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Frontiers in Endocrinology 2022Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients.
METHODS
A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks.
RESULTS
1) WC and BMI were decreased significantly in all groups except control group (all 0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all >0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all 0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment.
CONCLUSION
Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Non-alcoholic Fatty Liver Disease; Prospective Studies; Sitagliptin Phosphate; Triglycerides
PubMed: 36072931
DOI: 10.3389/fendo.2022.866189 -
Medicine Sep 2017The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes and provide reference basis for rational use of clinical drugs.
METHODS
Several databases were searched, including Web of science, PubMed, Cochrane library, CNKI, and Wanfang database. Only randomized controlled trials (RCTs) of liraglutide versus sitagliptin both in combination with metformin up to 31 August 2016 were included. Data were extracted independently by 2 reviewers, and a fixed or random effects model were used to analyze outcomes that were expressed as odds ratio (OR) or mean difference (MD) and 95% confidence intervals (95% CIs) for different situations.
RESULTS
Five RCTs involving 1440 participants were included. Compared with sitagliptin combination with metformin group, participants' treatment with 1.2 mg and 1.8 mg liraglutide with metformin could significantly lower the level of glycosylated hemoglobin (HbA1c) (P < .00001, MD = -0.35, 95% CI -0.51 to -0.20). Moreover, patients with 1.8 mg liraglutide group had significant body weight loss (P < .00001, MD = -1.12, 95% CI -1.54 to -0.70). However, there were no obvious differences in cutting down the systolic blood pressure and diastolic blood pressure between liraglutide-metformin and sitagliptin-metformin groups. The incidence of gastrointestinal problems was significantly higher than sitagliptin with metformin groups.
CONCLUSION
The results of this meta-analysis indicated that Liraglutide added on to metformin therapy could significantly lower the level of HbA1c and increase body weight loss. Meanwhile, the adverse reactions such as gastrointestinal problems were common in the liraglutide treatment group. Thus, this will provide an important reference for the treatment of patients with type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Treatment Outcome
PubMed: 28953663
DOI: 10.1097/MD.0000000000008161 -
BMJ Open Sep 2021Impaired glucose tolerance (IGT) is highly prevalent after stroke and is associated with recurrent stroke and unfavourable outcome. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Impaired glucose tolerance (IGT) is highly prevalent after stroke and is associated with recurrent stroke and unfavourable outcome.
OBJECTIVES
We aimed to assess the feasibility, safety and effects on glucose metabolism of metformin or sitagliptin in patients with transient ischaemic attack (TIA) or minor ischaemic stroke and IGT.
DESIGN
We performed a multicentre, randomised, controlled, open-label phase II trial with blinded outcome assessment.
INTERVENTIONS
Patients were randomised in a 2:1:1 ratio to 'no medication', sitagliptin or metformin.
PRIMARY AND SECONDARY OUTCOME MEASURES
Primary outcome measures were baseline adjusted differences of 2-hour postload glucose; secondary outcome measures fasting glucose, glycosylated haemoglobin 1c (HbA1c) levels, tolerability and safety of metformin and sitagliptin at 6 months. Patients on metformin or sitagliptin were contacted by telephone for recording of possible adverse events and to support continuation of treatment at 2 weeks, 6 weeks and 3 months after inclusion. These events were not analysed as outcome measures.
RESULTS
Fifty-three patients were randomised to control group, 26 to metformin and 22 to sitagliptin. We found no significant differences in 2-hour postload glucose between patients on antidiabetic drugs and controls ((-0.04 mmol/L (95% CI -0.53 to 0.45)). Patients in the treatment arms had reduced fasting glucose: ((-0.21 mmol/L (95% CI -0.36 to -0.06)) and HbA1c levels ((-1.16 mmol/mol (95% CI -1.84 to -0.49)). Thirteen patients (50%) on metformin and 7 (32%) on sitagliptin experienced side effects. Sixteen patients (61%) in the metformin and 13 (59%) in the sitagliptin group were still on treatment after 6 months.
