An efficient stereoselective synthesis of the rigid aza-bicyclo[3.2.0]heptane scaffold has been developed to provide 2-cyano-pyrrolidine alpha-amino amide 1 as DPP-4 inhibitor.
SGLT-2 inhibitors(SGLT-2Is)have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases,heart failure,and diabetic kidney disease.Similarly,GLP-1 receptor agonists(...SGLT-2 inhibitors(SGLT-2Is)have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases,heart failure,and diabetic kidney disease.Similarly,GLP-1 receptor agonists(GLP-1RAs)have significantly improved atherosclerotic cardiovascular outcomes.To this end,DPP-4 inhibitors(DPP-4Is)are cardiac-neutral drugs.While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is,there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is.Moreover,the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions,unlike DPP-4Is.Furthermore,the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c(8.0%-8.5%)compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c(>8.5%-9.0%).These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.展开更多
AIM: The purpose of this research was to determine the changes of the inflammatory parameters in the long term with the use of dipeptidyl peptidase-4 inhibitors. Material and Methods: In this research we have retrospe...AIM: The purpose of this research was to determine the changes of the inflammatory parameters in the long term with the use of dipeptidyl peptidase-4 inhibitors. Material and Methods: In this research we have retrospectively reviewed the records of 80 patients who had added dipeptidyl peptidase-4 inhibitors (40 sitagliptin and 40 vildagliptin) to their ongoing therapies. Patients’ values of inflammation at the beginning of this process were taken as initial values, while values at the end of this process were considered as final values. Results: A total of 80 patients [38.8% (n = 31) of the patients were male, while 61.3% (n = 49) were female] enrolled in the study. When the whole group was evaluated, the mean age was 56.1 ± 9.7 years. The median follow-up time of the patients with DPP-4 inhibitors was 18 (2 - 64) months. The mean MPV value was measured as 8.79 ± 1.71 fL before DPP-4 inhibitors and it was 10.06 ± 1.42 fL after the follow-up period (p < 0.001). The median value serum GGT was 30.5 (13 - 194) U/L before DPP-4 inhibitor and 29.5 (12 - 112) U/L at the end (p = 0.048). The mean uric acid level before the use of di-peptidyl peptidase-4 inhibitors was 4.7 ± 1.6 mg/dL, and this level was 5.0 ± 1.5 mg/dL after the follow-up period (p = 0.048). Conclusion: In this study, it was observed that MPV and GGT levels were improved by dipeptidyl peptidase-4 inhibitors in long-term.展开更多
Glucagon-like peptide-1 receptor agonists(GLP-1RAs)and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus(T2DM).Both anti-diabetic treatments function by playing ...Glucagon-like peptide-1 receptor agonists(GLP-1RAs)and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus(T2DM).Both anti-diabetic treatments function by playing key modulatory roles in the incretin system.Though these drugs have been deemed effective in treating T2DM,the Food and Drug Administration(FDA)and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints.As a result,since 2008,the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety.The present review article strives to assess the safety and benefits of incretin-based therapy,a new class of antidiabetic drug,on the health of patient cardiovascular systems.In the process,this review will also provide a physiological overview of the incretin system and how key components function in T2DM.展开更多
Objective: To investigate the effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus (T2DM). Methods: A total ...Objective: To investigate the effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 138 patients with newly diagnosed T2DM who were treated in the hospital between March 2016 and April 2017 were divided into routine group (n=69) and combined treatment group (n=69) by random number table method. Routine group were treated with metformin alone and combined treatment group received DPP-4 inhibitor combined with metformin therapy. The differences in blood glucose control as well as oxidative stress-related indicator and inflammatory factor contents were compared between the two groups before and after treatment. Results: Before treatment, the differences in blood glucose index levels in peripheral blood as well as the oxidative stress index and inflammatory mediator contents in serum were not statistically significant between the two groups. After 4 weeks of treatment, blood glucose indexes FBG and HOMA-IR levels in peripheral blood of combined treatment group were lower than those of routine group;oxidative stress indexes MDA and LHP contents in serum were lower than those of routine group whereas GSH-Px and T-AOC contents were higher than those of routine group;inflammatory mediators hs-CRP, IL-1 and IL-6 contents in serum were lower than those of routine group. Conclusion: DPP-4 inhibitor combined with metformin therapy can effectively control the blood glucose and suppress the systemic oxidative stress and inflammatory response in T2DM paients.展开更多
