The DPP-4 inhibitor sitagliptin improves glycaemic control and early-stage diabetic nephropathy in adolescents with type 1 diabetes using the MiniMed 780G advanced hybrid closed-loop system: a randomised controlled trial.

AIMS/HYPOTHESIS: Dipeptidyl peptidase-4 (DPP-4) inhibition has beneficial effects on various metabolic indicators in diabetes. Stromal cell-derived factor-1 (SDF-1) is expressed in diverse organs including the kidneys and is cleaved and inactivated by DPP-4 enzyme. The aim of this study was to conduct a randomised controlled trial to assess the effect of sitagliptin on diabetic nephropathy when used as an add-on therapy to the advanced hybrid closed-loop (AHCL) system in adolescents with type 1 diabetes and nephropathy. METHODS: This open-label, parallel-group, randomised controlled trial took place at the Pediatric Diabetes Clinic, Ain Shams University, Egypt. Forty-six adolescents aged 14.13 ± 2.43 years on the MiniMed 780G system for at least 6 months before study, with HbA1c ≤69 mmol/mol (8.5%) and diabetic nephropathy in the form of microalbuminuria, were randomly assigned to two groups (n=23 for each) based on a computer-generated randomisation sequence. The intervention group received oral sitagliptin 50 mg for 3 months. The other group used AHCL only and served as a control group. The primary outcome measure was the change in urinary albumin/creatinine ratio (UACR) after 3 months of administration of sitagliptin. The key secondary outcome measure was the change from baseline in SDF-1 levels after treatment. RESULTS: Data for all participants were analysed. No significant difference was found between the groups as regards baseline clinical and laboratory characteristics as well as AHCL system settings (p>0.05). Serum SDF-1 levels were higher in all individuals with type 1 diabetes vs healthy control individuals (p<0.001). After 3 months, sitagliptin resulted in a significant decrease of SDF-1 levels from 3.58 ± 0.73 to 1.99 ± 0.76 ng/ml (p<0.001), together with improvement of UACR from 7.27 ± 2.41 to 1.32 ± 0.31 mg/mmol (p<0.001). In addition, sitagliptin reduced postprandial glucose, sensor glucose, coefficient of variation and total daily dose of insulin, while time in range 3.9-10.0 mmol/l (70-180 mg/dl) and insulin-to-carbohydrate ratio were significantly increased. Sitagliptin was safe and well-tolerated without severe hypoglycaemia or diabetic ketoacidosis. CONCLUSIONS/INTERPRETATION: Sitagliptin as an add-on therapy to AHCL had a reno-protective effect for individuals with type 1 diabetes and diabetic nephropathy, in addition to the improvement of time in range while reducing glycaemic variability and without compromising safety. FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. TRIAL REGISTRATION: ClinicalTrials.gov NCT06115460.

Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes.

This study examines the impact of the combination of sitagliptin and L-theanine on the testis tissue of rats with experimental diabetes. Diabetes mellitus, a chronic metabolic illness, significantly reduces quality of life and can cause male infertility by decreasing sperm count, motility, and testosterone levels. Rats were allocated to five separate groups: control, diabetes, L-theanine, sitagliptin, and combination therapy. The measurements encompassed blood glucose levels, body weight, serum insulin levels, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The histological examination of testicular tissue was conducted using H&E, PASH, caspase-12, and PCNA staining techniques, in addition to a TUNEL assay to detect apoptosis. Levels of oxidative stress indicators, including glutathione peroxidase (GPX), malondialdehyde (MDA), and catalase, were also evaluated. The results showed that the group of individuals with diabetes had significantly higher levels of blood glucose, apoptotic indices, GPX, catalase, and MDA levels and activities in comparison with the control group. Although both the L-theanine and sitagliptin groups exhibited some improvement, the combination therapy demonstrated the most significant decrease in histopathological damage and apoptotic markers. These results indicate that the combination of sitagliptin and L-theanine may significantly decrease testicular damage caused by diabetes, making it a promising therapeutic strategy.

Miniature mass spectrometer-based point-of-care assay for quantification of metformin and sitagliptin in human blood and urine.

