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 th...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.展开更多
Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, t...Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.展开更多
GLP-1 receptor agonists are approved for the treatment of type 2 diabetes, and more recently for obesity treatment. The glucagon-like-peptide-1 (GLP-1) is a glucose dependent hormone produced by intestinal cells,...GLP-1 receptor agonists are approved for the treatment of type 2 diabetes, and more recently for obesity treatment. The glucagon-like-peptide-1 (GLP-1) is a glucose dependent hormone produced by intestinal cells, which is involved in insulin secretion and glucagon suppression. This hormone controls glucose plasma levels and reduces food intake. Additional effects were reported in slowing gastric emptying and in inducing satiety. In clinical practice, theGLP-1 receptor agonists are associated with significant reductions in glycosylated hemoglobin (HbA1c) and weight loss, despite showing a low risk of hypoglycemia. Beneficial effects have also been observed on blood pressure and lipid profile. The most common side effects associated with GLP-1 receptor agonists are gastro-intestinal motility disorders, such as nausea, vomiting and diarrhea, which are not associated with long-term health risks. Therefore, GLP-1 receptor agonists represent a relevant medication for type 2 diabetes, whose benefits may go far beyond glycemic control.展开更多
Aim: To assess the safety and efficacy of basal-supported prandial GLP-1 receptor agonist therapy (BPT)* in type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM, who had previously received insulin injection t...Aim: To assess the safety and efficacy of basal-supported prandial GLP-1 receptor agonist therapy (BPT)* in type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM, who had previously received insulin injection therapy and who had had their treatment switched to BPT (liraglutide), were retrospectively recruited. The efficacy of BPT was assessed by determining changes in HbA1c, body weight and total daily insulin dose from baseline to 4 months after BPT initiation. Safety was assessed by comparing the frequency of hypoglycemic episodes at baseline and after 4 months. The Wilcoxon test was used to analyze changes in parameters throughout the study period. Results: Twenty-nine patients, previously treated with basal-supported oral therapy (BOT), basal-bolus insulin, or pre-mixed insulin, were recruited. When analyzed together, there was no change in HbA1c throughout the study period, but body weight decreased (baseline 68.8 ± 13.2 kg vs. month 4 67.3 ± 13.1 kg;p < 0.001). Total daily insulin dose decreased after 4 months (baseline 24.4 ± 15.5 U/day vs. month 4 14.7 ± 9.2 U/day;p < 0.001), and there was no change in the frequency of hypoglycemic episodes. Analysis was conducted within sub-groups based on previous treatment modality. In the BOT group, HbA1c decreased from baseline after 2 months and body weight did not change throughout the study period. In both the basal-bolus insulin group and the pre-mixed insulin group, HbA1c remained steady throughout and there was a decrease in body weight. No change in the frequency of hypoglycemia was observed in any of the sub-groups. Conclusion: BPT in T2DM was associated with weight loss without changes in glycemic control over 4 months, suggesting that it may be an effective and safe therapy.展开更多
Glucagon-like peptide-1(GLP-1)promotes insulin secretion,inhibits glucagon secretion,and repairs pancreatic islet cell function to enhance islet cell proliferation and regeneration.Furthermore,it includes a mechanism ...Glucagon-like peptide-1(GLP-1)promotes insulin secretion,inhibits glucagon secretion,and repairs pancreatic islet cell function to enhance islet cell proliferation and regeneration.Furthermore,it includes a mechanism for weight loss and angiocarpy protection.This study covers the comparison of GLP-1 agonists with DPP-4 inhibitors and GLT-2 inhibitors,the mechanism of GLP-1 agonists,and its research possibilities based on a summary of current clinical tests of GLP-1 receptor agonists.展开更多
Glucagon peptide-like 1（GLP-1）and GLP-1 receptor（GLP-1R）：GLP-1 is an incretin hormone secreted from gut L cells.GLP-1 exerts its action through binding to its specific receptor,GLP-1R,which is a member of the G p...Glucagon peptide-like 1（GLP-1）and GLP-1 receptor（GLP-1R）：GLP-1 is an incretin hormone secreted from gut L cells.GLP-1 exerts its action through binding to its specific receptor,GLP-1R,which is a member of the G protein-coupled receptor superfamily.GLP-1R is reportedly expressed in various organs,such as the liver,kidney,and peripheral tissues.展开更多
Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucag...Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)>14 days)compared to t_(1/2)(<1 day)of GLP-1 in the blood plasma and in vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.展开更多
Incretins are gut-produced peptide-hormones that potentiate insulin secretion,especially after food intake.The concept of incretin was formed more than 100 years ago,even before insulin was isolated and utilized in th...Incretins are gut-produced peptide-hormones that potentiate insulin secretion,especially after food intake.The concept of incretin was formed more than 100 years ago,even before insulin was isolated and utilized in the treatment of subjects with type 1 diabetes.The first incretin,glucose-dependent insulinotropic polypeptide(GIP),was identified during later 1960’s and early 1970’s;while the second one,known as glucagon-like peptide-1(GLP-1),was recognized during 1980’s.Today,GLP-1-based therapeutic agents[also known as GLP-1 receptor(GLP-1R)agonists,GLP-1RAs]are among the first line drugs for type 2 diabetes.In addition to serving as incretin,extra-pancreatic functions of GLP-1RAs have been broadly recognized,including those in the liver,despite the absence of GLP-1R in hepatic tissue.The existence of insulin-independent or gut-pancreas-liver axis-independent hepatic function of GLP-1RAs explains why those therapeutic agents are effective in subjects with insulin resistance and their profound effect on lipid homeostasis.Following a brief review on the discovery of GLP-1,we reviewed literature on the exploration of hepatic function of GLP-1 and GLP-1RAs and discussed recent studies on the role of hepatic hormone fibroblast growth factor 21(FGF21)in mediating function of GLP-1RAs in animal models.This was followed by presenting our perspective views.展开更多
文摘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.
