Mini health technology assessment of weekly preparations of glucagon-like peptide-1 receptor agonist / 中国药房

OBJECTIVE To comprehensively evaluate four weekly preparations of glucagon-like peptide-1 receptor agonist （GLP-1RA） marketed in China，and to provide evidence for hospitals to optimize drug catalogs and clinical rational drug use. METHODS Mini health technology assessment method was used to establish detailed evaluation rules according to A Quick Guideline for Drug Evaluation and Selection in Chinese Medical Institutions， and conduct comprehensive evaluation of four GLP- 1RA weekly preparations from aspects of pharmaceutical characteristics， effectiveness， safety， economy and other attributes. RESULTS Mini health technology assessment scores of the four GLP-1RA weekly preparations from high to low were dulaglutide 78.60 points， semaglutide 77.35 points，polyethylene glycol loxenatide 67.40 points， and exenatide microspheres 65.50 points， respectively. Dulaglutide had advantages in reducing blood sugar， arteriosclerotic cardiovascular disease， kidney benefits， and cost- effectiveness. Semaglutide had advantages in reducing blood sugar and weight loss， but its cost-effectiveness was lower than that of dulaglutide. Exenatide microspheres had advantages in the use of children， but its daily average treatment cost is the highest. Polyethylene glycol loxenatide needed further clinical evidence. CONCLUSIONS Four GLP-1RA weekly preparations all have high pharmaceutical comprehensive scores. Dulaglutide and semaglutide may have more comprehensive pharmaceutical value among them， while the use of exenatide microspheres for children is unique.

Progress in research on neuroprotective mechanism of glucagon-like peptide-1 receptor agonists and analogues in Parkinson's disease / 中国生物制品学杂志

@#Parkinson's disease(PD)is the second common neurodegenerative disease that mostly occurs in middle-aged and elderly people. Currently,Levodopa is the main first-line treatment drug,but the long-term efficacy of patients is not good,and even side effects such as“on-off”phenomenon and orthostatic hypotension occur. Glucagon-like peptide-1receptor agonists(GLP-1RA)and analogues are endogenous peptide hormones that can be released into the blood and enter the central nervous system to exert neuroprotection by crossing the blood-brain barrier. Numerous studies have shown that GLP-1RA can improve movement disorders and restore dopaminergic neuron activity in PD. However,the mechanism of GLP-1RA is not yet fully clear. This paper summarized the mechanism of GLP-1RA and its analogues in improving PD movement disorders and restoring dopaminergic neuron activity,and reviewed the aspects of reducing neuroinflammation,inhibiting oxidative stress,inhibiting apoptosis,regulating mitochondrial morphology,increasing neuronal protrusions,enhancing autophagy,and regulating intestinal flora homeostasis,so as to provide new ideas for research of the mechanisms of PD and development of GLP-1RA-related new drugs.

Reappraisal of Systematic Reviews of Glucagon-like Peptide- 1 Receptor Agonist in the Treatment of Type 2 Diabetes Mellitus Based on GRADE System / 中国药房

OBJECTIVE：To reappraise systematic review/Meta-analysis （SRs/MAs）of the efficacy and safety of glucagon-like peptide 1（GLP-1）receptor agonist in the treatment of type 2 diabetes mellitus （T2DM），and to provide evidence-based reference for clinical use of these drugs in the treatment of T 2DM. METHODS ：Retireved from Cochrane library ，PubMed，Embase，CBM， Wanfang database and CNKI ，systematic review/Me ta-analysis about GLP- 1 receptor agonist in the treatment of T 2DM were collected during the inception to Dec. 2019. After data extraction of literatures met inclusion and exclusion criteria ，GRADE system was used to evaluate the quality of evidence included in the study ，and the evidence of efficacy and safety outcome indexes were summarized. RESULTS ：Finally 31 literatures were included ，involving 91 outcome indexes ，and GRADE evidence quality was medium，among which 4（4.4％）were very-low-quality ，33（36.3％）were low-quality ，45（49.5％）were medium-quality ，and 9 （9.9％）were high-quality outcome indicators. The results of evidence summary showed that GLP- 1 receptor agonists were better than or similar to placebo and other oral hypoglycemic drugs ， better than dipeptidyl peptidase 4 （DPP-4） inhibitors in . reducing the level of HbA 1c；better than or similar to placebo ， JDZX2015240） better than other oral hypoglycemic agents and DPP- 4 2276299207@qq.com inhibitors in reducing the level of fasting glucose ；similar to DDP-4 inhibitors，higher than or similar to placebo ，lower than other oral hypoglycemic dru gs in the incidence of hypoglycemia；higher than other oral hypoglycemic drugs ，placebo and DPP- 4 inhibitors in the incidence of diarrhea and nausea ； higher than other oral hypoglycemic drugs and placebo in the incidence of vomiting. CONCLUSIONS ：The evidence quality of systematic review/Meta-analysis about GLP- 1 receptor agonist in the treatment of T 2DM are moderate. These drugs have good clinical efficacy in the treatment of T 2DM，but their safety are not as good as placebo or other oral hypoglycemic drugs.

