RESUMEN
AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.
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Adamantano , Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Dipéptidos , Quimioterapia Combinada , Glucósidos , Hemoglobina Glucada , Hipoglucemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Metformina/uso terapéutico , Metformina/administración & dosificación , Metformina/efectos adversos , Glucósidos/administración & dosificación , Glucósidos/efectos adversos , Glucósidos/uso terapéutico , Masculino , Femenino , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/efectos adversos , Persona de Mediana Edad , Dipéptidos/efectos adversos , Dipéptidos/administración & dosificación , Dipéptidos/uso terapéutico , Adamantano/análogos & derivados , Adamantano/administración & dosificación , Adamantano/efectos adversos , Adamantano/uso terapéutico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Anciano , Resultado del Tratamiento , Hipoglucemia/inducido químicamente , Compuestos de Sulfonilurea/uso terapéutico , Compuestos de Sulfonilurea/administración & dosificación , Compuestos de Sulfonilurea/efectos adversos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Adulto , Aumento de Peso/efectos de los fármacos , Fosfato de Sitagliptina/uso terapéutico , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/efectos adversosRESUMEN
OBJECTIVE: To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM). METHODS: Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1, 2017 to December 31, 2022. According to drug prescription records, the patients were divided into metformin plus sitagliptin group (combination group) and metformin monotherapy group(monotherapy group). A series of retrospective cohorts were constructed according to the index date.Finally, full retrospective cohorts were constructed according to propensity score model, including baseline covariates that might be related to outcomes, to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics. The participants were followed up from the index date until the first occurrence of the following events: Diagnosis of outcomes, death, or the end of the study period (December 31, 2022). Cox proportional risk model was used to estimate the hazard ratio(HR)and 95% confidence interval (CI) of sitagliptin added to metformin on 3-point major adverse cardiovascular events (3P-MACE) combination outcome and secondary cardiovascular outcomes. RESULTS: Before propensity score matching, the proportion of the patients in combination group using insulin, α glucosidase inhibitors, sodium-glucose transporter 2 inhibitors (SGLT-2I) and glienides at baseline was higher than that in monotherapy group, and the baseline fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels in combination group were higher than those in monotherapy group. After propensity score matching, 5 416 subjects were included in the combination group and the monotherapy group, and baseline characteristics were effectively balanced between the groups. The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 person years, respectively. Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy (HR=1.00, 95% CI: 0.91-1.10). In secondary outcomes analysis, the incidence of cardiovascular death was lower in the combination group than in the monotherapy group (HR=0.59, 95% CI: 0.41-0.85), and no association was found between sitagliptin and the risk of myocardial infarction and stroke (HR=1.12, 95% CI: 0.89-1.41; HR=0.99, 95% CI: 0.91-1.12). CONCLUSION: In T2DM patients in Yinzhou district of Ningbo, compared with metformin alone, sitagliptin added to metformin may reduce the risk of cardiovascular death, and do not increase the incidence of overall cardiovascular events. The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hipoglucemiantes , Metformina , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fosfato de Sitagliptina/efectos adversos , Fosfato de Sitagliptina/uso terapéutico , Fosfato de Sitagliptina/administración & dosificación , Metformina/efectos adversos , Metformina/uso terapéutico , Metformina/administración & dosificación , Estudios Retrospectivos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Masculino , Femenino , Enfermedades Cardiovasculares/prevención & control , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , AncianoRESUMEN
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.
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Glucemia , Prueba de Tolerancia a la Glucosa , Secreción de Insulina , Insulina , Fosfato de Sitagliptina , Humanos , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/administración & dosificación , Masculino , Femenino , Adulto , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Glucemia/análisis , Adulto Joven , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Proyectos Piloto , Voluntarios Sanos , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/sangre , Persona de Mediana Edad , Factores SexualesRESUMEN
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.
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Glucemia , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hipoglucemiantes , Fosfato de Sitagliptina , Humanos , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/uso terapéutico , Fosfato de Sitagliptina/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Masculino , Persona de Mediana Edad , Femenino , Anciano , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/análisis , Glucemia/metabolismo , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Hospitalización/estadística & datos numéricos , Resultado del Tratamiento , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiologíaRESUMEN
CONTEXT: Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE: To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS: Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64â mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20â mg (SU), sitagliptin 100â mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3â mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS: SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3â mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION: Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.
