might have a role in the management of diabetic kidney disease(DKD).GLP-1 RAs appear to reduce the incidence of persistent macro-albuminuria in patients with type 2 diabetes mellitus.This beneficial effect appears to be mediated not only by the glucose-lowering action of these agents but also on their blood pressure lowering,anti-inflammatory and antioxidant effects.On the other hand,GLP-1 RAs do not appear to affect the rate of decline of glomerular filtration rate.However,this might be due to the relatively short duration of the trials that evaluated their effects on DKD.Moreover,these trials were not designed nor powered to assess renal outcomes.Given than macrolbuminuria is a strong risk factor for the progression of DKD,it might be expected that GLP-1 RAs will prevent the deterioration in renal function in the long term.Nevertheless,this remains to be shown in appropriately designed randomized controlled trials in patients with DKD.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Non-alcoholic fatty liver disease(NAFLD)is the predominant cause of chronic liver disease worldwide.NAFLD progresses in some cases to non-alcoholic steatohepatitis(NASH),which is characterized,in addition to liver fat deposition,by hepatocyte ballooning,inflammation and liver fibrosis,and in some cases may lead to hepatocellular carcinoma.NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus(T2DM).Currently,lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are used in the management of T2DM and do not have major side effects like hypoglycemia.In patients with NAFLD,the GLP-1 receptor production is down-regulated.Recently,several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation,alleviating the inflammatory environment and preventing NAFLD progression to NASH.In this review,we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH.Finally,as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD,we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.

Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin and a GLP-1RA, have potent anti-hyperglycemic effects and reduce the undesirable side-effects of each component, such as body weight gain, hypoglycemia, and gastrointestinal symptoms. Two FRCs-insulin degludec/Liraglutide and insulin glargine/Lixisenatide-are now clinically available and, to date, several phase Ⅱ/Ⅲ trials have been conducted in particular groups of subjects with T2D. However, their utility in real-world clinical settings is of interest for most clinicians. Recently reported real-world clinical trials of these two FRCs in various situations have demonstrated their efficacy regarding glycemic control and the quality of life of people with T2D. Their long-term safety and efficacy require confirmation, but a treatment strategy that includes an FRC may be compatible with the concept of “well-balanced” therapy in certain groups of patients with T2D who have inadequate glycemic control.

基于Markov模型的胰高血糖素样肽1受体激动剂联合二甲双胍治疗2型糖尿病药物经济学评价

目的 对胰高血糖素样肽1受体激动剂(GLP-1RA)联合二甲双胍治疗2型糖尿病(T2DM)进行经济学评价。方法 从我国卫生体系角度出发,基于7项GLP-1RA联合二甲双胍治疗T2DM的随机对照试验(RCT),构建二甲双胍单药或联合GLP-1RA治疗T2DM的Markov模型,模拟治疗期间T2DM无并发症、T2DM伴并发症以及死亡3种状态的动态变化。模型以质量调整生命年(QALYs)为健康产出指标、以3倍我国2023年人均国内生产总值(GDP)为意愿支付(WTP)阈值。模型循环周期设定为1年,共计模拟20年,采用Markov模型进行队列模拟,以增量成本-效用比(ICUR)为评价指标,从而获得每种治疗策略的长期成本、效用及其经济性。通过对成本、效用及贴现的敏感性分析,检验研究结果的稳定性。结果 与二甲双胍单药治疗相比,5种GLP-1RA类药物(利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽)联合二甲双胍治疗方案的ICUR均小于3倍我国2023年人均GDP,增加的成本可接受。敏感性分析中各参数在设定的范围内变化,或将模拟时间延长至30年或50年,对研究结论无显著影响;概率敏感性分析结果表明,WTP阈值为3倍我国2023年人均GDP值(268 074元)时,二甲双胍联合司美格鲁肽0.5 mg方案具有成本-效用优势的概率最高,约为99.7%。结论 对于T2DM患者,相比于二甲双胍单药治疗,利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽以说明书推荐剂量联合二甲双胍治疗方案均属于优势方案,具有经济性。