Objective: To study the effect of DPP-4 inhibitor combined with metformin on glucose and lipid metabolism and micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome. Metho...Objective: To study the effect of DPP-4 inhibitor combined with metformin on glucose and lipid metabolism and micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome. Methods: A total of 60 patients with type 2 diabetes mellitus complicated by metabolic syndrome who were treated in the hospital between February 2015 and December 2016 were divided into control group (n=30) and observation group (n=30) according to the random number table method. Control group received metformin therapy alone, observation group received DPP-4 inhibitor combined with metformin therapy, and the differences in levels of glucose and lipid metabolism indexes and inflammatory factors were compared between the two groups of patients before and after treatment. Results: Before treatment, the differences in glucose and lipid metabolism index levels in peripheral blood as well as inflammatory factor contents in serum were not statistically significant between the two groups. After treatment, the levels of glucose metabolism indexes FPG, FPI and HOMA-IR as well as lipid metabolism indexes TG and TC in peripheral blood of observation group were lower than those of control group while HDL-C level was higher than that of control group;the contents of inflammatory factors IL-6, CRP and TNF-α in serum were lower than those of control group. Conclusion: DPP-4 inhibitor combined with metformin therapy is more effective in controlling the glucose and lipid metabolism process and inhibiting the micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome.展开更多
Objective: To investigate the effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome. Methods: A total of 78 T2DM patients w...Objective: To investigate the effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome. Methods: A total of 78 T2DM patients with metabolic syndrome who were treated in the hospital were retrospectively analyzed and divided into the control group (n=41) who received metformin therapy and the combined group (n=37) who received metformin combined with DPP-4 inhibitor therapy, and both groups were treated for 12 weeks. The differences in micro-inflammatory state and insulin sensitivity were compared between the two groups before and after treatment. Results: There was no statistically significant difference in serum inflammatory factor contents and peripheral blood insulin sensitivity-related index levels between the two groups before treatment. After 12 weeks of treatment, serum inflammatory factors IL-1, hs-CRP and TNF-α contents of combined group were lower than those of control group;insulin sensitivity indexes FGP, FINS, ISI and HOMA-IR levels were lower than those of control group. Conclusion: metformin combined with DPP-4 inhibitor Sitagliptin can more effectively inhibit the micro-inflammatory state and improve the insulin sensitivity in T2DM patients with metabolic syndrome.展开更多
Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the thresho...Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-m TOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/m TOR pathway along with anti-apoptotic and anti-inflammatory mechanisms.Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.展开更多
Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic ...Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.展开更多
This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy(DCM)treatment by dipeptidyl peptidase-4(DPP-4)inhibitors.Zhang et al studied teneligliptin,a DPP-4 inhibitor used fo...This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy(DCM)treatment by dipeptidyl peptidase-4(DPP-4)inhibitors.Zhang et al studied teneligliptin,a DPP-4 inhibitor used for diabetes management,and its potential cardioprotective effects in a diabetic mouse model.They suggested teneligliptin administration may reverse established markers of DCM,including cardiac hypertrophy and compromised function.It also inhibited the NLRP3 inflammasome and reduced inflammatory cytokine production in diabetic mice.Macrophages play crucial roles in DCM pathogenesis.Chronic hyperglycemia disturbs the balance between pro-inflammatory(M1)and antiinflammatory(M2)macrophages,favoring a pro-inflammatory state contributing to heart damage.Here,we highlight the potential of DPP-4 inhibitors to modulate macrophage function and promote an anti-inflammatory environment.These compounds may achieve this by elevating glucagon-like peptide-1 levels and potentially inhibiting the NLRP3 inflammasome.Further studies on teneligliptin in combination with other therapies targeting different aspects of DCM could be suggested for developing more effective treatment strategies to improve cardiovascular health in diabetic patients.展开更多
文摘An efficient stereoselective synthesis of the rigid aza-bicyclo[3.2.0]heptane scaffold has been developed to provide 2-cyano-pyrrolidine alpha-amino amide 1 as DPP-4 inhibitor.