Metformin (MET) and sitagliptin (STG) are widely used as the first-line and long-term oral hypoglycemic agents for managing type 2 diabetes mellitus (T2DM). However, the current lack of convenient and rapid measurement methods poses a challenge for individualized management. This study developed a point-of-care (POC) assay method utilizing a miniature mass spectrometer, enabling rapid and accurate quantification of MET and STG concentrations in human blood and urine. By combining the miniature mass spectrometer with paper spray ionization, this method simplifies the process into three to four steps, requires minimal amounts of bodily fluids (50 µL of blood and 2 µL of urine), and is able to obtain quantification results within approximately 2 min. Stable isotope-labeled internal standards were employed to enhance the accuracy and stability of measurement. The MS/MS responses exhibited good linear relationship with concentration, with relative standard deviations (RSDs) below 25%. It has the potential to provide immediate treatment feedback and decision support for patients and healthcare professionals in clinical practice.

Sitagliptin synergizes 5-fluorouracil efficacy in colon cancer cells through MDR1-mediated flux impairment and down regulation of NFκB2 and p-AKT survival proteins.

5-fluorouracil (5-FU) is an inexpensive treatment for colon cancer; however, its efficacy is limited by chemoresistance. This study investigates the combination therapy approach of 5-FU with Sitagliptin (Sita), a diabetic drug with potential cancer-modulating effects. The combination was evaluated in vitro and in silico, focusing on the effects of Sita and 5-FU on colon cancer cells. The results showed that the addition of Sita significantly decreased the IC50 of 5-FU compared to 5-Fu monotherapy. The study also found that Sita and 5-FU interact synergistically, with a combination index below 1. Sita successfully lowered the 5-FU dosage reduction index, decreasing the expression of MDR1 mRNA and p-AKT and NFκB2 subunits p100/p52 protein. Molecular docking analyses confirmed Sita's antagonistic action on MDR1 and thymidylate synthase proteins. The study concludes that sitagliptin can target MDR1, increase apoptosis, and significantly reduce the expression of p-AKT and NFκB2 cell-survival proteins. These effects sensitize colon cancer cells to 5-FU. Repurposing sitagliptin may enhance the anticancer effects of 5-FU at lower dosages.

Analytical quality by design approach for the development of high-performance liquid chromatography method for simultaneous analysis of metformin and sitagliptin in the presence of major degradation products.

An analytical quality by design-based high-performance liquid chromatography method for determining metformin (MET) and sitagliptin (SIT) in stress-degraded samples was developed and validated. The analytical target profile and risk assessment-driven critical method variables, for example, pH, % aqueous, and buffer concentration, were studied for their effect on method responses of retention time and resolution using a central composite design. The correlation regression coefficient was more than 0.8, and variables interaction was significant on method responses with curvature effect. The method operable design region afforded an aqueous range of 55%-70% and an ortho-phosphoric acid buffer of 0.1% with a pH of 3.0-4.0 as a robust region for the suitable method performance characteristics. The separation of MET and SIT from their degradants (m/z 85.0509; m/z 193.0694) on the C8 column was achieved using a mobile phase consisting of 0.1% ortho-phosphoric acid and methanol (60:40% v/v; pH 3.0). The optimized method eluted MET and SIT at 4.3 ± 0.2 and 7.1 ± 0.2 min, respectively, with acceptable specificity and resolution. The linearity ranges of 25-250 µg/mL (r2 : 0.9982) and 5-50 µg/mL (r2 : 0.9989) was established for MET and SIT, respectively. The % recovery (98.81%-102.17%), precision (0.55%-1.65%), and robustness study for method variables were acceptable.

Sitagliptin Extends Lifespan of Caenorhabditis elegans by Inhibiting Insulin/Insulin-Like Signaling and Activating Dietary Restriction-Like Signaling Pathways.

INTRODUCTION: The discovery of longevity molecules that delay aging and prolong lifespan has always been a dream of humanity. Sitagliptin phosphate (SIT), an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, is an oral drug commonly used in the treatment of type 2 diabetes (T2D). In addition to being antidiabetic, previous studies have reported that SIT has shown potential to improve health. However, whether SIT plays a role in the amelioration of aging and the underlying molecular mechanism remain undetermined. METHODS: Caenorhabditis elegans (C. elegans) was used as a model of aging. Lifespan assays were performed with adult-stage worms on nematode growth medium plates containing FUdR with or without the specific concentration of SIT. The period of fast body movement, body bending rates, and pharyngeal pumping rates were recorded to assess the healthspan of C. elegans. Gene expression was confirmed by GFP fluorescence signal of transgenic worms and qPCR. In addition, the intracellular reactive oxygen species levels were measured using a free radical sensor H2DCF-DA. RESULTS: We found that SIT significantly extended lifespan and healthspan of C. elegans. Mechanistically, we found that several age-related pathways and genes were involved in SIT-induced lifespan extension. The transcription factors DAF-16/FOXO, SKN-1/NRF2, and HSF-1 played important roles in SIT-induced longevity. Moreover, our findings illustrated that SIT-induced survival benefits by inhibiting the insulin/insulin-like signaling pathway and activating the dietary restriction-related and mitochondrial function-related signaling pathways. CONCLUSION: Our work may provide a theoretical basis for the development of anti-T2D drugs as antiaging drugs, especially for the treatment of age-related disease in diabetic patients.

