Macrophage modulation with dipeptidyl peptidase-4 inhibitors:A new frontier for treating diabetic cardiomyopathy?

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.

DPP-4 inhibitors and GLP-1RAs:cardiovascular safety and benefits

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.

Dipeptidyl Peptidase-4 Inhibitors and Inflammation: Dpp-4 Inhibitors Improve Mean Pleatelet Volume and Gamma Glutamyl Transferase Level

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.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins(or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins(or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use(utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

MK-0626,a selective DPP-4 inhibitor,attenuates hepatic steatosis in ob/ob mice

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors:A meta-analysis of cardiovascular outcome trials

BACKGROUND Dipeptidyl peptidase-4(DPP-4)inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus(T2DM).Recently,a series of large,randomized controlled trials(RCTs)addressing cardiovascular outcomes with DPP-4 inhibitors have been published.AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias.METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020.We extracted data concerning the following“hard”efficacy outcomes:fatal and non-fatal myocardial infarction,fatal and non-fatal stroke,hospitalization for heart failure,hospitalization for unstable angina,hospitalization for coronary revascularization and cardiovascular death.We also extracted data regarding the risk for major cardiac arrhythmias,such as atrial fibrillation,atrial flutter,ventricular fibrillation and ventricular tachycardia.RESULTS We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo.DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction[risk ratio(RR)=1.02,95%CI:0.94-1.11,I2=0%],hospitalization for heart failure(RR=1.09,95%CI:0.92-1.29,I2=65%)and cardiovascular death(RR=1.02,95%CI:0.93-1.11,I2=0%).DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke(RR=0.96,95%CI:0.85-1.08,I2=0%)and coronary revascularization(RR=0.99,95%CI:0.90-1.09,I2=0%),Finally,DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina(RR=1.00,95%CI:0.85-1.18,I2=0%).As far as cardiac arrhythmias are concerned,DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation(RR=0.95,95%CI:0.78-1.17,I2=0%),while they were associated with a significant increase in the risk for atrial flutter,equal to 52%(RR=1.52,95%CI:1.03-2.24,I2=0%).DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias.CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM,while they do not seem to be associated with a significant risk for any major cardiac arrhythmias,except for atrial flutter.Therefore,this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors,except for those cases when newer antidiabetics(glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors)are not tolerated,contraindicated or not affordable for the patient.

Design and synthesis of DPP-4 inhibitor for the treatment of type 2 diabetes

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.

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases:Current evidence

Dipeptidyl peptidase-4 inhibitors(DPP-4i)have an important place in the management of type 2 diabetes.The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions.DPP-4 regulates several immune functions,including T-cell activation,macrophage function,and secretion of cytokines.Studies have reported an increase in autoimmune diseases like bullous pemphigoid,inflammatory bowel disease,and arthritis with DPP-4i use.The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly.Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue.Nevertheless,a heightened awareness from the clinicians is required to identify and treat any such diseases.Through this review,we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.

Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors

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.

Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and metaanalysis of randomized trials

AIM: To systematically assess risk of pancreatic adverse events with glucagon-like peptide-1(GLP-1) receptor agonist and dipeptidyl peptidase-4(DPP-4) inhibitor drugs.METHODS: We searched Pub Med, Embase, CINAHL, Cochrane review of clinical trials, pharmaceutical company clinical trials register, United States Food and Drug Administration website, European Medicines Agency website and Clinical Trials.gov for randomized controlled trials from inception to October 2013. Randomized control trial studies were selected for inclusion if they reported on pancreatic complication events and/or changes in pancreatic enzyme levels(serum amylase and serum lipase) as adverse events or as serious adverse events for patients who were on GLP-1 receptor agonist and DPP-4 inhibitor drugs. Two independent reviewers extracted data directly. We performed Peto odds ratio(OR) fixed effect meta-analysis of pancreatic adverse events a, and assessed heterogeneity with the I^2 statistic.RESULTS: Sixty-eight randomized controlled trials were eligible. A total of 60720 patients were included in our analysis of the association of risk of pancreatic complication events with GLP-1 agents. A total of 89 pancreatic related adverse events occurred among the GLP-1 agents compared to 74 events among the controls. There was a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1 agents compared with control(Peto OR = 3.15, 95%CI: 1.56-6.39, P = 0.001, I2 = 0%). There was no statistically significant difference in the risk of pancreatic adverse event associated with GLP-1 agent compared with controls(Peto OR = 1.00, 95%CI: 0.73-1.37, P = 1.00, I2 = 0%). There were a total of 71 pancreatitis events in patients on GLP-1 agents and 56 pancreatitis events occurred in the control patients. There were 36 reports of pancreatic cancer in these studies. Of these cases, 2 used linagliptin, 2 used alogliptin, 1 used vildagliptin, 7 used saxagliptin while 6 used sitagliptin. The remaining 18 cases occurred among controls.CONCLUSION: Although GLP-1 based agents are associated with pancreatic enzyme elevation, we were unable to confirm a significant risk of pancreatitis or pancreatic cancer.

Effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus

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.

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

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.