Anti-inflammatory effects of liraglutide on innate lymphoid cells in mice with inflammatory bowel disease / 上海交通大学学报（医学版）

Objective • To investigate the role and mechanism of glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide in dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD). Methods • The drinking water with DSS concentration of 3% was prepared by using DSS and sterile water, and the mice were free to drink for 7 days, to construct IBD model. The experimental mice were randomly divided into four groups with five mice in each group: the control group [drinking sterile water, intraperitoneal injection of phosphate buffered saline (PBS)], the liraglutide group (drinking sterile water, intraperitoneal injection of 0.6 mg/kg liraglutide), the model group (drinking DSS water solution, intraperitoneal injection of PBS) and the treatment group (drinking DSS water solution, intraperitoneal injection of 0.6 mg/kg liraglutide). During the experiment, the fecal morphology, body weight, and colon length were observed. And hematoxylin-eosin (H-E) staining was used to observe the degree of colitis in mice. Flow cytometry was used to detect the proportion of neutrophils and eosinophils, as well as the changes of the innate lymphoid cell (ILC) subsets and function in the colon. Results • Compared with the model group, the symptoms of loose stool and bloody stool were improved, and the shortened colon length was also improved (P=0.007) in the treatment group. H-E staining showed that the infiltration of inflammatory cells in the colon of the treatment group was significantly reduced. Flow cytometry analysis of the colonic lamina propria showed that the proportion of neutrophils in the colon of the treatment group was significantly reduced (P=0.004), and the proportion of eosinophils was also reduced (P=0.002); the proportion of ILC (ILC2) in group 2 decreased (P=0.032), but the proportion of ILC (ILC3) in group 3 increased (P=0.008); the cytokine interleukin-22 secreted by ILC3 was increased (P=0.008). Conclusion • Liraglutide may delay the development of IBD by affecting the proportion of ILC subsets and secretion function.

Efficacy and Safety of Long-acting GLP- 1 Receptor Agonist Semaglutide for Type 2 Diabetes：A Systematic Review / 中国药房

OBJECTIVE： To systematically evaluate therapeutic efficacy and safety of long-acting glucagon like peptide-1 （GLP-1） receptor agonist Semaglutide vs. placebo or other glucose-lowering drugs in the treatment of type 2 diabetes mellitus （T2DM）， and to provide evidence-based reference for T2DM in clinic. METHODS： Retrieved from PubMed， Embase， Medline， Cochrane library， randomized controlled trials （RCT） about Semaglutide （trial group） vs. placebo or other glucose-lowering drugs （control group） in the treatment of T2DM were selected during the establishment of database to Sept. 2018. After data extraction and quality evaluation with Cochrane system evaluator manual 5.1.0， Meta-analysis was performed for HbA1c level and compliance rate， fasting plasma glucose （FPG） level， systolic blood pressure （SBP）， diastolic blood pressure （DBP）， body mass index （BMI）， body weight pulse frequency level， the incidence of hypoglycemia and gastrointestinal reaction by using Rev Man 5.3 software.  RESULTS： A total of 12 RCTs involving 9 966 patients were included. The results of Meta-analysis showed that compared with control group， trial group could effectively decrease the levels of HbA1c [MD＝－1.03， 95％CI（－1.22，－0.85）， P＜0.001] and FPG [MD＝－1.14， 95％CI（－1.53，－0.76）， P＜0.001]， increase compliance rate of HbA1c [RD＝0.40， 95％CI（0.31，0.49）， P＜0.001]， reduce SBP [MD＝－2.61， 95％CI （－3.23， －1.98）， P＜0.001] and DBP [MD＝－0.56， 95％CI     （－0.96， －0.16）， P＝0.006]， decrease BMI [MD＝－1.25， 95％CI （－1.51， －0.99）， P＜0.001] and body weight [MD＝     －3.60， 95％CI（－4.24， －2.96）， P＜0.001]， increase pulse frequency [MD＝2.16， 95％CI （1.51， 2.81）， P＜0.001]. The major adverse drug reactions were gastrointestinal reaction； the incidence of gastrointestinal reaction was higher than control group [RD＝0.20， 95％CI（0.15，0.26）， P＜0.001]， but there was no statistical significance in the incidence of hypoglycemia events between 2 groups [RD＝0.00， 95％CI（－0.01，0.02）， P＝0.44]. CONCLUSIONS： Semaglutide can significantly decrease HbA1c， FPG， body weight， blood pressure and increase pulse frequency in T2DM patients， and increase the compliance rate of HbA1c. Although the incidence of gastrointestinal reaction is higher than control group， but the risk of hypoglycemia is not higher， indicating Semaglutide is well tolerated and safe.