Preclinical Repurposing of Sitagliptin as a Drug Candidate for Colorectal Cancer by Targeting CD24/CTNNB1/SOX4-Centered Signaling Hub.

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, ß-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.

[Cardiovascular safety of sitagliptin added to metformin in real world patients with type 2 diabetes].

OBJECTIVE: To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM). METHODS: Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1, 2017 to December 31, 2022. According to drug prescription records, the patients were divided into metformin plus sitagliptin group (combination group) and metformin monotherapy group(monotherapy group). A series of retrospective cohorts were constructed according to the index date.Finally, full retrospective cohorts were constructed according to propensity score model, including baseline covariates that might be related to outcomes, to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics. The participants were followed up from the index date until the first occurrence of the following events: Diagnosis of outcomes, death, or the end of the study period (December 31, 2022). Cox proportional risk model was used to estimate the hazard ratio(HR)and 95% confidence interval (CI) of sitagliptin added to metformin on 3-point major adverse cardiovascular events (3P-MACE) combination outcome and secondary cardiovascular outcomes. RESULTS: Before propensity score matching, the proportion of the patients in combination group using insulin, α glucosidase inhibitors, sodium-glucose transporter 2 inhibitors (SGLT-2I) and glienides at baseline was higher than that in monotherapy group, and the baseline fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels in combination group were higher than those in monotherapy group. After propensity score matching, 5 416 subjects were included in the combination group and the monotherapy group, and baseline characteristics were effectively balanced between the groups. The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 person years, respectively. Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy (HR=1.00, 95% CI: 0.91-1.10). In secondary outcomes analysis, the incidence of cardiovascular death was lower in the combination group than in the monotherapy group (HR=0.59, 95% CI: 0.41-0.85), and no association was found between sitagliptin and the risk of myocardial infarction and stroke (HR=1.12, 95% CI: 0.89-1.41; HR=0.99, 95% CI: 0.91-1.12). CONCLUSION: In T2DM patients in Yinzhou district of Ningbo, compared with metformin alone, sitagliptin added to metformin may reduce the risk of cardiovascular death, and do not increase the incidence of overall cardiovascular events. The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.

Comparison of the effects of sitagliptin and dapagliflozin on time in range in Japanese patients with type 2 diabetes stratified by body mass index: A sub-analysis of the DIVERSITY-CVR study.

AIMS: To compare the effects of baseline background characteristics in patients treated with dapagliflozin and sitagliptin in the DIVERSITY-CVR study and to analyse the time in range (TIR), a metric for glycaemic control. MATERIALS AND METHODS: This prospective, randomized, multicentre study included 340 Japanese patients with early-stage type 2 diabetes. To examine the effects of dapagliflozin and sitagliptin on glycaemic variability, we re-examined the primary endpoint (glycated haemoglobin [HbA1c] < 7.0%, body weight loss ≥ 3.0%, and avoidance of hypoglycaemia) achievement rate in participants stratified by baseline background characteristics. RESULTS: Sitagliptin was significantly superior in achieving HbA1c level <7.0% in the lower body mass index (BMI) group (71.1% vs. 43.6%; P < 0.05), with no significant differences in other subgroups. In the lower BMI group, the rate of achievement of TIR > 70% after 24-week treatment was significantly higher with sitagliptin than with dapagliflozin (91.9% vs. 69.4%; P < 0.05). In contrast, dapagliflozin was superior to sitagliptin in achieving TIR > 70% in the higher BMI group (85.7% vs. 52.9%; P < 0.01). CONCLUSION: In Japanese patients with early-stage type 2 diabetes, sitagliptin was associated with improved TIR in patients with a lower BMI. Dapagliflozin was effective in patients with a higher BMI.

Vascular and metabolic effects of ipragliflozin versus sitagliptin (IVS) in type 2 diabetes treated with sulphonylurea and metformin: IVS study.