Efficacy of omarigliptin,once-weekly dipeptidyl peptidase-4 inhibitor,in patients with type 2 diabetes

BACKGROUND Omarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors(DPP-4is).Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice,data regarding its efficacy in patients with type 2 diabetes(T2D)after switching are limited.AIM To analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents.METHODS Forty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is:switched from linagliptin,switched from sitagliptin,and switched from vildagliptin.During a 3-mo follow-up,the clinical parameters among these groups were assessed and compared,with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups.RESULTS Hemoglobin A1c levels saw a significant decrease of-0.32%±0.41%in the add-on group(P=0.002).However,the other groups’variables depended on the preswitch daily DPP-4i:switched from linagliptin,-0.05%±0.22%;switched from sitagliptin,-0.17%±0.33%;and switched from vildagliptin,0.45%±0.42%,which saw significant worsening(P=0.0007).Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control(P=0.0013).The mean and standard deviation of sensor glucose value,the mean amplitude of glycemic excursions,and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin.However,in patients switched from vildagliptin,not only did the glucose variability indices see no improvements,the mean of daily difference even underwent significant worsening.CONCLUSION Administering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin,but not vildagliptin,improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

Effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome

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.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

DPP-4 Inhibitor Linagliptin is Neuroprotective in Hyperglycemic Mice with Stroke via the AKT/mTOR Pathway and Anti-apoptotic Effects

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.

Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy

Background: Treatment with the dipeptidyl peptidase-4 inhibitors (DPP4i) and angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy (DN) has not been well characterized. This study aimed to assess the renoprotection of this combined treatment in DN patients.Methods: A total of 159 type 2 DN patients from 2013 to 2015 were enrolled retrospectively from a prospective DN cohort at the National Clinical Research Center of Kidney Diseases, Jinling Hospital (China). Fifty-seven patients received DPP4i and ARB treatment, and 102 patients were treated with ARBs alone. All patients were followed up for at least 12 months. Statistical analyses were performed using Stata version 12.0.Results: There were no significant differences at baseline for age, sex, body mass index, duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) between the two groups. Antihypertensive and antidiabetic medication use was similar in each group except calcium channel antagonists (P = 0.032). No significant changes in FBG and HbA1c were observed in the two groups after treatment. The eGFR decreased slower in the DPP4i + ARB group than in the ARB group at 12 months (?12 months: -2.48 ± 13.86 vs. -6.81 ± 12.52 ml·min–1·1.73m–2,P = 0.044). In addition, proteinuria was decreased further in the DPP4i + ARB group than in the ARB group after 24 months of treatment (?24 months: -0.18 [-1.00, 0.17] vs. 0.32 [-0.35, 0.88],P = 0.031). There were 36 patients with an eGFR decrease of more than 30% over 24 months. After adjusting for FBG, HbA1c, and other risk factors, DPP4i + ARB treatment was still associated with a reduced incidence of an eGFR decrease of 20% or 30%.Conclusions: The combined treatment of DPP4i and ARBs is superior to ARBs alone, as evidenced by the greater proteinuria reduction and lower eGFR decline. In addition, the renoprotection of DPP4i combined with ARBs was independent of glycemic control.

Synthesis and biological evaluation of piperazine derivatives on dipeptidyl peptidase-4

A series of （4-（2,4,5-trifluorophenyl）piperazin-1-yl） methanone derivatives 9a–k as potential dipeptidyl peptidase-4 （DPP-4） inhibitors were synthesized by microwave assisted nucleophilic substitution of 1,2,4,5-tetrafluorobenzene with piperazine, followed by carbamoylation and condensation. The inhibitory activities of these new compounds on DPP-4 were evaluated in vitro, and compounds 9d and 9g showed moderate inhibitory activities.

二肽基肽酶4抑制剂西格列汀对胰岛基质细胞衍生因子1α降解及胰岛β细胞再生的影响

目的探讨二肽基肽酶4(DPP-4)抑制剂西格列汀对基质细胞衍生因子1α(SDF-1α)降解及胰岛β细胞再生的影响。方法将高脂-小剂量STZ糖尿病模型大鼠分为糖尿病模型组与西格列汀组,正常大鼠为健康对照(NC)组,给药12周后测量FPG、FIns、胰腺DPP-4、SDF-1α、胰岛β细胞增殖、细胞骨髓瘤(C-myc)mRNA和细胞周期蛋白D1(CyclinD1)mRNA。结果治疗后与NC组比较,糖尿病模型组FPG[(5.0±0.4)vs(26.8±3.6)mmol/L]、DPP-4[(14.63±2.19)vs(17.51±2.11)]、SDF-Iα[(2.84±1.97)vs(6.23±1.85)]升高,FIns[(24.9±7.4)vs(9.1±3.2)mU/L]降低(P<0.05);与糖尿病模型组比较,西格列汀组FPG[(26.8±3.6)vs(10.8±5.4)mmol/L]、DPP-4[(17.51±2.11)vs(9.33±2.21)]降低,FIns[(9.1±3.2)讲(16.7±6.5)mU/L]、SDF-1α[(6.23±1.85)vs(11.38±2.02)]增高(P<0.05);NC组增殖细胞核抗原(PCNA)弱表达,糖尿病模型组PCNA弱阳性表达,西格列汀组PCNA强阳性表达;与NC组比较,糖尿病模型组和西格列汀组C-myc mRNA[(I.0±0.2)讲(1.5±0.6)vs(3.7±1.1)]和CyclinD1 mRNA[(1.0±0.3)vs(1.7±0.5)vs(4.0±0.7)]均升高(P<0.05)。结论DPP-4抑制剂西格列汀可抑制DPP-4酶活性而阻滞SDF-1α降解,提高WNT信号通路靶基因C-myc与Cyclin D1 mRNA表达,促使胰岛β细胞增殖再生。

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin(including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies.