Hyperglycemia Management In Patients With Posttransplantation Diabetes

Objective: Posttransplantation diabetes (PTDM) is a common occurrence after solid-organ transplantation and is associated with increased morbidity, mortality, and health care costs. There is a limited number of studies addressing strategies for hyperglycemia management in this population, with a few articles emerging recently.Methods: We performed a PubMed search of studies published in English addressing hyperglycemia management of PTDM/new-onset diabetes after transplant (NODAT). Relevant cited articles were also retrieved.Results: Most of the 25 publications eligible for review were retrospective studies. Insulin therapy during the early posttransplantation period showed promise in preventing PTDM development. Thiazolidinediones have been mostly shown to exert glycemic control in retrospective studies, at the expense of weight gain and fluid retention. Evidence with metformin, sulfonylureas, and meglitinides is very limited. Incretins have shown promising results in small prospective studies using sitagliptin, linaglitpin, and vildagliptin and a case series using liraglutide.Conclusion: Prospective randomized studies assessing the management of hyperglycemia in PTDM are urgently needed. In the meantime, clinicians need to be aware of the high risk of PTDM and associated complications and current concepts in management.Abbreviations:A1c = glycated hemoglobin A1cCHF = congestive heart failureCNI = calcineurin inhibitorsCS = corticosteroidsDM = diabetes mellitusDPP-4 = dipeptidyl peptidase-4GLP-1 = glucagon-like peptide-1ICU = intensive care unitIGT = impaired glucose toleranceNODAT = new-onset diabetes after transplantationOGTT = oral glucose tolerance testPTDM = posttransplantation diabetesSU = sulfonylureaT2DM = type 2 diabetes mellitusTZD = thiazolidinedione     

The Rationale for use of Incretins in the Management of new Onset Diabetes After Transplantation (NODAT)

Objective: Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed.Methods: The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia.Results: Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation.Conclusion: Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.Abbreviations: CNI = calcineurin inhibitor DPP-4 = dipeptidyl peptidase 4 GLP-1 = glucagon-like peptide-1 HbA1c = glycated hemoglobin HLA = human leukocyte antigen NODAT = new onset diabetes after transplantation     

Safety And Efficacy Of Dpp-4 Inhibitors For The Management Of Hospitalized General Medicine And Surgery Patients with Type 2 Diabetes

Objective: DPP-4 inhibitors (DPP-4i) have been shown to be effective for the management of inpatient diabetes. We report pooled data from 3 prospective studies using DPP-4i in general medicine and surgery patients with type 2 diabetes (T2D).Methods: We combined data from 3 randomized studies comparing DPP-4i alone or in combination with basal insulin or a basal-bolus insulin regimen. Medicine (n = 266) and surgery (n = 319) patients admitted with a blood glucose (BG) between 140 and 400 mg/dL, treated with diet, oral agents, or low-dose insulin therapy were included. Patients received DPP-4i alone (n = 144), DPP-4i plus basal insulin (n = 158) or basal-bolus regimen (n = 283). All groups received correctional doses with rapid-acting insulin for BG >140 mg/dL. The primary endpoint was differences in mean daily BG between groups. Secondary endpoints included differences in hypoglycemia and hospital complications.Results: There were no differences in mean hospital daily BG among patients treated with DPP-4i alone (170 ± 37 mg/dL), DPP-4i plus basal (172 ± 42 mg/dL), or basalbolus (172 ± 43 mg/dL), P = .94; or in the percentage of BG readings within target of 70 to 180 mg/dL (63 ± 32%, 60 ± 31%, and 64 ± 28%, respectively; P = .42). There were no differences in length of stay or complications, but hypoglycemia was less common with DPP-4i alone (2%) compared to DPP-4i plus basal (9%) and basal-bolus (10%); P = .004.Conclusion: Treatment with DPP-4i alone or in combination with basal insulin is effective and results in a lower incidence of hypoglycemia compared to a basal-bolus insulin regimen in general medicine and surgery patients with T2D.Abbreviations: BG = blood glucose; BMI = body mass index; CI = confidence interval; DPP-4i = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; OR = odds ratio; T2D = type 2 diabetes     

Dpp4 Inhibitor Sitagliptin As A Potential Treatment Option In Metformin-Intolerant Obese Women With Polycystic Ovary Syndrome: A Pilot Randomized Study