CONCLUSIONS
Metformin and sitagliptin were both effective in reducing fasting glucose and HbA1c levels in patients with recent TIA or minor ischaemic stroke and IGT. However, the reduction of glucose levels and sample size was relatively small. The clinical relevance, therefore, needs to be tempered. A phase III trial is needed to investigate whether medical treatment, compared with lifestyle intervention or a combination of both, not only improves glucose metabolism in IGT, but also leads to reduction of recurrent TIA or ischaemic stroke in these patients.
TRIAL REGISTRATION NUMBER
NL3048.
Topics: Blood Glucose; Brain Ischemia; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Feasibility Studies; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Ischemic Attack, Transient; Ischemic Stroke; Metformin; Sitagliptin Phosphate; Stroke; Treatment Outcome
PubMed: 34531203
DOI: 10.1136/bmjopen-2020-046113 -
Inflammopharmacology Dec 2022Coronavirus disease 2019 (Covid-19) is caused by severe acute respiratory syndrome type 2 (SARS-CoV-2). Covid-19 is characterized by hyperinflammation, oxidative stress,... (Review)
Review
Coronavirus disease 2019 (Covid-19) is caused by severe acute respiratory syndrome type 2 (SARS-CoV-2). Covid-19 is characterized by hyperinflammation, oxidative stress, and multi-organ injury (MOI) such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Covid-19 is mainly presented with respiratory manifestations; however, extra-pulmonary manifestations may also occur. Extra-pulmonary manifestations of Covid-19 are numerous including: neurological, cardiovascular, renal, endocrine, and hematological complications. Notably, a cluster of differentiation 26 (CD26) or dipeptidyl peptidase-4 (DPP-4) emerged as a new receptor for entry of SARS-CoV-2. Therefore, DPP-4 inhibitors like sitagliptin could be effective in treating Covid-19. Hence, we aimed in the present critical review to assess the potential role of sitagliptin in Covid-19. DPP-4 inhibitors are effective against the increased severity of SARS-CoV-2 infections. Moreover, DPP-4 inhibitors inhibit the interaction between DPP-4 and scaffolding proteins which are essential for endosome formation and replication of SARS-CoV-2. Therefore, sitagliptin through attenuation of the inflammatory signaling pathway and augmentation of stromal-derived factor-1 (SDF-1) may decrease the pathogenesis of SARS-CoV-2 infection and could be a possible therapeutic modality in treating Covid-19 patients. In conclusion, the DPP-4 receptor is regarded as a potential receptor for the binding and entry of SARS-CoV-2. Inhibition of these receptors by the DPP-4 inhibitor, sitagliptin, can reduce the pathogenesis of the infection caused by SARS-CoV-2 and their associated activation of the inflammatory signaling pathways.
Topics: Humans; SARS-CoV-2; Sitagliptin Phosphate; Dipeptidyl-Peptidase IV Inhibitors; Lung; COVID-19 Drug Treatment
PubMed: 36180664
DOI: 10.1007/s10787-022-01078-9 -
Drugs in R&D Sep 2015Imeglimin is a novel agent currently in development to treat type 2 diabetes. Laboratory studies have demonstrated that it has the potential to impact the three main... (Review)
Review
Imeglimin is a novel agent currently in development to treat type 2 diabetes. Laboratory studies have demonstrated that it has the potential to impact the three main pathophysiologic components of type 2 diabetes: impaired glucose uptake by muscle tissue, excess hepatic gluconeogenesis, and increased beta-cell apoptosis. Preliminary human studies that have been published within the last 2 years demonstrate that imeglimin improves hemoglobin A1c and fasting plasma glucose similarly when compared with metformin and with sitagliptin. There has also been a low incidence of adverse effects, especially hypoglycemia, reported in these early human studies. Currently, imeglimin is lacking long-term evidence to demonstrate any effects on its cardiovascular safety, and data on morbidity and mortality, though some studies are currently in progress. There is great potential for imeglimin, if FDA approved, to play a significant role in the type 2 diabetes management algorithm.
Topics: Apoptosis; Blood Glucose; Diabetes Mellitus, Type 2; Gluconeogenesis; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Metformin; Sitagliptin Phosphate; Triazines
PubMed: 26254210
DOI: 10.1007/s40268-015-0099-3 -
Endocrine Practice : Official Journal... Jun 2018Few randomized controlled trials have focused on the optimal management of patients with type 2 diabetes (T2D) during the transition from the inpatient to outpatient... (Clinical Trial)
Clinical Trial
OBJECTIVE
Few randomized controlled trials have focused on the optimal management of patients with type 2 diabetes (T2D) during the transition from the inpatient to outpatient setting. This multicenter open-label study explored a discharge strategy based on admission hemoglobin A1c (HbA1c) to guide therapy in general medicine and surgery patients with T2D.