Effect of glucagon-like peptide 1 receptor agonists on body fat redistribution and muscle mass in overweight and obese type 2 diabetic patients / 南方医科大学学报

OBJECTIVE@#To investigate the effect of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on body fat redistribution and muscle mass in overweight/obese patients with type 2 diabetes (T2DM).@*METHODS@#We retrospectively analyzed the data of 76 patients with body mass indexes (BMI)≥24 kg/m, who had an established diagnosis of T2DM in our department between December, 2014 and September, 2015. We divided these patients according to their BMI in overweight group (BMI of 24-27.9 kg/m, =14), obese group (BMI of 28-31.9 kg/m, =35) and severely obese group (BMI≥32 kg/m, =27). All the patients received treatment with GLP-1RAs (Exenatide or Liraglutide) for 3.0 to 29.0 weeks (mean 8.9 weeks), and their blood glucose, HbA1c and serum lipids were analyzed. For each patient, the fat and muscle masses were analyzed using a human body composition analyzer (JAWON-IOI353, Korea) before and after GLP-1RAs treatment.@*RESULTS@#Treatment with GLP-1RAs significantly decreased BMI and visceral adiposity index (VAI) in all the patients in the 3 groups ( < 0.05). The treatment significantly decreased the body weight in the overweight group and obese group by 2.70 kg (0.60-4.95 kg) and 2.65 kg (1.45-6.40 kg), respectively ( < 0.05), and significantly decreased the waist-to-hip ratio (WHR) in the overweight group ( < 0.05). The obese and severely obese patients showed significantly decreased percentage body fat (including both subcutaneous and visceral fat) and increased muscle mass after the treatment ( < 0.05). Compared with those in the overweight group, the percentage body fat and VAI were significantly decreased in the obese group after the treatment ( < 0.05), and the percentage of subcutaneous fat reduced and the muscle ratio increased more obviously in the obese and severely obese patients ( < 0.05).@*CONCLUSIONS@#GLP-1RAs treatment can significantly lower BMI and improve body fat distribution in obese patients with T2DM, especially in patients with a greater BMI.

Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association / 임상당뇨병

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy, which was a change from the previous guideline that recommended them only as a combination therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) have demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RAs may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA.

Cardiovascular Outcome Trials of Incretin Therapy (Dipeptidyl Peptidase-4 Inhibitors/Glucagon-Like Peptide-1 Receptor Agonist)

In 2008, the United States Food and Drug Administration issued guidance which mandated long-term cardiovascular outcome trials (CVOTs) to assess the safety of new antidiabetic drugs for type 2 diabetes. Since 2008, three CVOTs that have studied dipeptidyl peptidase-4 (DPP-4) inhibitors and four CVOTs of a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) have been reported. Each of the completed CVOTs showed the noninferiority of respective drugs to placebo for primary CV composite endpoint. Among them, liraglutide and semaglutide showed a reduction of major adverse cardiovascular events. However, the mechanisms for the observed cardiovascular differences between DPP-4 inhibitors and GLP-1RA, and across individual GLP-1RA are not clearly understood. Therefore, this review will summarize the CVOTs of the DPP-4 inhibitors and GLP-1RA, interpretation of cardioprotective results of incretin-based therapy and the possible mechanism of action.

A Meta-Analysis of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists on Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus / 中国药学杂志

OBJECTIVE: To evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: The randomized controlled trials (RCTs) of GLP- 1 RA, placebo, and anti-diabetes drugs in the treatment of NAFLD in patients with T2DM were collected from PubMed, Embase, CNKI, Wangfang database, VIP, and CBM. The trials were evaluated for the quality and selected, and the results of the studies were reviewed and analyzed using RevMan 5.2 software. RESULTS: Four RCTs were included, involving 154 patients. The Meta-analysis showed that compared with the control group, GLP-1RA could significantly improve the ALT [MD: -8.36, 95% CI(-13.41-3.31), P = 0.001], HbA1c [MD: -0.43%, 95% CI(-0.73-0.31), P = 0.005], FBG [MD: -0.71%, 95% CI(-1. 39-0.03), P = 0.04], BMI [MD: -1.38%, 95% CI(-2.18-0.58), P = 0.000 8], TG [MD: -0.49%, 95% CI(-0.82-0.16), P = 0.004]. CONCLUSION: GLP-1 RA can obviously improve the metabolic index of patients with NAFLD and T2DM. Given the quality and quantity of the literature, large RCTs are still needed in the future.

Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA.

An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans.