胰高血糖素样肽1受体激动剂治疗合并超重或肥胖的2型糖尿病的疗效和安全性的Meta分析

目的系统评价胰高血糖素样肽1受体激动剂(GLP-1RA)治疗合并超重或肥胖2型糖尿病(T2DM)患者的有效性与安全性。方法计算机检索PubMed、Embase、Cochrane Library、Ovid、ClinicalTrial.gov、SinoMed、CNKI、WanFang Data和VIP数据库,搜集有关GLP-1RA治疗T2DM合并超重或肥胖患者的随机对照试验(RCT),检索时限均从2005年1月1日至2023年11月1日。由2位研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用R软件进行Meta分析,并采用GRADE系统进行证据质量评价。结果共纳入71个RCT,包括29476例患者。Meta分析结果显示,相比于其他降糖药,GLP-1RA在改善糖化血红蛋白[WMD=-0.55,95%CI(-0.65,-0.45),P<0.001]、减重[WMD=-2.61,95%CI(-3.25,-1.97),P<0.001]方面均具有优势;GLP-1RA对空腹血糖的改善效果呈时间依赖性[16周以内:WMD=0.25,95%CI(-0.17,0.66),P=0.250;16~52周:WMD=-0.06,95%CI(-0.32,0.20),P=0.650;>52~104周:WMD=-1.67,95%CI(-1.91,-1.43),P<0.001];安全性方面,GLP-1RA的总体不良反应发生率较高[RR=1.11,95%CI(1.07,1.15),P<0.001];但低血糖发生率低于胰岛素[RR=0.58,95%CI(0.48,0.71),P<0.001],而与口服降糖药的差异无统计学意义[RR=0.83,95%CI(0.58,1.19),P=0.310]。GRADE系统评价显示,仅低血糖发生率的证据等级为中等,其余结局指标的证据水平均为低级。结论当前证据显示,对于T2DM合并肥胖或超重患者,GLP-1RA尤其是司美格鲁肽相比于安慰剂、胰岛素或口服降糖药,能更有效兼顾降糖和减重,虽总体不良反应较多,但可减少低血糖发生。

5种GLP-1RAs治疗二甲双胍控制不佳的2型糖尿病的成本-效用分析

目的评估5种胰高血糖素样肽-1受体激动剂(GLP-1RAs)治疗二甲双胍控制血糖不佳的2型糖尿病(T2DM)的长期经济性。方法提取既往发表的荟萃分析及其纳入的随机对照研究(RCT)中患者的基线数据,使用英国前瞻性糖尿病研究结果模型2.1预测各组患者的生存情况、长期疗效和成本,采用成本-效用分析法比较5种GLP-1RAs(利拉鲁肽、利司那肽、艾塞那肽、度拉糖肽和司美格鲁肽)的经济性;采用敏感性分析和情境分析验证基础分析结果的稳定性。结果共纳入21项RCT,6796名患者。生存曲线表明,司美格鲁肽在降低因心血管疾病死亡风险上、度拉糖肽在降低全因死亡风险上较其他GLP-1RAs具有优势。成本-效用分析结果显示,5种方案的经济性从优到劣排序依次为利司那肽、司美格鲁肽、艾塞那肽、度拉糖肽和利拉鲁肽。单因素敏感性分析和概率敏感性分析表明基础分析结果稳健。情境分析结果显示,司美格鲁肽的价格至少降低54.64%,降至369.21元,其对比利司那肽才具有经济性。结论对于使用二甲双胍治疗后血糖控制不佳的我国T2DM患者,临床可考虑优先选择利司那肽和司美格鲁肽。

哮喘治疗中β_(2)-AR激动药诱发受体脱敏的发生机制及预防进展

β_(2)-肾上腺素受体(β_(2)-AR)激动药作为治疗支气管哮喘(以下简称“哮喘”)的一线药物,在临床中广泛应用,然而长期使用可导致β_(2)-AR脱敏,降低其临床疗效,致使部分哮喘患者症状控制欠佳。β_(2)-AR激动药引起β_(2)-AR脱敏的机制主要包括慢速脱敏(与气道黏膜β_(2)-AR密度减小有关)和快速脱敏(与刺激性G蛋白脱偶联机制有关)。环磷酸腺苷(cAMP)-蛋白激酶A和cAMPcAMP激活的交换蛋白信号通路与β_(2)-AR脱敏过程关系密切。糖皮质激素、过氧化物酶体增殖物激活受体γ激动药、ASM-024、中药单药及成方等与β_(2)-AR激动药联合使用时能改善β_(2)-AR的敏感性,从而更好地控制哮喘症状。