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Journal of Pharmaceutical Sciences Feb 2024The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier...
Solid-State Phase Transformation of Monohydrate and Anhydrous Form II of Sitagliptin Phosphate into a Novel Anhydrous Form IV - Solvent-Driven, Temperature-Induced and Stress Testings.
The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time.
Topics: Temperature; Solvents; Sitagliptin Phosphate; X-Ray Diffraction; Spectroscopy, Fourier Transform Infrared; Ethanol; Calorimetry, Differential Scanning
PubMed: 37972890
DOI: 10.1016/j.xphs.2023.11.007 -
Gerontology 2024The discovery of longevity molecules that delay aging and prolong lifespan has always been a dream of humanity. Sitagliptin phosphate (SIT), an oral dipeptidyl...
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.
Topics: Animals; Humans; Caenorhabditis elegans; Longevity; Insulin; Caenorhabditis elegans Proteins; Sitagliptin Phosphate; Diabetes Mellitus, Type 2; Signal Transduction; Forkhead Transcription Factors; Oxidative Stress
PubMed: 37952525
DOI: 10.1159/000534863 -
BMC Endocrine Disorders Nov 2023Maintaining 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,... (Clinical Trial)
Clinical Trial
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.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Quality of Life; Glycated Hemoglobin; Glycemic Control; Prospective Studies; Blood Glucose; Metformin; Sitagliptin Phosphate; Drug Therapy, Combination
PubMed: 37940936
DOI: 10.1186/s12902-023-01492-2 -
Diabetes, Obesity & Metabolism Feb 2024To assess how long participants with type 2 diabetes spent with HbA1c less than 7.0% and how likely they were to maintain this target with oral semaglutide 7 mg...
AIM
To assess how long participants with type 2 diabetes spent with HbA1c less than 7.0% and how likely they were to maintain this target with oral semaglutide 7 mg versus sitagliptin 100 mg or oral semaglutide 14 mg versus empagliflozin 25 mg, sitagliptin 100 mg or subcutaneous liraglutide 1.8 mg.
MATERIALS AND METHODS
Analyses used on-treatment data without rescue medication for all randomized participants (semaglutide [approved maintenance doses], n = 1880; comparators [not including placebo], n = 1412). Duration of time with HbA1c less than 7.0% was calculated using an HbA1c time curve. A binary endpoint of achieving HbA1c less than 7.0% at weeks 26 (week 24 for PIONEER 7) and 52 of each trial (and week 78 for PIONEER 3) was analysed.
RESULTS
Mean duration of time with HbA1c less than 7.0% was greater with oral semaglutide 7 mg versus sitagliptin in PIONEER 3 (27 vs. 22 weeks) and with oral semaglutide 14 mg versus empagliflozin and sitagliptin (27-34 vs. 19 vs. 22 weeks, respectively), and similar versus subcutaneous liraglutide. A greater proportion of participants achieved and maintained HbA1c less than 7.0% for more than 75% of the trial with oral semaglutide 14 mg versus oral comparators. The odds of achieving HbA1c less than 7.0% at weeks 24/26 and 52/78 were significantly greater with oral semaglutide 14 mg versus oral comparators or subcutaneous liraglutide, and with oral semaglutide 7 mg versus sitagliptin.
CONCLUSIONS
Oral semaglutide 7 and 14 mg resulted in greater time spent with HbA1c less than 7.0%, and a greater likelihood of achieving and maintaining HbA1c less than 7.0% versus oral comparators.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glycated Hemoglobin; Liraglutide; Glucagon-Like Peptides; Sitagliptin Phosphate
PubMed: 37935463
DOI: 10.1111/dom.15339 -
Clinical Drug Investigation Dec 2023Dipeptidyl peptidase-4 inhibitors have limited efficacy in improving glycemic control for obese Japanese patients with type 2 diabetes mellitus. Sodium-glucose...
Efficacy and Safety of Switching from Sitagliptin to Ipragliflozin in Obese Japanese Patients with Type 2 Diabetes Mellitus: A Single-Arm Multicenter Interventional Study.
