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PloS One 2022Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used orally in conjunction with diet and exercise to control sugar levels in type 2 Diabetes Mellitus...
Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used orally in conjunction with diet and exercise to control sugar levels in type 2 Diabetes Mellitus patients. This study aimed to extemporaneously prepare SiP solution (1% w/v) using pure Sitagliptin phosphate (SiP) powder and assess its stability according to pharmaceutical regulatory guidelines. Four SiP solutions, coded T1, T2, T3, and T4, were extemporaneously prepared using pure SiP powder as a source of API. The most suitable one, in terms of general organoleptic properties, was selected for further investigations, including stability studies. For this last purpose, samples of the T4 solution were kept under two storage conditions, room temperature (25˚C and 60% Relative Humidity) and accelerated stability conditions (40˚C and 75% Relative Humidity). Assay, pH, organoleptic properties, related substances, and microbial contamination were evaluated for 4 consecutive weeks. A High-Performance Liquid Chromatography (HPLC) analytical method was developed and validated to be used for the analysis and quantification of SiP in selected solution formulation. The adopted formula had a pH on the average of 3 to 4. During the stability tests, all pH values remained constant. Furthermore, after 4 weeks of storage under both conditions, the SiP concentration was close to 100%. A stable SiP extemporaneous solution was successfully prepared using pure SiP powder. Patients with swallowing problems who use feeding tubes and are unable to take oral solid dosage forms may benefit from this research. Community pharmacists can prepare the solution using sitagliptin powder as the source of the active ingredient.
Topics: Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Drug Compounding; Drug Stability; Drug Storage; Humans; Powders; Sitagliptin Phosphate
PubMed: 35294449
DOI: 10.1371/journal.pone.0262068 -
Diabetes, Obesity & Metabolism Feb 2023To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial.
AIM
To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms.
MATERIALS AND METHODS
Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR).
RESULTS
Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1).
CONCLUSION
Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.
Topics: Humans; Incretins; Liraglutide; Plasminogen Activator Inhibitor 1; Prediabetic State; Fibrinolysis; Insulin Resistance; Diet, Reducing; Obesity; Hypoglycemic Agents; Sitagliptin Phosphate; Weight Loss; Inflammation; Glucagon-Like Peptide-1 Receptor
PubMed: 36306151
DOI: 10.1111/dom.14903 -
Clinical and Molecular Hepatology Sep 2018
Topics: Blood Glucose; Humans; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate; Synbiotics
PubMed: 30196651
DOI: 10.3350/cmh.2018.1006 -
Frontiers in Endocrinology 2022Type 2 diabetes is more common in adults, but is becoming the major concern in children and adolescent recently. This study aimed to provide additional pharmaceutical... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Type 2 diabetes is more common in adults, but is becoming the major concern in children and adolescent recently. This study aimed to provide additional pharmaceutical management for children and adolescents with type 2 diabetes by assessing the efficacy and safety of several glucose-lowering drugs.
METHODS
Searches were performed in PubMed, Medline, Ovid, Cochrane Controlled Register of Trials (CENTRAL), and ClinicalTrials.gov that reported the efficacy and safety of drugs for children and adolescents with type 2 diabetes. Pooled effects were calculated by frequentist fixed effects network meta-analyses and additive network meta-analyses.
RESULTS
A total of 12 trials assessing eight glucose-lowering drugs were included, which compose of seven trials with monotherapy and five trials with combination therapies. Network meta-analysis results showed compared to placebo, saxagliptin+metformin (mean difference (MD) -1.91% [-2.85%, -0.97%]), liraglutide+metformin (MD -1.45% [-1.65%, -1.26%]), and liraglutide (MD -0.90% [-1.35%, -0.45%]) were the top 3 drugs that significantly reduced hemoglobin A1c (HbA1c). Sitagliptin+metformin, dapagliflozin, exenatide-2mcg, linagliptin-5mg, metformin, exenatide-5/10mcg, glimepiride, and sitagliptin also showed significant reduction in HbA1c. There were no significant differences between treatments in the incidence of adverse events, except that liraglutide+metformin had significant adverse effect such as abdominal pain. In addition, dapagliflozin, sitagliptin+metformin, and saxagliptin+metformin showed better efficacy compared with FDA-approved drugs.
CONCLUSIONS
The top 10 treatments of type 2 diabetes in children and adolescents aged 10-17 years were saxagliptin+metformin, liraglutide+metformin, liraglutide, dapagliflozin, exenatide-2 mcg, sitagliptin+metformin, linagliptin-5 mg, linagliptin-1 mg, metformin, and exenatide-5/10 mcg.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=284897, identifier CRD42021284897.
Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 2; Exenatide; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Metformin; Network Meta-Analysis; Sitagliptin Phosphate
PubMed: 36034458
DOI: 10.3389/fendo.2022.897776 -
Annals of Medicine 2023The emergence of genetically-modified human proteins and glucagon-like peptide-1 (GLP-1) receptor agonists have presented a promising strategy for effectively managing... (Meta-Analysis)
Meta-Analysis
Comparative efficacy and safety profile of once-weekly Semaglutide versus once-daily Sitagliptin as an add-on to metformin in patients with type 2 diabetes: a systematic review and meta-analysis.
BACKGROUND
The emergence of genetically-modified human proteins and glucagon-like peptide-1 (GLP-1) receptor agonists have presented a promising strategy for effectively managing diabetes. Due to the scarcity of clinical trials focusing on the safety and efficacy of semaglutide as an adjunctive treatment for patients with type 2 diabetes who had inadequate glycemic control with metformin, we conducted a systematic review and meta-analysis. This was necessary to fill the gap and provide a comprehensive assessment of semaglutide compared to sitagliptin, a commonly prescribed DPP-4 inhibitor, in this patient population.
METHODS
A comprehensive and systematic search was carried out on reputable databases including PubMed, the Cochrane Library, and Elsevier's ScienceDirect to identify relevant studies that compared the efficacy of once-weekly Semaglutide with once-daily Sitagliptin in individuals diagnosed with type 2 diabetes mellitus. The analysis of the gathered data was performed utilizing the random-effects model, which considers both within-study and between-study variations.
RESULTS
The meta-analysis incorporated three randomized controlled trials (RCTs), encompassing 2401 participants, with a balanced distribution across the treatment groups. The primary focus of the study revolved around evaluating changes in HbA1C, blood pressure, pulse rate, body weight, waist circumference, and BMI. The findings revealed that once-weekly Semaglutide showed substantially improved HbA1C (WMD: -0.98; 95% CI: -1.28, -0.69, p-value: < 0.0001; I2: 100%), systolic (WMD: -3.73; 95% CI: -5.42, -2.04, p-value: <0.0001; I2: 100%) and diastolic blood pressures (WMD: -0.66; 95% CI: -1.02, -0.29, p-value: 0.0005; I2: 100%), and body weight (WMD: -3.17; 95% CI: -3.84, -2.49, p-value: <0.00001; I2: 100%) compared to once-daily Sitagliptin. However, there was an observed increase in pulse rate (WMD: 3.33; 95% CI: 1.61, 5.06, p-value: <0.00001; I2: 100%) associated with Semaglutide treatment. Regarding secondary outcomes, there was an elevated risk of total adverse events and premature treatment discontinuation with Semaglutide. The risk of serious, severe, moderate, and mild adverse events did not significantly differ between the two treatments.
CONCLUSIONS
In conclusion, the administration of once-weekly Semaglutide exhibited a substantial reduction in HbA1c, average systolic blood pressure (SBP), mean diastolic blood pressure (DBP), body weight, waist circumference, body mass index (BMI), and a rise in pulse rate, as opposed to the once-daily administration of Sitagliptin.
Topics: Humans; Metformin; Sitagliptin Phosphate; Glycated Hemoglobin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Body Weight
PubMed: 37498865
DOI: 10.1080/07853890.2023.2239830 -
BMJ Open Diabetes Research & Care Dec 2020The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in... (Randomized Controlled Trial)
Randomized Controlled Trial
Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial.
INTRODUCTION
The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.
RESEARCH DESIGN AND METHODS
A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA and body weight.
RESULTS
In the durability part, mean (SD) changes in HbA and body weight from week 0 were -1.5% (0.8) and -1.3% (1.0) and -2.8 kg (3.8) and -3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA from week 52 to week 104 were -0.2% for oral semaglutide and 0.1% for sitagliptin (difference -0.3% (95% CI -0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were -2.4 kg and -0.9 kg (difference -1.5 kg (95% CI -2.8 to -0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.
CONCLUSIONS
Long-term oral semaglutide with flexible dose adjustment maintained HbA reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA reductions, helped more patients achieve HbA targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.
TRIAL REGISTRATION NUMBER
NCT02849080.
Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Sitagliptin Phosphate
PubMed: 33318068
DOI: 10.1136/bmjdrc-2020-001649 -
BMJ (Clinical Research Ed.) Oct 2022To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly... (Observational Study)
Observational Study
OBJECTIVE
To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A (HbA).
DESIGN
Observational study.
SETTING
OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019.
PARTICIPANTS
Adults with type 2 diabetes and HbA 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine.
MAIN OUTCOME MEASURES
The primary outcome was time to HbA ≥7.0%. Secondary outcomes were time to HbA >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression.