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Glucemia , Estudios Cruzados , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Quimioterapia Combinada , Hipoglucemiantes , Células Secretoras de Insulina , Compuestos de Sulfonilurea , Humanos , Masculino , Femenino , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Persona de Mediana Edad , Glucemia/efectos de los fármacos , Glucemia/análisis , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Compuestos de Sulfonilurea/administración & dosificación , Compuestos de Sulfonilurea/uso terapéutico , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Anciano , Adulto , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/uso terapéutico , Metformina/administración & dosificación , Metformina/uso terapéutico , Gliclazida/administración & dosificación , Gliclazida/farmacología , Gliclazida/uso terapéuticoRESUMEN
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/m2) 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/m2 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.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Sustitución de Medicamentos , Hipoglucemiantes , Metformina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Glucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Quimioterapia Combinada , Pueblos del Este de Asia , Hemoglobina Glucada , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/tratamiento farmacológico , Fosfato de Sitagliptina/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Resultado del TratamientoRESUMEN
It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/administración & dosificación , Péptido 1 Similar al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Incretinas/administración & dosificación , Secreción de Insulina/efectos de los fármacos , Metformina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada/métodos , Femenino , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa/métodos , Humanos , Hipoglucemiantes/sangre , Incretinas/sangre , Insulina/sangre , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Fosfato de Sitagliptina/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. OBJECTIVE: We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. METHODS: In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. RESULTS: A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5-11.6). At 24 weeks, the mean difference from baseline in PASI (-1.0 [95% CI -2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (-2.5 [95% CI -4.0 to -1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0-0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. CONCLUSION: Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.
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Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Psoriasis/terapia , Fosfato de Sitagliptina/administración & dosificación , Terapia Ultravioleta/métodos , Adulto , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.
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Hepatopatías/tratamiento farmacológico , Prostaglandinas/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Fosfato de Sitagliptina/administración & dosificación , Animales , Quimiocina CXCL12/genética , Cromatografía Liquida , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Hepatopatías/etiología , Ratas , Receptores CXCR4/genética , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Daño por Reperfusión/complicaciones , Transducción de Señal/efectos de los fármacos , Fosfato de Sitagliptina/farmacología , Espectrometría de Masas en Tándem , Péptido Intestinal Vasoactivo/genéticaRESUMEN
AIMS: Glucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism. MATERIALS AND METHODS: Adult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses. KEY FINDINGS: Dexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances. SIGNIFICANCE: Coadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.
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Dexametasona/efectos adversos , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Conducta Alimentaria/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Masculino , Ratas , Ratas WistarRESUMEN
Purpose: Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context. Materials and Methods: In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters. Results: Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy. Conclusions: These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/economía , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/economía , Metformina/administración & dosificación , Metformina/economía , Adamantano/administración & dosificación , Adamantano/análogos & derivados , Adamantano/economía , China , Análisis Costo-Beneficio , Dipéptidos/administración & dosificación , Dipéptidos/economía , Resistencia a Medicamentos , Quimioterapia Combinada , Humanos , Linagliptina/administración & dosificación , Linagliptina/economía , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/economía , Ensayos Clínicos Controlados Aleatorios como Asunto , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/economía , Uracilo/administración & dosificación , Uracilo/análogos & derivados , Uracilo/economía , Vildagliptina/administración & dosificación , Vildagliptina/economíaAsunto(s)
Interpretación Estadística de Datos , Modelos Estadísticos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Fosfato de Sitagliptina/administración & dosificaciónRESUMEN