BACKGROUND
Dipeptidyl peptidase-4 inhibitors have limited efficacy in improving glycemic control for obese Japanese patients with type 2 diabetes mellitus. Sodium-glucose co-transporter 2 inhibitors are recommended for use in patients with type 2 diabetes with obesity. Nevertheless, there has been no previously published study on the effect of switching from dipeptidyl peptidase-4 inhibitors to sodium-glucose co-transporter 2 inhibitors on the systemic and organic effects in obese Japanese patients with type 2 diabetes.
OBJECTIVES
We evaluated the efficacy and safety of switching from sitagliptin to ipragliflozin for 24 weeks in obese Japanese patients with inadequately controlled type 2 diabetes.
METHODS
Fifty-one obese patients with type 2 diabetes (body mass index > 25 kg/m) treated with sitagliptin (50 mg) and metformin but with inadequate glycemic control (glycosylated hemoglobin [HbA1c] > 7.5% and < 9.0%) were enrolled. After a 4-week observation period, sitagliptin was switched to ipragliflozin (50 mg) for 24 weeks. The primary outcome was the change in HbA1c from baseline to the end of treatment. The secondary outcomes were changes in clinical characteristics and other biochemical variables.
RESULTS
Fifty-one patients with an average HbA1c of 8.37 ± 0.48% and body mass index of 28.8 ± 3.8 kg/m were enrolled. Fifty patients completed the study, one patient stopped ipragliflozin at 4 weeks because of the development of hyperosmolar hyperglycemic syndrome. No significant change in HbA1c from baseline to the end of treatment was observed (- 0.02 ± 0.75%). However, fasting plasma glucose was reduced (- 16.2 ± 28.4 mg/dL, p < 0.001), and biochemical variables associated with insulin resistance, oxidative stress, and hepatic and renal functions showed significant improvements. No severe adverse effects were observed, except in the one aforementioned case.
CONCLUSIONS
Switching from sitagliptin to ipragliflozin did not alter HbA1c in obese patients with type 2 diabetes, while improving parameters related to organ homeostasis. These data provide novel information useful for selecting oral anti-diabetic agents for patients with type 2 diabetes with obesity, a risk factor for developing various complications of diabetes.
CLINICAL TRIAL REGISTRATION
Japan Registry of Clinical Trials identifier: jRCT#031190022.
Topics: Humans; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; East Asian People; Glycated Hemoglobin; Hypoglycemic Agents; Metformin; Obesity; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Drug Substitution
PubMed: 37934351
DOI: 10.1007/s40261-023-01317-z -
Diabetes Jan 2024Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1.
ARTICLE HIGHLIGHTS
Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
Topics: Humans; Liraglutide; Insulin Resistance; Glucagon-Like Peptide-1 Receptor; Dipeptidyl Peptidase 4; Glucagon; Prediabetic State; Diet, Reducing; Cross-Over Studies; Obesity; Blood Glucose; Hypoglycemic Agents; Sitagliptin Phosphate; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Weight Loss
PubMed: 37874653
DOI: 10.2337/db23-0356 -
Journal of Diabetes Feb 2024To evaluate the glycemic control effects of vhiglitazar (carfloglitazar), a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2...
BACKGROUND
To evaluate the glycemic control effects of vhiglitazar (carfloglitazar), a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes mellitus (T2DM) with metabolic syndrome (MetS) or insulin resistance (IR) using pooled data analysis of two phase III clinical trials.
METHODS
Data were collected from two randomized phase III clinical trials in China, comparing chiglitazar to placebo or sitagliptin in T2DM patients. The MetS was defined by the Adult Treatment Panel III MetS criteria, and IR was defined by homeostatic model assessment for insulin resistance (HOMA-IR) ≥4.31 (male) or 4.51 (female). The main end point of this analysis was glycemic control in the different arms within each subgroup.
RESULTS
In the MetS subgroup, changes in glycated hemoglobin (HbA1c) from baseline at week 24 in the chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg arms were -1.44%, -1.68%, and -1.37%, respectively; p < .05 was obtained when chiglitazar 48 mg was compared with sitagliptin. In the IR subgroup, the changes in HbA1c were -1.58%, -1.56%, and -1.26% in chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg arms, respectively; p < .05 was obtained when chiglitazar 32 mg was compared with sitaligptin. The two doses of chiglitazar demonstrated a greater reduction in fasting plasma glucose and 2 h postprandial plasma glucose than sitagliptin in the pooled population and in the MetS and IR subgroups.
