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Clinical and Translational Science May 2024DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic...
DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.
Topics: Humans; Sitagliptin Phosphate; Male; Female; Glucose Tolerance Test; Adult; Insulin; Insulin Secretion; Blood Glucose; Young Adult; Dipeptidyl-Peptidase IV Inhibitors; Pilot Projects; Healthy Volunteers; Glucagon-Like Peptide 1; Middle Aged; Sex Factors
PubMed: 38700326
DOI: 10.1111/cts.13809 -
Frontiers in Endocrinology 2024Blood glycosylated hemoglobin level can be affected by various factors in patients with type 2 diabetes and cardiovascular diseases. Frequent measurements are expensive,...
UNLABELLED
Blood glycosylated hemoglobin level can be affected by various factors in patients with type 2 diabetes and cardiovascular diseases. Frequent measurements are expensive, and a suitable estimation method could improve treatment outcomes.
PATIENTS AND METHODS
93 patients were recruited in this research. We analyzed a number of parameters such as age, glucose level, blood pressure, Body Mass Index, cholesterol level, echocardiography et al. Patients were prescribed metformin. One group (n=60) additionally was taking sitagliptin. We applied eight machine learning methods (k nearest neighbors, Random Forest, Support Vector Machine, Extra Trees, XGBoost, Linear Regression including Lasso, and ElasticNet) to predict exact values of glycosylated hemoglobin in two years.
RESULTS
We applied a feature selection approach using step-by-step removal of them, Linear Regression on remaining features, and Pearson's correlation coefficient on the validation set. As a result, we got four different subsets for each group. We compared all eight Machine Learning methods using different hyperparameters on validation sets and chose the best models. We tested the best models on the external testing set and got R = 0.88, C Index = 0.857, Accuracy = 0.846, and MAE (Mean Absolute Error) = 0.65 for the first group, R = 0.86, C Index = 0.80, Accuracy = 0.75, and MAE = 0.41 for the second group.
CONCLUSION
The resulting algorithms could be used to assist clinical decision-making on prescribing anti-diabetic medications in pursuit of achieving glycemic control.
Topics: Humans; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Cardiovascular Diseases; Metformin; Sitagliptin Phosphate
PubMed: 38638138
DOI: 10.3389/fendo.2024.1305640 -
Acta Dermato-venereologica Apr 2024Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors...
Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.
Topics: Humans; Dipeptidyl-Peptidase IV Inhibitors; Vildagliptin; Pemphigoid, Bullous; Diabetes Mellitus, Type 2; Linagliptin; Retrospective Studies; Sodium Potassium Chloride Symporter Inhibitors; Risk Factors; Sitagliptin Phosphate; Dementia
PubMed: 38576104
DOI: 10.2340/actadv.v104.26663 -
Scientific Reports Mar 2024Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA....
Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.
Topics: Rats; Animals; Male; Cyclosporine; NF-kappa B; Catalase; Tumor Necrosis Factor-alpha; bcl-2-Associated X Protein; Hesperidin; NF-E2-Related Factor 2; Rats, Wistar; Sitagliptin Phosphate; Creatinine; Kidney Diseases; Kidney; Oxidative Stress; Renal Insufficiency; Glutathione; Urea; Superoxide Dismutase; Glucose
PubMed: 38548778
DOI: 10.1038/s41598-024-57300-x -
Frontiers in Endocrinology 2024To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients.
MATERIALS AND METHODS
32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix.
RESULTS
Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-E model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V), and V increased with the increase of TBIL.
CONCLUSIONS
Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; C-Peptide; Blood Glucose; Sitagliptin Phosphate; Glucagon-Like Peptide 1; Insulin
PubMed: 38529396
DOI: 10.3389/fendo.2024.1359407 -
Physiological Reports Mar 2024Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap...
Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.
Topics: Swine; Humans; Animals; Dipeptidyl-Peptidase IV Inhibitors; Proteome; Oxidative Phosphorylation; Sitagliptin Phosphate; Proteomics; Myocardium; Myocardial Ischemia; Hypoglycemic Agents; Disease Models, Animal
PubMed: 38472161
DOI: 10.14814/phy2.15976 -
Journal For Immunotherapy of Cancer Mar 2024Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate...
BACKGROUND
Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy.
METHODS
We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo.
RESULTS
Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery.
CONCLUSIONS
Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.
Topics: Mice; Animals; Humans; Dipeptidyl Peptidase 4; Dendritic Cells; Sitagliptin Phosphate; Diabetes Mellitus, Type 2; Neoplasms; Antigen Presentation; Antineoplastic Agents
PubMed: 38458637
DOI: 10.1136/jitc-2023-008254 -
Cardiovascular Diabetology Feb 2024SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters.
METHODS
This is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20-74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120-399 mg/dL (1.35-4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment.
RESULTS
Ipragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin.
CONCLUSIONS
While ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.
Topics: Adult; Aged; Humans; Middle Aged; Young Adult; Apolipoproteins; Apolipoproteins E; Blood Glucose; Diabetes Mellitus, Type 2; Glucosides; Glycated Hemoglobin; Hypoglycemic Agents; Sitagliptin Phosphate; Thiophenes
PubMed: 38331780
DOI: 10.1186/s12933-024-02149-7 -
Diabetes & Metabolism Journal Mar 2024We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2...
BACKGRUOUND
We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus.
METHODS
We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months.
RESULTS
After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of β-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis.
CONCLUSION
Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.
Topics: Humans; Diabetes Mellitus, Type 2; Metformin; Sitagliptin Phosphate; Glycated Hemoglobin; Sodium-Glucose Transporter 2 Inhibitors; Albuminuria; Blood Glucose; Treatment Outcome; Benzhydryl Compounds; Glucosides
PubMed: 38273791
DOI: 10.4093/dmj.2023.0128 -
International Journal of Molecular... Jan 2024Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells...
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 / expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating + cancer-associated fibroblasts (CAFs), suggesting that the /-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the /-centered signaling, , and . Emerging evidence indicates that plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted /-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.
Topics: Humans; Sitagliptin Phosphate; Dipeptidyl Peptidase 4; Drug Repositioning; Molecular Docking Simulation; beta Catenin; Colorectal Neoplasms; Tumor Microenvironment; SOXC Transcription Factors; CD24 Antigen
PubMed: 38203779
DOI: 10.3390/ijms25010609