BACKGROUND: Oral semaglutide is the first orally administered glucagon-like peptide-1 receptor agonist (GLP-1RA) approved by the FDA. Clinical trials found that oral semaglutide 14 mg had a greater reduction in hemoglobin A1c (A1c) compared with empagliflozin 25 mg and sitagliptin 100 mg and was noninferior to liraglutide 1.8 mg. However, US cost-effectiveness data for oral semaglutide are limited and do not consider the costs of adverse events. OBJECTIVE: To assess the short-term cost-effectiveness of oral semaglutide compared with empagliflozin, sitagliptin, and liraglutide in patients with type 2 diabetes. METHODS: A decision analysis over a 52-week time horizon was used to evaluate the incremental cost-effectiveness of oral semaglutide vs empagliflozin, sitagliptin, and liraglutide from a US health care payer's perspective. Data on efficacy, adverse events, and discontinuation were derived from 52-week data from phase 3, head-to-head clinical trials (PIONEER 2, 3, and 4). Costs included drug and administration cost and treatment of gastrointestinal adverse events. Incremental cost-effectiveness ratios (ICERs) were calculated as the difference in cost over the difference in A1c reduction between oral semaglutide and comparators. RESULTS: In the base-case analysis, 52-week treatment costs with oral semaglutide were $2,660 and $3,104 higher and $2,337 less than empagliflozin, sitagliptin, and liraglutide, respectively. Incremental (greater) A1c reductions were seen with oral semaglutide at 0.40%, 0.50%, and 0.30% vs empagliflozin, sitagliptin, and liraglutide, respectively. ICERs per 1% reduction in A1c for oral semaglutide were $6,650 and $6,207 vs empagliflozin and sitagliptin, respectively. Oral semaglutide was dominant vs liraglutide (ICER of -$7,790). CONCLUSIONS: Oral semaglutide was dominant relative to liraglutide, offering a cost-saving GLP-1RA oral alternative. While there is not a recognized willingness-to-pay threshold for a 1% reduction in A1c, oral semaglutide may be cost-effective relative to empagliflozin and sitagliptin if a decision maker's willingness-to-pay threshold exceeds $6,650 and $6,207, respectively. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Costos de los Medicamentos , Péptidos Similares al Glucagón/economía , Administración Oral , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/economía , Análisis Costo-Beneficio , Péptidos Similares al Glucagón/administración & dosificación , Glucósidos/administración & dosificación , Glucósidos/economía , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/economía , Liraglutida/administración & dosificación , Liraglutida/economía , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/economía , Estados UnidosRESUMEN
There have been a few reports on Dipeptidyl peptidase (DPP)-4 inhibitor-induced dropped head syndrome. However, there has been no known report on temporal changes in MRI findings. The patient described here was a 63-year-old man who was prescribed oral sitagliptin (50 mg/day) in February 2019. He experienced a dropped head from mid-January 2020, and in early April that year, he was admitted to our hospital for further evaluation. Weakness of the cervical extensor muscles (MMT 3) was noted, and MRI findings showed that the posterior cervical muscle group was hyperintense on short inversion time inversion recovery (STIR). We suspected sitagliptin to be the cause of his dropped head and discontinued it. On the 10th day of admission, his posture improved to the median position. One month after discontinuation of sitagliptin, MRI findings showed an improvement in the STIR hyperintensity of the posterior cervical muscle. In conclusion, if the initiation of a DPP-4 inhibitor results in dropped head syndrome, discontinuation of the drug should be considered.
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Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Cabeza , Debilidad Muscular/inducido químicamente , Enfermedades Musculares/inducido químicamente , Músculos del Cuello , Postura , Fosfato de Sitagliptina/efectos adversos , Administración Oral , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Cabeza/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Debilidad Muscular/diagnóstico por imagen , Enfermedades Musculares/diagnóstico por imagen , Músculos del Cuello/diagnóstico por imagen , Fosfato de Sitagliptina/administración & dosificación , Síndrome , Privación de TratamientoAsunto(s)
Colecalciferol/uso terapéutico , Inmunoglobulina G/sangre , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Mononeuropatías/tratamiento farmacológico , Fosfato de Sitagliptina/uso terapéutico , Colecalciferol/administración & dosificación , Humanos , Inmunoglobulina G/inmunología , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/inmunología , Masculino , Persona de Mediana Edad , Mononeuropatías/inmunología , Fosfato de Sitagliptina/administración & dosificación , Factores de TiempoRESUMEN
BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).
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Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Fosfato de Sitagliptina/uso terapéutico , Adulto , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Sirolimus/uso terapéutico , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/efectos adversos , Análisis de Supervivencia , Tacrolimus/uso terapéutico , Trasplante Homólogo , Adulto JovenRESUMEN
Diabetes is one of the World's most concerning health problems and millions of patients are using anti-diabetic drugs (ADDs) in order to control blood glucose. The in vitro H295R steroidogenesis assay was implemented to investigate endocrine effects of three ADDs, metformin (MET), glimepiride (GLIM), sitagliptin (SIT) and the cholesterol-lowering drug simvastatin (SIM) individually and in three binary mixtures. Steroid hormones were analyzed using LC-MS/MS. Mixture effects were assessed by applying the Concentration Addition (CA) model. All tested drugs and binary mixtures interrupted the H295R steroidogenesis with different potency. The effects of MET:GLIM on the steroidogenesis were overall similar to the steroidogenic profile of GLIM, however effects were less pronounced. The binary mixture of MET:SIT showed overall minor effects on steroid production and only at very high concentrations. The SIM:SIT mixture showed inhibition downstream from cholesterol, which was attributed to the effects of SIM. The CA model partly predicted the effect of MET:SIT on some steroids but significantly overestimated the effects of MET:GLIM and SIM:SIT. Thus, the applicability of the CA model was limited and cocktail effects appeared to be intermediate responses of individual drugs, rather than additive. The complexity of dynamic pathways such as steroidogenesis appears to significantly reduce the use of the CA model. In conclusion, more dynamic models are needed to predict mixture effects in complex systems.