基金Supported by the Natural Science Foundation of China(81172971,81222043)the Program for New Century Excellent Talents in University(NECT11-0170)+2 种基金the Municiple Key Technology Program of Wuhan(Wuhan Bureau of Science & Technology,201260523174)the Clinical Research Foundation of the Health Bureau of Wuhan(WX12B06)the Natural Science Foundation of Hubei Province(2013CFB359)
文摘Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.
文摘GLP-1 receptor agonists are approved for the treatment of type 2 diabetes, and more recently for obesity treatment. The glucagon-like-peptide-1 (GLP-1) is a glucose dependent hormone produced by intestinal cells, which is involved in insulin secretion and glucagon suppression. This hormone controls glucose plasma levels and reduces food intake. Additional effects were reported in slowing gastric emptying and in inducing satiety. In clinical practice, theGLP-1 receptor agonists are associated with significant reductions in glycosylated hemoglobin (HbA1c) and weight loss, despite showing a low risk of hypoglycemia. Beneficial effects have also been observed on blood pressure and lipid profile. The most common side effects associated with GLP-1 receptor agonists are gastro-intestinal motility disorders, such as nausea, vomiting and diarrhea, which are not associated with long-term health risks. Therefore, GLP-1 receptor agonists represent a relevant medication for type 2 diabetes, whose benefits may go far beyond glycemic control.
文摘Aim: To assess the safety and efficacy of basal-supported prandial GLP-1 receptor agonist therapy (BPT)* in type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM, who had previously received insulin injection therapy and who had had their treatment switched to BPT (liraglutide), were retrospectively recruited. The efficacy of BPT was assessed by determining changes in HbA1c, body weight and total daily insulin dose from baseline to 4 months after BPT initiation. Safety was assessed by comparing the frequency of hypoglycemic episodes at baseline and after 4 months. The Wilcoxon test was used to analyze changes in parameters throughout the study period. Results: Twenty-nine patients, previously treated with basal-supported oral therapy (BOT), basal-bolus insulin, or pre-mixed insulin, were recruited. When analyzed together, there was no change in HbA1c throughout the study period, but body weight decreased (baseline 68.8 ± 13.2 kg vs. month 4 67.3 ± 13.1 kg;p < 0.001). Total daily insulin dose decreased after 4 months (baseline 24.4 ± 15.5 U/day vs. month 4 14.7 ± 9.2 U/day;p < 0.001), and there was no change in the frequency of hypoglycemic episodes. Analysis was conducted within sub-groups based on previous treatment modality. In the BOT group, HbA1c decreased from baseline after 2 months and body weight did not change throughout the study period. In both the basal-bolus insulin group and the pre-mixed insulin group, HbA1c remained steady throughout and there was a decrease in body weight. No change in the frequency of hypoglycemia was observed in any of the sub-groups. Conclusion: BPT in T2DM was associated with weight loss without changes in glycemic control over 4 months, suggesting that it may be an effective and safe therapy.
文摘Glucagon-like peptide-1(GLP-1)promotes insulin secretion,inhibits glucagon secretion,and repairs pancreatic islet cell function to enhance islet cell proliferation and regeneration.Furthermore,it includes a mechanism for weight loss and angiocarpy protection.This study covers the comparison of GLP-1 agonists with DPP-4 inhibitors and GLT-2 inhibitors,the mechanism of GLP-1 agonists,and its research possibilities based on a summary of current clinical tests of GLP-1 receptor agonists.
基金supported financially by a research grant from National Research Foundation of Korea(NRF-2010-0023627)
文摘Glucagon peptide-like 1（GLP-1）and GLP-1 receptor（GLP-1R）：GLP-1 is an incretin hormone secreted from gut L cells.GLP-1 exerts its action through binding to its specific receptor,GLP-1R,which is a member of the G protein-coupled receptor superfamily.GLP-1R is reportedly expressed in various organs,such as the liver,kidney,and peripheral tissues.
基金supported by NIH R01AI152416(to Jianfeng Cai,USA)NIH R01 AG056569(to Jianfeng Cai,USA)。
文摘Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)>14 days)compared to t_(1/2)(<1 day)of GLP-1 in the blood plasma and in vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.
基金supported by the Canadian Institute of Health Research (PJT159735 to T.J.).
文摘Incretins are gut-produced peptide-hormones that potentiate insulin secretion,especially after food intake.The concept of incretin was formed more than 100 years ago,even before insulin was isolated and utilized in the treatment of subjects with type 1 diabetes.The first incretin,glucose-dependent insulinotropic polypeptide(GIP),was identified during later 1960’s and early 1970’s;while the second one,known as glucagon-like peptide-1(GLP-1),was recognized during 1980’s.Today,GLP-1-based therapeutic agents[also known as GLP-1 receptor(GLP-1R)agonists,GLP-1RAs]are among the first line drugs for type 2 diabetes.In addition to serving as incretin,extra-pancreatic functions of GLP-1RAs have been broadly recognized,including those in the liver,despite the absence of GLP-1R in hepatic tissue.The existence of insulin-independent or gut-pancreas-liver axis-independent hepatic function of GLP-1RAs explains why those therapeutic agents are effective in subjects with insulin resistance and their profound effect on lipid homeostasis.Following a brief review on the discovery of GLP-1,we reviewed literature on the exploration of hepatic function of GLP-1 and GLP-1RAs and discussed recent studies on the role of hepatic hormone fibroblast growth factor 21(FGF21)in mediating function of GLP-1RAs in animal models.This was followed by presenting our perspective views.