Objective: Metformin has an established role in the management of polycystic ovary syndrome (PCOS). Some patients cannot tolerate it due to associated gastrointestinal adverse events. The present study evaluated the dipeptidyl peptidase 4 inhibitor sitagliptin as a potential treatment option in metformin-intolerant PCOS.Methods: We conducted a 12-week, prospective, randomized, open-label study with 30 obese metformin-intolerant women with PCOS (age 35.0 ± 7.2 years; body mass index, 36.9 ± 5.5 kg/m²). After metformin withdrawal, they were randomized to lifestyle intervention and sitagliptin 100 mg daily (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric and endocrine measurements and oral glucose tolerance testing. Model-derived indexes of insulin resistance and beta-cell function were calculated.Results: SITA improved beta-cell function as assessed by the homeostasis model assessment for beta-cell function index (HOMA-B) of 45.9 ± 35.8 (P = .001), modified beta-cell function index (MBCI) of 7.9 ± 7 (P = .002), and quantitative insulin-sensitivity check index (QUICKI) of -0.03 ± 0.03 (P = .002). By contrast, beta-cell function decreased in CON. The between-group differences were significant for HOMA-B (P = 0.001), MBCI (P = .010), and QUICKI (P = .025). The conversion rate to impaired glucose homeostasis was prevented in SITA: 3 of 15 subjects had impaired glucose tolerance (IGT) before and after the study. In CON, none had type 2 diabetes (T2D), and 4 had IGT at the beginning. After 12 weeks, IGT was observed in 2 and T2D in 3 subjects.Conclusion: SITA improved beta-cell function and prevented a conversion to IGT and T2D in metformin-intolerant obese PCOS patients.Abbreviations: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; DXA = dual energy X-ray absorptiometry; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HOMA-B = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment of insulin resistance; IAI = insulin action index; IGT = impaired glucose tolerance; IR = insulin resistance; MBCI = modified beta-cell function index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index; PCOS = polycystic ovary syndrome; SHBG = sex hormone–binding globulin; T2D = type 2 diabetes     

Design,synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors

Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model. From this, best 25 derivatives were docked onto the active site of DPP-4 enzyme and in silico ADMET properties were also predicted. Finally, top 17 derivatives were synthesized and characterized using FT-IR, Mass, ¹H NMR and ¹³C NMR spectroscopy. Purity of compounds was checked using HPLC. These derivatives were then evaluated for in vitro DPP-4 inhibition. The most promising compound 15q showed 28.05 μM DPP-4 IC₅₀ with 8–10-fold selectivity over DPP-8 and DPP-9 so selected for further in vivo anti-diabetic evaluation. During OGTT in normal C57BL/6J mice, compound 15q reduced blood glucose excursion in a dose-dependent manner. Chronic treatment for 28 days with compound 15q improved the serum glucose levels in type 2 diabetic Sprague Dawley rats wherein diabetes was induced by high fat diet and low dose streptozotocin. This suggested that compound 15q is a moderately potent and selective hit molecule which can be further optimized structurally to increase the efficacy and overall pharmacological profile as DPP-4 inhibitor.     

Effect of Sitagliptin on Post-Prandial Glucagon and GLP-1 Levels in Patients With Type 1 Diabetes: Investigator-Initiated,Double-Blind,Randomized, Placebo-Controlled Trial

ObjectivePeripheral insulin resistance in type 1 diabetes may be related to a paradoxical postprandial glucagon increase. This study evaluated the effects of sitagliptin (dipeptidyl peptidase-IV [DPP-IV] inhibitor, approved for patients with type 2 diabetes), in adults with type 1 diabetes to improve glycemic control through decreasing postprandial glucagon.MethodsThis investigator-initiated, double-blind, randomized-parallel 20-week study enrolled 141 subjects. Subjects received sitagliptin 100 mg/day or placebo for 16 weeks. A subset of 85 patients wore blinded continuous glucose monitors (CGM) for 5 separate 7-day periods. The primary outcome was post-meal (Boost™) reduction in 4-hour glucagon area under the curve (AUC). Secondary endpoints included changes in glycated hemoglobin (A1c), CGM data, insulin dose, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and C-peptide levels.ResultsThere were no differences at screening between groups; however, after a 4-week run-in phase, A1c was significantly lower in the sitagliptin vs. placebo group. Post-meal GLP-1 levels were higher (P<.001) and GIP levels lower (P = .03), with glucagon suppression at 30 minutes (LS means 23.2 ± 1.9 versus 16.0 ± 1.8; P = .006) in the sitagliptin group at 16 weeks. There were no differences between the groups in change in A1c, insulin dose, weight, or C-peptide after 16 weeks of treatment. However, C-peptide positive patients randomized to sitagliplin had a non-significant trend toward decrease in A1c, mean glucose, and time spent in hyperglycemia.ConclusionSitagliptin use in type 1 diabetes did not change glucagon AUC, A1c, insulin dose, or weight despite post-meal rise in GLP-1 levels. C-peptide positive subjects treated with sitagliptin had a nonsignificant trend in decreasing hyperglycemia, which needs further evaluation. (Endocr Pract. 2013;19:19-28)     

Design,synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors

A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC₅₀ values of 64.47?nM, 188.7?nM and 65.36?nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure–activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.     