文摘SGLT-2 inhibitors(SGLT-2Is)have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases,heart failure,and diabetic kidney disease.Similarly,GLP-1 receptor agonists(GLP-1RAs)have significantly improved atherosclerotic cardiovascular outcomes.To this end,DPP-4 inhibitors(DPP-4Is)are cardiac-neutral drugs.While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is,there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is.Moreover,the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions,unlike DPP-4Is.Furthermore,the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c(8.0%-8.5%)compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c(>8.5%-9.0%).These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.
文摘AIM: The purpose of this research was to determine the changes of the inflammatory parameters in the long term with the use of dipeptidyl peptidase-4 inhibitors. Material and Methods: In this research we have retrospectively reviewed the records of 80 patients who had added dipeptidyl peptidase-4 inhibitors (40 sitagliptin and 40 vildagliptin) to their ongoing therapies. Patients’ values of inflammation at the beginning of this process were taken as initial values, while values at the end of this process were considered as final values. Results: A total of 80 patients [38.8% (n = 31) of the patients were male, while 61.3% (n = 49) were female] enrolled in the study. When the whole group was evaluated, the mean age was 56.1 ± 9.7 years. The median follow-up time of the patients with DPP-4 inhibitors was 18 (2 - 64) months. The mean MPV value was measured as 8.79 ± 1.71 fL before DPP-4 inhibitors and it was 10.06 ± 1.42 fL after the follow-up period (p < 0.001). The median value serum GGT was 30.5 (13 - 194) U/L before DPP-4 inhibitor and 29.5 (12 - 112) U/L at the end (p = 0.048). The mean uric acid level before the use of di-peptidyl peptidase-4 inhibitors was 4.7 ± 1.6 mg/dL, and this level was 5.0 ± 1.5 mg/dL after the follow-up period (p = 0.048). Conclusion: In this study, it was observed that MPV and GGT levels were improved by dipeptidyl peptidase-4 inhibitors in long-term.
基金supported by the National Natural Science Foundation of China(81974254,31870906,and 82170470)。
文摘Glucagon-like peptide-1 receptor agonists(GLP-1RAs)and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus(T2DM).Both anti-diabetic treatments function by playing key modulatory roles in the incretin system.Though these drugs have been deemed effective in treating T2DM,the Food and Drug Administration(FDA)and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints.As a result,since 2008,the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety.The present review article strives to assess the safety and benefits of incretin-based therapy,a new class of antidiabetic drug,on the health of patient cardiovascular systems.In the process,this review will also provide a physiological overview of the incretin system and how key components function in T2DM.
文摘Objective: To investigate the effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 138 patients with newly diagnosed T2DM who were treated in the hospital between March 2016 and April 2017 were divided into routine group (n=69) and combined treatment group (n=69) by random number table method. Routine group were treated with metformin alone and combined treatment group received DPP-4 inhibitor combined with metformin therapy. The differences in blood glucose control as well as oxidative stress-related indicator and inflammatory factor contents were compared between the two groups before and after treatment. Results: Before treatment, the differences in blood glucose index levels in peripheral blood as well as the oxidative stress index and inflammatory mediator contents in serum were not statistically significant between the two groups. After 4 weeks of treatment, blood glucose indexes FBG and HOMA-IR levels in peripheral blood of combined treatment group were lower than those of routine group;oxidative stress indexes MDA and LHP contents in serum were lower than those of routine group whereas GSH-Px and T-AOC contents were higher than those of routine group;inflammatory mediators hs-CRP, IL-1 and IL-6 contents in serum were lower than those of routine group. Conclusion: DPP-4 inhibitor combined with metformin therapy can effectively control the blood glucose and suppress the systemic oxidative stress and inflammatory response in T2DM paients.