METHODS
Patients with HbA1c ≤7% (53 mmol/mol) were discharged on sitagliptin and metformin; patients with HbA1c between 7 and 9% (53-75 mmol/mol) and those >9% (75 mmol/mol) were discharged on sitagliptinmetformin with glargine U-100 at 50% or 80% of the hospital daily dose. The primary outcome was change in HbA1c at 3 and 6 months after discharge.
RESULTS
Mean HbA1c on admission for the entire cohort (N = 253) was 8.70 ± 2.3% and decreased to 7.30 ± 1.5% and 7.30 ± 1.7% at 3 and 6 months ( P<.001). Patients with HbA1c <7% went from 6.3 ± 0.5% to 6.3 ± 0.80% and 6.2 ± 1.0% at 3 and 6 months. Patients with HbA1c between 7 and 9% had a reduction from 8.0 ± 0.6% to 7.3 ± 1.1% and 7.3 ± 1.3%, and those with HbA1c >9% from 11.3 ± 1.7% to 8.0 ± 1.8% and 8.0 ± 2.0% at 3 and 6 months after discharge (both P<.001). Clinically significant hypoglycemia (<54 mg/dL) was observed in 4%, 4%, and 7% among patients with a HbA1c <7%, 7 to 9%, and >9%, while a glucose <40 mg/dL was reported in <1% in all groups.
CONCLUSION
The proposed HbA1c-based hospital discharge algorithm using a combination of sitagliptin-metformin was safe and significantly improved glycemic control after hospital discharge in general medicine and surgery patients with T2D.
ABBREVIATIONS
BG = blood glucose; DPP-4 = dipeptidyl peptidase-4; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; T2D = type 2 diabetes.
Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Male; Metformin; Middle Aged; Patient Discharge; Prospective Studies; Sitagliptin Phosphate
PubMed: 29949432
DOI: 10.4158/EP-2018-0036 -
Medical Science Monitor : International... Apr 2020BACKGROUND Fibroblasts activation-induced fibrosis can cause idiopathic pulmonary fibrosis (IPF). Excessive activation of fibroblasts contributes to poor healing or...
BACKGROUND Fibroblasts activation-induced fibrosis can cause idiopathic pulmonary fibrosis (IPF). Excessive activation of fibroblasts contributes to poor healing or severe visceral fibrosis and even organ dysfunction. Sitagliptin acts as a dipeptidyl peptidase 4 inhibitor to reduce glucose level in type 2 diabetes, but its role in fibrosis of lung fibroblasts is elusive. We investigated the mechanism of sitagliptin in TGF-ß-activated lung fibroblasts and evaluated the efficacy of sitagliptin in extracellular matrix accumulation and fibroblasts proliferation. MATERIAL AND METHODS By in vitro lung fibroblasts culture, we assessed the expression of lung fibroblasts biomarker (alpha-SMA) and extracellular matrix (Col-1, Col-3, fibronectin) following TGF-ß stimulation and treatment with sitagliptin. Mechanistically, the phosphorylation level of Smad-3 protein in cells was analyzed using Western blotting, and the apoptosis level was assessed by Western blotting and flow cytometry. The degree of proliferation was determined using immunofluorescence and scratch-healing assay. RESULTS We found that treatment with sitagliptin attenuates fibroblasts activation following TGF-ß stimulation. Furthermore, the extracellular matrix was decreased by sitagliptin treatment by suppressing the phosphorylation level of Smad-3 protein. We found that sitagliptin does not affect apoptosis in fibroblasts, but it does affect the degree of proliferation of lung fibroblasts, thus ameliorating fibrosis after TGF-ß stimulation. CONCLUSIONS Sitagliptin inhibits fibrosis in TGF-ß-induced lung fibroblasts activation, which restrains extracellular matrix formation and cell proliferation in fibroblasts. Therefore, sitagliptin appears to have promise as a treatment of fibroproliferative disease caused by activation and proliferation of fibroblasts.