(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design,synthesis, biological evaluation,and molecular modeling

A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC₅₀s of 0.07, 0.07, 0.14, and 0.17 μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F = 96.3%, t_1/2 = 10.5 h).     

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.     

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

Background

In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.

Methods

The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.

Results

Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.

Conclusions

In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.     

Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice

Incretin therapy has emerged as one of the most popular medications for type 2 diabetes. We have previously reported that the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin attenuates neointima formation after vascular injury in non-diabetic mice. In the present study, we examined whether combined treatment with linagliptin and the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates neointima formation in diabetic mice after vascular injury. Diabetic db/db mice were treated with 3 mg/kg/day linagliptin and/or 30 mg/kg/day empagliflozin from 5 to 10 weeks of age. Body weight was significantly decreased by empagliflozin and the combined treatment. Blood glucose levels and glucose tolerance test results were significantly improved by empagliflozin and the combined treatment, but not by linagliptin. An insulin tolerance test suggested that linagliptin and empagliflozin did not improve insulin sensitivity. In a model of guidewire-induced femoral artery injury in diabetic mice, neointima formation was significantly decreased in mice subjected to combined treatment. In an in vitro assay using rat aortic smooth muscle cells (RASMC), 100, 500, or 1000 nM empagliflozin significantly decreased the RASMC number in a dose-dependent manner. A further significant reduction in RASMC proliferation was observed after combined treatment with 10 nM linagliptin and 100 nM empagliflozin. These data suggest that combined treatment with the DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice in vivo and smooth muscle cell proliferation in vitro.     

Reduction of serum FABP4 level by sitagliptin,a DPP-4 inhibitor,in patients with type 2 diabetes mellitus

Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4.     

Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC₅₀ = 0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4 = 1324; DPP-9/DPP-4 = 1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.     

Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.     

Synthesis,nitric oxide release,and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC₅₀ value of 0.060?μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.     

Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors

A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC₅₀ values in 3.79–25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC₅₀ value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.     

The Emerging Role Of Adjunctive Noninsulin Antihyperglycemic Therapy In The Management Of Type 1 Diabetes

Objective: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.Methods: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term “type 1 diabetes” and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.Results: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.Conclusion: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.Abbreviations:A1C = glycated hemoglobinBMI = body mass indexCI = confidence intervalDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase 4GLP-1 = glucagonlike peptide 1PYY = polypeptide tyrosine tyrosineSGLT = sodium-glucose cotransporterSGLT1 = sodium-glucose cotransporter 1SGLT2 = sodium-glucose cotransporter 2T1D = type 1 diabetesT2D = type 2 diabetesTDD = total daily dosage     

The Efficacy and Safety of Co-Administration of Sitagliptin With Metformin in Patients With Type 2 Diabetes at Hospital Discharge

Objective: Few randomized controlled trials have focused on the optimal management of patients with type 2 diabetes (T2D) during the transition from the inpatient to outpatient setting. This multicenter open-label study explored a discharge strategy based on admission hemoglobin A1c (HbA1c) to guide therapy in general medicine and surgery patients with T2D.Methods: Patients with HbA1c ≤7% (53 mmol/mol) were discharged on sitagliptin and metformin; patients with HbA1c between 7 and 9% (53–75 mmol/mol) and those >9% (75 mmol/mol) were discharged on sitagliptinmetformin with glargine U-100 at 50% or 80% of the hospital daily dose. The primary outcome was change in HbA1c at 3 and 6 months after discharge.Results: Mean HbA1c on admission for the entire cohort (N = 253) was 8.70 ± 2.3% and decreased to 7.30 ± 1.5% and 7.30 ± 1.7% at 3 and 6 months (P<.001). Patients with HbA1c <7% went from 6.3 ± 0.5% to 6.3 ± 0.80% and 6.2 ± 1.0% at 3 and 6 months. Patients with HbA1c between 7 and 9% had a reduction from 8.0 ± 0.6% to 7.3 ± 1.1% and 7.3 ± 1.3%, and those with HbA1c >9% from 11.3 ± 1.7% to 8.0 ± 1.8% and 8.0 ± 2.0% at 3 and 6 months after discharge (both P<.001). Clinically significant hypoglycemia (<54 mg/dL) was observed in 4%, 4%, and 7% among patients with a HbA1c <7%, 7 to 9%, and >9%, while a glucose <40 mg/dL was reported in <1% in all groups.Conclusion: The proposed HbA1c-based hospital discharge algorithm using a combination of sitagliptin-metformin was safe and significantly improved glycemic control after hospital discharge in general medicine and surgery patients with T2D.Abbreviations: BG = blood glucose; DPP-4 = dipeptidyl peptidase-4; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; T2D = type 2 diabetes