OBJECTIVE: In patients with type 2 diabetes who were inadequately controlled with metformin and sulphonylurea, we compared the glucose-lowering efficacy, cardiometabolic parameters and safety of two drugs, ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, and sitagliptin, a dipeptidyl peptidase-4 inhibitor. MATERIALS AND METHODS: Patients with 7.5%-9.0% glycated haemoglobin treated with metformin and sulphonylurea were randomly assigned to ipragliflozin (50 mg, n = 70) or sitagliptin (100 mg, n = 70) therapy for 24 weeks. Measures of glycaemic control, fatty liver indices, other metabolic parameters and subclinical atherosclerosis were compared by a paired t-test before and after 24 weeks of treatment. RESULTS: Mean glycated haemoglobin levels decreased from 8.5% to 7.5% in the ipragliflozin group and from 8.5% to 7.8% in the sitagliptin group, resulting in a 0.34% between-group difference (95% confidence interval, 0.10%-0.43%, p = .088). Fasting and postprandial 2-h glucose levels also showed a similar trend, with a greater reduction with ipragliflozin therapy. An increase of over 70% in ketone levels and a decrease in whole body and abdominal fat masses were observed with ipragliflozin treatment. Fatty liver indices also improved with ipragliflozin treatment. Despite no difference in carotid intima-media thickness and ankle-brachial index, ipragliflozin therapy improved flow-mediated vasodilation, reflecting endothelial function, while sitagliptin did not. The safety profile did not differ between the two groups. CONCLUSIONS: Ipragliflozin add-on therapy can be a viable option for better glycaemic control with multiple vascular and metabolic benefits in patients with type 2 diabetes who are inadequately controlled with metformin and sulphonylurea.

Impact of Treviamet® & Treviamet XR® on quality of life besides glycemic control in type 2 DM patients.

BACKGROUND: Maintaining the quality of life is the main objective of managing type 2 diabetes (T2DM) (QoL). Since it is a key factor in patient motivation and adherence, treatment-related QoL has always been considered when choosing glucose-lowering medicines. The objective of the study was to evaluate the quality of life besides glycemic control among type 2 diabetes mellitus patients receiving Treviamet® & Treviamet XR® (Sitagliptin with Metformin) in routine care. METHODS: It was a prospective, open-label, non-randomized clinical trial including T2DM patients uncontrolled on Metformin therapy. All patients received Treviamet® & Treviamet XR® for six months. Sequential changes in QoL, fasting plasma glucose, HbA1c, body weight, and blood pressure were monitored from baseline to 3 consecutive follow-up visits. The frequency of adverse events (AEs) was also noted throughout the study. RESULTS: A total of 504 patients were screened; 188 completed all three follow-ups. The mean QoL score significantly declined from 57.09% at baseline to 33.64% at the 3rd follow-up visit (p < 0.01). Moreover, a significant decline in mean HbA1c and FPG levels was observed from baseline to 3rd follow-up visit (p < 0.01). Minor adverse events were observed, including abdominal discomfort, nausea, flatulence, and indigestion. Gender, HbA1c, diarrhea, and abdominal discomfort were significant predictors of a patient's QoL, as revealed by the Linear Regression Model (R2 = 0.265, F(16, 99) = 2.231). CONCLUSION: Treviamet® & Treviamet XR® significantly improved glycemic control (HbA1c levels) and QoL in T2DM patients without serious adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT05167513), Date of registration: December 22, 2021.

Comparative evaluation of metformin & sitaformin in classic PCOS patients undergoing intracytoplasmic sperm injection: A randomized controlled pilot study.

Background & objectives: Studies have shown that insulin resistance and hyperinsulinaemia play a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, the use of insulin sensitizing drugs in the treatment of PCOS has attracted the attention of medicine and researchers. The aim of this study was to investigate the effects of sitaformin (sitagliptin/metformin) and metformin on the quality of oocyte and embryo in classic PCOS patients undergoing intracytoplasmic sperm injection (ICSI). Methods: Sixty patients of PCOS (25-35 yr) were randomly allocated into three groups (n=20, each group): a metformin-treated group (administered metformin 500 mg twice daily), a sitaformin-treated group (administered sitaformin 50/500 mg twice daily) and a placebo group. Participants in all the groups received the drug two months prior to the start of the ovulation cycle and treatment continued until the day of the oocyte aspiration. Results: Serum insulin and total testosterone levels decreaseed significantly after treatment in both the treatment groups as compared to the placebo (P<0.05). A significant decrease in the number of immature oocytes [MI + germinal vesicle (GV) stage] was observed in metformin and sitaformin groups as compared to the placebo. In addition, sitaformin group when compared to the metformin group showed a significant decrease in the number of immature oocytes (P<0.05). The number of mature and normal MII oocytes increased significantly in both the treatment groups compared to the placebo group (P<0.05). The number of mature and normal oocytes increased in sitaformin group in comparison to the metformin group, but the difference was not significant. There was a significant increase in the number of grade I embryos, fertilization and cleavage rates in the sitaformin group compared to the other groups (P<0.05). Interpretation & conclusions: This is the first study to compare the impact of sitaformin with metformin on oocyte and embryo quality in women with PCOS undergoing a gonadotropin-releasing hormone (GnRH) antagonist cycle. In conclusion, sitaformin can be more effective in decreasing immature oocytes and increasing the quality of embryos than the use of metformin.