文摘Objective: To study the effect of DPP-4 inhibitor combined with metformin on glucose and lipid metabolism and micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome. Methods: A total of 60 patients with type 2 diabetes mellitus complicated by metabolic syndrome who were treated in the hospital between February 2015 and December 2016 were divided into control group (n=30) and observation group (n=30) according to the random number table method. Control group received metformin therapy alone, observation group received DPP-4 inhibitor combined with metformin therapy, and the differences in levels of glucose and lipid metabolism indexes and inflammatory factors were compared between the two groups of patients before and after treatment. Results: Before treatment, the differences in glucose and lipid metabolism index levels in peripheral blood as well as inflammatory factor contents in serum were not statistically significant between the two groups. After treatment, the levels of glucose metabolism indexes FPG, FPI and HOMA-IR as well as lipid metabolism indexes TG and TC in peripheral blood of observation group were lower than those of control group while HDL-C level was higher than that of control group;the contents of inflammatory factors IL-6, CRP and TNF-α in serum were lower than those of control group. Conclusion: DPP-4 inhibitor combined with metformin therapy is more effective in controlling the glucose and lipid metabolism process and inhibiting the micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome.
文摘Objective: To investigate the effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome. Methods: A total of 78 T2DM patients with metabolic syndrome who were treated in the hospital were retrospectively analyzed and divided into the control group (n=41) who received metformin therapy and the combined group (n=37) who received metformin combined with DPP-4 inhibitor therapy, and both groups were treated for 12 weeks. The differences in micro-inflammatory state and insulin sensitivity were compared between the two groups before and after treatment. Results: There was no statistically significant difference in serum inflammatory factor contents and peripheral blood insulin sensitivity-related index levels between the two groups before treatment. After 12 weeks of treatment, serum inflammatory factors IL-1, hs-CRP and TNF-α contents of combined group were lower than those of control group;insulin sensitivity indexes FGP, FINS, ISI and HOMA-IR levels were lower than those of control group. Conclusion: metformin combined with DPP-4 inhibitor Sitagliptin can more effectively inhibit the micro-inflammatory state and improve the insulin sensitivity in T2DM patients with metabolic syndrome.
基金supported by the John E. Steinhaus Endowment fund.
文摘Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-m TOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/m TOR pathway along with anti-apoptotic and anti-inflammatory mechanisms.Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences[CIFMS](Grant Nos.2021-I2M-1-014 and 2022-I2M-2-002).
文摘Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.
文摘This editorial introduces the potential of targeting macrophage function for diabetic cardiomyopathy(DCM)treatment by dipeptidyl peptidase-4(DPP-4)inhibitors.Zhang et al studied teneligliptin,a DPP-4 inhibitor used for diabetes management,and its potential cardioprotective effects in a diabetic mouse model.They suggested teneligliptin administration may reverse established markers of DCM,including cardiac hypertrophy and compromised function.It also inhibited the NLRP3 inflammasome and reduced inflammatory cytokine production in diabetic mice.Macrophages play crucial roles in DCM pathogenesis.Chronic hyperglycemia disturbs the balance between pro-inflammatory(M1)and antiinflammatory(M2)macrophages,favoring a pro-inflammatory state contributing to heart damage.Here,we highlight the potential of DPP-4 inhibitors to modulate macrophage function and promote an anti-inflammatory environment.These compounds may achieve this by elevating glucagon-like peptide-1 levels and potentially inhibiting the NLRP3 inflammasome.Further studies on teneligliptin in combination with other therapies targeting different aspects of DCM could be suggested for developing more effective treatment strategies to improve cardiovascular health in diabetic patients.