Comparison of glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mettilus / 中华内分泌代谢杂志

Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus.lncretin-based therapies could be classified into 2 categories with different mechanisms of action:glucagon-like peptide 1 ( GLP-1 ) receptor agonists ( e.g.liraglutide,exenatide twice daily,and exenatide once weekly),and the dipeptidyl peptidase 4 ( DPP-4 ) inhibitors ( e.g.sitagliptin,linagliptin,saxagliptin,and vildagliptin),which inhibit the breakdown of endogenous GLP-1.Both categories share some specific characteristics,such as glucose-dependent insulin stimulation and low incidence of hypoglycemia.But there are also different profiles in efficacy between these 2 classes.This article reviews the pharmacokinetics and clinical aspects of efficacy and safety of these 2 classes of incretin-based therapies and elucidates their roles in treating type 2 diabetes mellitus.

Relationship between nitric oxide release from pig iliac endothelial cells caused by Exendin-4 and change in intracellular calcium / 解放军医学杂志

Objective To study the effects of Exendin-4 (Ex-4) on the function of endothelial cells by investigating the relationship of Ex-4 induced nitric oxide (NO) release from pig iliac endothelial cells (PIEC) and changes in intracellular calcium. Methods Glucagon-like peptide-1 receptor (GLP-1R) was confirmed to be present in PIEC by immunofluorescence assay. Intracellular NO production was probed using DAF-FM DA, and then measured with fluorescence microplate reader at the timepoints of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12h. The intracellular Ca2+ concentration was probed with Fura-2 AM at 0-30min, 4-4.5h and 8-8.5h and measured with fluorescence microplate reader. The relationship between Ex-4 induced NO release in PIEC and intracellular Ca2+ concentration was evaluated. Results GLP-1R was expressed in PIEC. Ex-4 increased the intracellular NO level in PIEC in a time-dependent manner. NO level was significantly higher 4 hours after Ex-4 treatment compared with that of 0-hour group (P<0.05). The intracellular NO level reached the top value 8 hours after Ex-4 treatment (P<0.05). The intracellular Ca2+ concentrations were significantly higher during the periods of 0-30min, 4-4.5h and 8-8.5h after Ex-4 treatment than those of their control groups (2.042±2.115 vs 0.634±0.352, P<0.01; 0.413±0.154 vs 0.113±0.111, P<0.01; 0.309±0.133 vs 0.063±0.120, P<0.01). During the period of 0-30min after Ex-4 treatment, the intracellular Ca2+ concentration increased gradually (fitted curve: y=0.106x+1.326); while during the periods of 4-4.5h (y=0.003x+0.374) and 8-8.5h (y=-0.001x+0.324) after Ex-4 treatment, the intracellular Ca2+ concentrations, and the NO levels were higher than those of their control groups, but without significant variation. Conclusions Ex-4 may increase the NO release in endothelial cells, and intracellular calcium ions may participate in the process.

Relationship between nitric oxide release from pig iliac endothelial cells caused by Exendin-4 and change in intracellular calcium / 解放军医学杂志

Objective To study the effects of Exendin-4 (Ex-4) on the function of endothelial cells by investigating the relationship of Ex-4 induced nitric oxide (NO) release from pig iliac endothelial cells (PIEC) and changes in intracellular calcium. Methods Glucagon-like peptide-1 receptor (GLP-1R) was confirmed to be present in PIEC by immunofluorescence assay. Intracellular NO production was probed using DAF-FM DA, and then measured with fluorescence microplate reader at the timepoints of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12h. The intracellular Ca2+ concentration was probed with Fura-2 AM at 0-30min, 4-4.5h and 8-8.5h and measured with fluorescence microplate reader. The relationship between Ex-4 induced NO release in PIEC and intracellular Ca2+ concentration was evaluated. Results GLP-1R was expressed in PIEC. Ex-4 increased the intracellular NO level in PIEC in a time-dependent manner. NO level was significantly higher 4 hours after Ex-4 treatment compared with that of 0-hour group (P<0.05). The intracellular NO level reached the top value 8 hours after Ex-4 treatment (P<0.05). The intracellular Ca2+ concentrations were significantly higher during the periods of 0-30min, 4-4.5h and 8-8.5h after Ex-4 treatment than those of their control groups (2.042±2.115 vs 0.634±0.352, P<0.01; 0.413±0.154 vs 0.113±0.111, P<0.01; 0.309±0.133 vs 0.063±0.120, P<0.01). During the period of 0-30min after Ex-4 treatment, the intracellular Ca2+ concentration increased gradually (fitted curve: y=0.106x+1.326); while during the periods of 4-4.5h (y=0.003x+0.374) and 8-8.5h (y=-0.001x+0.324) after Ex-4 treatment, the intracellular Ca2+ concentrations, and the NO levels were higher than those of their control groups, but without significant variation. Conclusions Ex-4 may increase the NO release in endothelial cells, and intracellular calcium ions may participate in the process.