CONCLUSIONS
Chiglitazar shows promising efficacy for glycemic control in patients with T2DM associated with MetS or IR. Further prospective trials are required to validate these findings.
Topics: Adult; Humans; Male; Female; Diabetes Mellitus, Type 2; Metabolic Syndrome; Insulin Resistance; Glycated Hemoglobin; Blood Glucose; Glycemic Control; Hypoglycemic Agents; Sitagliptin Phosphate; Carbazoles; Propionates
PubMed: 37853916
DOI: 10.1111/1753-0407.13484 -
Scientific Reports Oct 2023The solubility of an anti-hyperglycemic agent drug, (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)...
The solubility of an anti-hyperglycemic agent drug, (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl) butan-2-amine (also known as Sitagliptin phosphate) in supercritical carbon dioxide (scCO) was determined by ananalytical and dynamic technique at different temperatures (308, 318, 328 and 338 K) and pressure (12-30 MPa) values. The measured solubilities were in the range of 3.02 × 10 to 5.17 × 10, 2.71 × 10 to 5.83 × 10, 2.39 × 10 to 6.51 × 10 and 2.07 × 10 to 6.98 × 10 in mole fraction at (308, 318, 328 and 338) K, respectively. The solubility data were correlated with existing density models and with a new association model.
PubMed: 37845347
DOI: 10.1038/s41598-023-44787-z -
Advances in Medical Sciences Sep 2023Dipeptidyl peptidase 4 (DPP) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP) by DPP directly...
PURPOSE
Dipeptidyl peptidase 4 (DPP) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP) by DPP directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP using in silico approaches.
MATERIALS AND METHODS
Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP-sitagliptin complex was visualized with Pymol software.
RESULTS
The best affinity energy to form the DPP-sitagliptin complex was E-value = - 8.1 kcal mol, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr and Val, hydrogen bonds (Glu, Glu, Tyr, and Tyr), π-Stacking interactions (Phe and Tyr), and halogenic bonds (Arg, Glu, and Arg) were prevalent in the DPP-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP did not have a significant change in its topology, even after the formation of the DPP-sitagliptin complex.
CONCLUSION
The stable interaction between the sitagliptin ligand and the DPP enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP inhibitors.
Topics: Humans; Sitagliptin Phosphate; Molecular Docking Simulation; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Peptides; Diabetes Mellitus, Type 2
PubMed: 37837799
DOI: 10.1016/j.advms.2023.10.002 -
International Journal of Biological... Dec 2023The application of (R)-ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by inadequate stereoselectivity and narrow substrate spectrum....
The application of (R)-ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by inadequate stereoselectivity and narrow substrate spectrum. Herein, an effective evolution strategy for (R)-ω-transaminase designing for the asymmetric synthesis of sitagliptin intermediate is presented. Since natural transaminases lack activity toward bulky prositagliptin ketone, transaminase scaffolds with catalytic machinery and activity toward the truncated prositagliptin ketone were firstly screened based on substrate walking principle. A transaminase chimera was established synchronously conferring catalytic activity and (R)-selectivity toward prositagliptin ketone through motif swapping, followed by stepwise evolution. The process resulted in a "best" engineered variant MwTA, which exhibited 79.2-fold higher activity than the chimeric scaffold MwTA. Structural analysis revealed that the heightened activity is mainly due to the enlarged and adaptive substrate pocket and tunnel. The novel (R)-transaminase exhibited unsatisfied industrial operation stability, which is expected to further modify the protein to enhance its tolerance to temperature, pH, and organic solvents to meet sustainable industrial demands. This study underscores a useful evolution strategy of engineering biocatalysts to confer new properties and functions on enzymes for synthesizing high-value drug intermediates.
Topics: Transaminases; Sitagliptin Phosphate; Catalytic Domain; Catalysis; Ketones; Substrate Specificity; Amines
PubMed: 37820904
DOI: 10.1016/j.ijbiomac.2023.127348