-
Journal of Diabetes and Its... May 2024To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D). (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Efficacy and safety of sitagliptin with basal-plus insulin regimen versus insulin alone in non-critically ill hospitalized patients with type 2 diabetes: SITA-PLUS hospital trial.
AIMS
To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D).
METHODS
This open-label, randomized clinical trial included inpatients with a previous diagnosis of T2D and blood glucose (BG) between 180 and 400 mg/dL. Participants received basal and correctional insulin doses (BP regimen) either with or without sitagliptin. The primary outcome was the difference in the mean daily BG among the groups.
RESULTS
Seventy-six patients (mean age 60 years, 64 % men) were randomized. Compared with BP insulin therapy alone, the sitagliptin-BP combination led to a lower mean daily BG (158.8 vs 175.0 mg/dL, P = 0.014), a higher percentage of readings within a BG range of 70-180 mg/dL (75.9 % vs 64.7 %, P < 0.001), and a lower number of BG readings >180 mg/dL (P < 0.001). Sitagliptin-BP resulted in fewer basal and supplementary insulin doses (P = 0.024 and P = 0.017, respectively) and lower daily insulin injections (P = 0.023) than those with insulin alone. The proportion of patients with hypoglycemia was similar in the two groups.
CONCLUSIONS
For inpatients with T2D and hyperglycemia, the sitagliptin and BP regimen combination is safe and more effective than insulin therapy alone.
CLINICALTRIALS
gov identifier: NCT05579119.
Topics: Humans; Sitagliptin Phosphate; Diabetes Mellitus, Type 2; Male; Middle Aged; Female; Aged; Hypoglycemic Agents; Drug Therapy, Combination; Blood Glucose; Insulin; Hospitalization; Treatment Outcome; Hypoglycemia
PubMed: 38581842
DOI: 10.1016/j.jdiacomp.2024.108742 -
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 -
Journal of Cardiovascular Pharmacology Jun 2024Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based...
Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for type 2 diabetes mellitus treatment as monotherapy and in combination. We aimed to study the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7-36), GLP-1 (9-36), and exendin-4 (1-39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9-39), nitro- l -arginine methyl ester hydrochloride, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.
Topics: Animals; Sitagliptin Phosphate; Glucagon-Like Peptide-1 Receptor; Male; Heart Atria; Diabetes Mellitus, Experimental; Heart Rate; Hypoglycemic Agents; Rats; Rats, Wistar; Diabetes Mellitus, Type 2; Exenatide; Incretins; Glucagon-Like Peptide 1; Pyrazines; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38547520
DOI: 10.1097/FJC.0000000000001564 -
European Journal of Clinical... Jul 2024Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal...
PURPOSE
Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.
METHODS
Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.
RESULTS
A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h vs. 5.18 h) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.
CONCLUSION
The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K value suggests that assessing renal OAT1 activity by CL has no relevant misspecification error with the cocktail doses used.
Topics: Humans; Organophosphonates; Adenine; Male; Adult; Models, Biological; Female; Organic Anion Transport Protein 1; Drug Interactions; Phenotype; Middle Aged; Young Adult; Digoxin; Metformin; Sitagliptin Phosphate; Biological Availability
PubMed: 38546841
DOI: 10.1007/s00228-024-03673-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 of Separation Science Mar 2024An analytical quality by design-based high-performance liquid chromatography method for determining metformin (MET) and sitagliptin (SIT) in stress-degraded samples was...
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 C 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 (r : 0.9982) and 5-50 μg/mL (r : 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.
Topics: Chromatography, High Pressure Liquid; Sitagliptin Phosphate; Metformin; Methanol; Phosphoric Acids
PubMed: 38466156
DOI: 10.1002/jssc.202300605 -
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 -
Diabetes Care Apr 2024We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other...
Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).
OBJECTIVE
We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments.
RESEARCH DESIGN AND METHODS
The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8-8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up.
RESULTS
Across treatments, diabetes distress (-0.24, P < 0.0001) and depressive symptoms (-0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (-0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (-0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms.
CONCLUSIONS
Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM.
Topics: Adult; Female; Humans; Middle Aged; Male; Diabetes Mellitus, Type 2; Liraglutide; Insulin Glargine; Depression; Glucagon-Like Peptide 1; Blood Glucose; Glycated Hemoglobin; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Drug Therapy, Combination; Treatment Outcome; Sulfonylurea Compounds
PubMed: 38416773
DOI: 10.2337/dc23-2459