RESULTS
8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes.
CONCLUSIONS
In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.
Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Liraglutide; Metformin; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome
PubMed: 36191949
DOI: 10.1136/bmj-2022-070717 -
European Heart Journal Jun 2023The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This... (Comparative Study)
Comparative Study Observational Study
AIMS
The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction.
METHODS AND RESULTS
Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding.
CONCLUSION
In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Heart Failure; Sitagliptin Phosphate; Cohort Studies; Aged; Male; Female; Diabetes Mellitus, Type 2; Canagliflozin; Benzhydryl Compounds; Glucosides; Heart Failure, Diastolic; Hospitalization; Medicare; Treatment Outcome
PubMed: 37259575
DOI: 10.1093/eurheartj/ehad273 -
European Review For Medical and... Aug 2023This study aimed to compare 12.5 mg empagliflozin effectiveness and safety vs. 50 mg sitagliptin twice daily as an add-on triple medication in Egyptians with type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Adding empagliflozin to sitagliptin plus metformin vs. adding sitagliptin to empagliflozin plus metformin as triple therapy in Egyptian patients with type 2 diabetes: a 12-week open trial.
OBJECTIVE
This study aimed to compare 12.5 mg empagliflozin effectiveness and safety vs. 50 mg sitagliptin twice daily as an add-on triple medication in Egyptians with type 2 diabetes.
PATIENTS AND METHODS
Patients with hemoglobin A1c (HbA1c) between 53 and 86 mmol/mol after receiving open-label either sitagliptin 50 mg (n = 85) or empagliflozin 12.5 mg (n = 85) twice daily for 12 weeks were afterward taken into account for the administration of open-label empagliflozin 12.5 mg (n = 40) and sitagliptin 50 mg (n = 28) respectively twice daily for another 12 weeks of treatment as an added-on triple therapy. Both groups of patients kept taking metformin and empagliflozin 12.5 mg or sitagliptin 50 mg twice daily as prescribed. The HbA1c change from baseline after 12 weeks of triple-added-on therapy was the main endpoint.
RESULTS
The sitagliptin group receiving empagliflozin saw a substantial drop in HbA1c, fasting and postprandial plasma glucose levels, body weight, and blood pressure compared to the starting point. As opposed to that, adding sitagliptin to the empagliflozin group non-significantly reduced HbA1c, fasting, and postprandial plasma glucose levels, and systolic blood pressure from baseline but significantly reduced body weight and diastolic blood pressure. Comparing the two groups, adding empagliflozin significantly reduced HbA1c, fasting, and postprandial plasma glucose levels (p < 0.001 for all except fasting plasma glucose level, p = 0.002). While the patient's weight and blood pressure were not significantly affected.
CONCLUSIONS
Empagliflozin was superior to sitagliptin in relation to glycemic control, weight, and systolic/diastolic blood pressure reduction.
Topics: Humans; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Egypt; Glycated Hemoglobin; Metformin; Sitagliptin Phosphate
PubMed: 37606137
DOI: 10.26355/eurrev_202308_33300 -
Acta Biochimica Et Biophysica Sinica Oct 2022Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with increasing incidence. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin has...
Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with increasing incidence. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin has been used for the treatment of T2DM worldwide. Although sitagliptin has excellent therapeutic outcome, adverse effects are observed. In addition, previous studies have suggested that sitagliptin may have pleiotropic effects other than treating T2DM. These pieces of evidence point to the importance of further investigation of the molecular mechanisms of sitagliptin, starting from the identification of sitagliptin-binding proteins. In this study, by combining affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), we discover seven high-confidence targets that can interact with sitagliptin. Surface plasmon resonance (SPR) assay confirms the binding of sitagliptin to three proteins, . ., LYPLAL1, TCP1, and CCAR2, with binding affinities (K ) ranging from 50.1 μM to 1490 μM. Molecular docking followed by molecular dynamic (MD) simulation reveals hydrogen binding between sitagliptin and the catalytic triad of LYPLAL1, and also between sitagliptin and the P-loop of ATP-binding pocket of TCP1. Molecular mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis indicates that sitagliptin can stably bind to LYPLAL1 and TCP1 in active sites, which may have an impact on the functions of these proteins. SPR analysis validates the binding affinity of sitagliptin to TCP1 mutant D88A is ~10 times lower than that to the wild-type TCP1. Our findings provide insights into the sitagliptin-targets interplay and demonstrate the potential of sitagliptin in regulating gluconeogenesis and in anti-tumor drug development.
Topics: Humans; Adaptor Proteins, Signal Transducing; Carrier Proteins; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Molecular Docking Simulation; Sitagliptin Phosphate
PubMed: 36239351
DOI: 10.3724/abbs.2022142