DPP4 Inhibitor Sitagliptin Reduces Inflammatory Responses and Mast Cell Activation in Allergic Rhinitis.

INTRODUCTION: DPP4 is thought to be involved in certain immune processes and plays an important role in allergic reactions in the lungs. The effect of the DPP4 inhibitor sitagliptin on the effector phase of allergic rhinitis (AR) in ovalbumin (OVA)-sensitized mice and on mast cell degranulation in vitro was assessed. METHODS: The AR mouse model was established by intraperitoneal injection combined with OVA intranasal method. OVA was injected intraperitoneally 3 times for the first 2 weeks, and the mice were subsequently given DPP4 inhibitors by oral gavage, accompanied by an OVA intranasal challenge. The impacts of DPP4 inhibitors on DPP4 levels in mouse model were determined. Nasal mucosa tissue was collected for H&E staining and toluidine blue staining. Immunoglobulin E (IgE) levels and histamine levels were analyzed, and IL-4, IL-5, and IL-12 as well as IFN-γ levels were assessed. Following the treatment of dinitrophenol (DNP)-IgE or DNP-IgE plus sitagliptin in RBL-2H3 cells, ß-hexosaminidase activity was analyzed and toluidine blue staining was performed. RESULTS: DPP4 level was reduced in AR patients, as well as in AR mouse models. Nasal allergic symptoms such as sneezing and nose-scratching showed high frequency in OVA-induced mice. Sitagliptin treatment during the intranasal challenge of OVA decreased DPP4 levels, suppressed allergic symptoms, eosinophil infiltration, IgE levels, mast cell infiltration, as well as the levels of inflammatory cytokines. We further found that sitagliptin inhibited mast cell activation and histamine levels in vitro. CONCLUSION: Sitagliptin suppresses the effector phase of AR, and this mechanism is partly attributed to the suppression of inflammatory response and mast cell degranulation.

A new application of isoindole fluorophore derivative in sitagliptin antidiabetic medication assay: Application to dosage forms and biological fluid evaluation.

Dipeptidyl peptidase-4 enzyme suppressant is a unique category of oral antidiabetic medication. Sitagliptin (STG) is a perfect member of this category and is pharmaceutically marketed alone or in combination with metformin. Here, the ideal application of an isoindole derivative for STG assay was developed using a feasible, easy-to-use, economic, and affordable method. STG as an amino group donor can form a luminescent derivative: isoindole on interaction with o-phthalaldehyde and the existence of (2-mercaptoethanol) 0.02% (v/v) as a thiol group donor. Excitation (339.7 nm) and emission (434.6 nm) wavelengths were used to monitor the isoindole fluorophore yield; moreover, each experimental variable was carefully investigated and adjusted. The calibration graph was constructed by plotting fluorescence intensities against STG concentrations, and controlled linearity was observed at concentrations ranging from 50 to 1000 ng/ml. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines were analyzed in depth to prove the technique validation. The implementation of the present technique was extended successfully to the evaluation of various types of STG dose forms and spiking samples of human plasma and urine. The developed technique was shown to be an effective, simple, and quick replacement for quality control and clinical study evaluation of STG.

Environmentally friendly protocol for the determination of sitagliptin phosphate in pharmaceutical preparations and biological fluids using l-tyrosine as a fluorescence probe.