Topics: Cell Line; Cell Proliferation; Dipeptidyl-Peptidase IV Inhibitors; Extracellular Matrix; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Sitagliptin Phosphate
PubMed: 32301442
DOI: 10.12659/MSM.922644 -
Diabetes Care Feb 2017We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).
RESEARCH DESIGN AND METHODS
In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, a cardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitis and pancreatic cancer were collected prospectively for 14,671 participants during a median follow-up time of 3 years, and were adjudicated blindly.
RESULTS
Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96-3.88], P = 0.065; 0.107 vs. 0.056/100 patient-years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28-1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient-years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13-2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28-1.04], P = 0.07).
CONCLUSIONS
Pancreatitis and pancreatic cancer were uncommon events with rates that were not statistically significantly different between the sitagliptin and placebo groups, although numerically more sitagliptin participants developed pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small absolute increased risk for pancreatitis with DPP-4i therapy.
Topics: Acute Disease; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Proportional Hazards Models; Risk Factors; Sitagliptin Phosphate; Treatment Outcome
PubMed: 27630212
DOI: 10.2337/dc15-2780 -
Drug Delivery Dec 2021Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an...
Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The digestion, bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The pharmacokinetic parameters of SNEDDS showed significant increase in (1.99 ± 0.21 µg mL), AUC (17.94 ± 1.25 µg mL), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.
Topics: Animals; Area Under Curve; Benzhydryl Compounds; Chemistry, Pharmaceutical; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Combinations; Drug Liberation; Emulsions; Glucosides; Hypoglycemic Agents; Male; Metabolic Clearance Rate; Mice; Microscopy, Electron, Transmission; Nanoparticles; Particle Size; Plant Oils; Rats; Rats, Wistar; Sitagliptin Phosphate; Solubility; Surface Properties
PubMed: 33345632
DOI: 10.1080/10717544.2020.1859001 -
Nutrition, Metabolism, and... Sep 2016Diabetes treatments aim at preventing undesirable metabolic effects of hyperglycemia and at preventing/reducing tissue damage, including cardiovascular (CV) events. For... (Review)
Review
AIMS
Diabetes treatments aim at preventing undesirable metabolic effects of hyperglycemia and at preventing/reducing tissue damage, including cardiovascular (CV) events. For approval, novel diabetes drugs undergo early systematic investigation to assess CV safety. This review provides an updated analysis of the results of recent studies examining novel diabetes medications and CV outcomes.
DATA SYNTHESIS
The new regulatory guidelines enforce adjudication of all CV events when testing novel diabetes drugs. Endpoints of CV mortality, myocardial infarction (MI), stroke and hospitalization for heart failure (HF) were included in the most recent clinical studies on novel antihyperglycemics. These are: the incretin mimetics glucagon-like peptide 1 (GLP-1) receptor agonists (GLP1-RA), the incretin enhancers dipeptidylpeptidase-4 (DPP-4) inhibitors (DPP4-I or gliptins), and the sodium-glucose cotransporter (SGLT2) inhibitors (SGLT2-I or gliflozins). The studies ELIXA and EXAMINE, testing lixisenatide and alogliptin, respectively, revealed non-inferiority versus placebo in terms of CV safety. The SAVOR-TIMI 53 results confirmed overall CV safety of saxagliptin, but raised a warning related to the increase in the risk of hospitalization for HF in the saxagliptin group. Recently, TECOS revealed a particularly favorable CV profile for sitagliptin while EMPA-REG showed a significant CV risk reduction in empagliflozin treated subjects. Ongoing studies will provide additional data on CV safety for other GLP1-RAs, DPP4-I and SGLT2-I.
CONCLUSIONS
Results of safety outcome studies focused on CV events, including HF and mortality for CV causes, are not homogeneous. A critical analysis of these studies may help cardiologists and diabetes specialists to adapt their therapeutic choices to individual patients.
Topics: Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucosides; Humans; Hypoglycemic Agents; Incretins; Patient Safety; Patient Selection; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Treatment Outcome
PubMed: 27373139
DOI: 10.1016/j.numecd.2016.05.007