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Disruptores Endocrinos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Simvastatina/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Esteroides/biosíntesis , Compuestos de Sulfonilurea/administración & dosificación , Administración Oral , Línea Celular , Cromatografía Liquida , Interacciones Farmacológicas , Humanos , Espectrometría de Masas en TándemRESUMEN
Aim: The objective of this study is to investigate the changes of UA with sitagliptin in relation to its glycemic/non-glycemic efficacies.Methods: Drug naïve subjects with T2DM (n = 62) were administered 25-50 mg/day sitagliptin monotherapy for 3 months. The subjects were divided into two subgroups according to the changes in (Δ) UA (above the median [group A, n = 31]: ΔUA = 23.3%, p < 0.00001, and below the median [group B, n = 31]: ΔUA = -0.9%, n.s.). Changes in glycemic/non-glycemic parameters were compared between these two groups, which acted as a control for each other.Results: In the overall subjects, UA significantly increased (10.8%, p < 0.00001). Significant correlations between ΔUA and ΔBMI (R = 0.252), ΔHOMA-B (R = 0.309) or ΔCPR-index (R = 0.258), and significant negative correlations between ΔUA and ΔHbA1c (R = -0.290) or ΔFFA (R = -0.271) were seen. Between group A and group B, some parameters displayed distinct regulatory patterns. HbA1c significantly decreased in both groups (group A: from 9.97% to 7.65%, group B: from 10.41% to 8.85%) with significant inter-group differences (higher reductions in group A, p < 0.05). C-peptide (+10.6%) and BMI (+1.7%) significantly increased, and FFA (-20.5%) decreased in group A. HOMA-R or 20/(C-peptide x FBG) had no changes in either group, while HOMA-B (group A: +85.1%, group B: +38.8%) or CPR-index (group A: +37.7%, group B: +20.5%) increased in both groups with significant inter-group differences (both p < 0.01). TG (-18.8%) significantly decreased, and T-C (-3.5%) and non-HDL-C (-4%) had a tendency to decrease in group B.Conclusions: These results suggest that UA and beta-cell functions/glycemic efficacy are closely linked during sitagliptin therapy. Those with elevated UA had better beta-cell enhancing and glyemic efficacies. Body weights increased and FFA decreased in these populations. By contrast, those without changes in UA had favorable profiles in atherogenic lipids.
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Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/farmacología , Ácido Úrico/sangre , Anciano , Diabetes Mellitus Tipo 2 , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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 in vitro digestion, in vivo 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 in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), 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.
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Compuestos de Bencidrilo/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Emulsiones/química , Glucósidos/administración & dosificación , Nanopartículas/química , Fosfato de Sitagliptina/administración & dosificación , Animales , Área Bajo la Curva , Compuestos de Bencidrilo/farmacocinética , Química Farmacéutica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Combinación de Medicamentos , Liberación de Fármacos , Glucósidos/farmacocinética , Hipoglucemiantes , Masculino , Tasa de Depuración Metabólica , Ratones , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Aceites de Plantas/química , Ratas , Ratas Wistar , Fosfato de Sitagliptina/farmacocinética , Solubilidad , Propiedades de SuperficieRESUMEN
The therapeutic mechanism of action of methionine aminopeptidase 2 (MetAP2) inhibitors for obesity-diabetes has not yet been fully defined. Xenin, a K-cell derived peptide hormone, possesses an N-terminal Met amino acid residue. Thus, elevated xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting xenin analogues have been shown to improve obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor, TNP-470, to augment the antidiabetic utility of the incretin-enhancer drug, sitagliptin, in high fat fed (HFF) mice. TNP-470 (1 mg/kg) and sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual therapy with TNP-470 or sitagliptin resulted in numerous metabolic benefits including reduced blood glucose, increased circulating and pancreatic insulin and improved glucose tolerance, insulin sensitivity, pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with TNP-470 alone, or in combination with sitagliptin, reduced food intake and body weight, as well as elevating plasma and intestinal xenin. Importantly, combined sitagliptin and TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that TNP-470 increases plasma and intestinal xenin levels, and augments the antidiabetic advantages of sitagliptin.