A responsive spectrofluorometric method was developed for the determination of sitagliptin phosphate using l-tyrosine as a fluorescence probe. The fluorescence intensity of l-tyrosine was quenched with sitagliptin phosphate. The fluorescence intensity was recorded at 307 nm using a 272 nm excitation wavelength. The calibration plot between fluorescence intensity and the concentration of drug was linear in the range of 0.1 to 2.0 mM with a good correlation value of 0.997. The limit of detection and quantification were established to be 3.7 × 10-4 and 1.23 × 10-3  mM, respectively. Commonly used excipients did not interfere with sitagliptin phosphate measurement. The proposed method was used to measure the sitagliptin phosphate in its standard type, dosage form, and biological samples. The percent recovery ranged from 97.41-103.36%. The static quenching was shown to be responsible for quenching as indicated by the Stern-Volmer plot. The method was validated using ICH guidelines and profitably applied for the content uniformity test, resulting in a high percent recovery and small relative standard deviation. The proposed approach is effortless, susceptible, selective, economic, and provides a high precision and accuracy, and can be used to determine sitagliptin phosphate in the pharmaceutical industry.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Antidiabetic Drug Sitagliptin with Divalent Transition Metals Manganese and Cobalt: Synthesis, Structure, Characterization Antibacterial and Antioxidative Effects in Liver Tissues.

Metals and their complexes have an increasing number of medical applications. Sitagliptin (STG) acts as an antidiabetic drug. Mn(II) and Co(II) complexes were studied and characterized based on physical characterization, FT-IR, DG/TG, XRD, ESM, and TEM. Data revealed that STG acts as a bidentate ligand through the oxygen atom of a carbonyl group and the nitrogen atom of an amino group. Magnetic measurement data revealed that the Mn/STG metal complex has a square planner geometry. The experiment was performed on 40 male albino rats who were divided into four groups: the control group, STG group, group treated with STG/Mn, and group treated with Co/STG. Biomarkers for hepatic enzymes and antioxidants were found in the blood, and hepatic tissue histology was evaluated. STG in combination with Mn and Co administration showed potent protective effects against hepatic biochemical alterations induced by STG alone, as well as suppressing oxidative stress and structural alterations. These complexes prevented any stress and improved hepatic enzymatic levels more than STG alone. The STG/Mn complex was highly effective against Bacillus subtilis and Streptococcus pneumonia, while STG/Co was highly effective against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureas. Therefore, STG combined with Mn and Co produced a synergistic effect against oxidative stress and improved the histological structure of the liver tissues. STG metal complexes with Mn and Co showed the most potential ameliorative antioxidant and hepatoprotective effects.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Regulation of Adropin by Sitagliptin monotherapy in participants with newly diagnosed type 2 Diabetes.

BACKGROUND: Adropin is a potent metabolic regulator of insulin sensitivity and glycolipid metabolism. The present study investigated the effects of sitagliptin on adropin and metabolic parameters in participants with newly diagnosed type 2 diabetes (T2D). METHODS: Thirty-five participants newly-diagnosed with T2D were prescribed sitagliptin 100 mg once daily for 17 weeks. Twenty-eight age-, sex-, and BMI-matched healthy subjects were included as the control group. Adropin and clinical parameters were assessed at baseline and after treatment. RESULTS: At baseline, serum adropin levels were lower in T2D participants than in the healthy individuals (3.12 ± 0.73 vs. 5.90 ± 1.22 ng/ml, P <  0.01). Serum adropin levels were significantly higher in T2D patients after sitagliptin treatment (4.97 ± 1.01 vs. 3.12 ± 0.73 ng/ml, P <  0.01). The changes in serum adropin levels after sitagliptin treatment were associated with the improvements of fasting blood glucose (FBG) (ß = - 0.71, P <  0.01), glycosylated hemoglobin (HbA1c) (ß = - 0.44, P <  0.01) and homeostatic model assessment of ß-cell function (HOMA-ß) (ß = 9.02, P <  0.01). CONCLUSIONS: Sitagliptin treatment could significantly increase serum adropin levels in participants with newly diagnosed T2D. The increase in serum adropin levels could be associated with the amelioration of glucose metabolism, which might be involved in beneficial glucose-lowering mechanisms of sitagliptin. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04495881 . Retrospectively registered on 03/08/2020.

Sitagliptin and Narrow-Band Ultraviolet-B for Moderate Psoriasis (DINUP): A Randomised Controlled Clinical Trial.

BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. OBJECTIVE: We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. METHODS: In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. RESULTS: A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5-11.6). At 24 weeks, the mean difference from baseline in PASI (-1.0 [95% CI -2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (-2.5 [95% CI -4.0 to -1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0-0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. CONCLUSION: Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.