RESUMO
AIMS: To evaluate whether there is a difference between the effects of dapagliflozin and gliclazide modified release (MR) on glycaemic variability (GV) and glycaemic control, as assessed by continuous glucose monitoring (CGM), in individuals with uncontrolled type 2 diabetes. MATERIALS AND METHODS: This randomized, open-label, active-controlled study was conducted in individuals with uncontrolled type 2 diabetes who were drug-naïve or on steady-dose metformin monotherapy. Participants were treated once daily with 10 mg dapagliflozin or 120 mg gliclazide MR. CGM and GV index calculations were performed at baseline and after 12 weeks. RESULTS: In total, 97 participants (age 57.9 ± 8.7 years, 50.5% men, baseline glycated haemoglobin 63 ± 9.8 mmol/mol [7.9 ± 0.9%]) were randomized, and 94 completed the 12-week protocol. Intention-to-treat (ITT) and per-protocol (PP) analyses showed that the reduction in GV, as measured by the mean amplitude of glycaemic excursions, was superior in the dapagliflozin group versus the gliclazide MR group (-0.9 mmol/L [95% CI -1.5, -0.4] vs -0.2 mmol/L [95% CI -0.6, 0.3]; P = 0.030 [ITT]). The reductions in GV estimated by the coefficient of variation and SD were greater in the dapagliflozin group. Moreover, dapagliflozin increased the glucose time in range (TIR; 3.9-10 mmol/L) by 24.9% (95% CI 18.6, 31.2) vs. 17.4% (95% CI 11.6, 23.3) in the gliclazide MR group (P = 0.089 [ITT]; P = 0.041 [PP]). CONCLUSIONS: Dapagliflozin improved GV and increased TIR more efficiently than gliclazide MR in individuals with type 2 diabetes over 12 weeks, as demonstrated by CGM.
Assuntos
Diabetes Mellitus Tipo 2 , Gliclazida , Idoso , Compostos Benzidrílicos , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Gliclazida/uso terapêutico , Glucosídeos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The aim of this study was to evaluate the effects of gliclazide on oxidative stress, inflammation, and bone loss in an experimental periodontal disease model. MATERIAL AND METHODS: Male albino Wistar rats were divided into no ligature, ligature, and ligature with 1, 5, and 10 mg/kg gliclazide groups. Maxillae were fixed and scanned using micro-computed tomography to quantify linear and bone volume/tissue volume (BV/TV) and volumetric bone loss. Histopathological, immunohistochemical and immunofluorescence analyses were conducted to examine matrix metalloproteinase-2 (MMP-2), cyclooxygenase 2 (COX-2), cathepsin K, members of the receptor activator of the nuclear factor kappa-Β ligand (RANKL), receptor activator of nuclear factor kappa-Β (RANK), osteoprotegerin (OPG) pathway, macrophage migration inhibitory factor (MIF), superoxide dismutase-1 (SOD-1), glutathione peroxidase-1 (GPx-1), NFKB p 50 (Cytoplasm), NFKB p50 NLS (nuclear localization signal), PI3 kinase and AKT staining. Myeloperoxidase activity, malondialdehyde and glutathione levels, while interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels were evaluated by spectroscopic ultraviolet-visible analysis. A quantitative reverse transcription polymerase chain reaction was used to quantify the gene expression of the nuclear factor kappa B p50 subunit (NF-κB p50), phosphoinositide 3-kinase (PI3k), protein kinase B (AKT), and F4/80. RESULTS: Micro-computed tomography showed that the 1 mg/kg gliclazide treatment reduced linear bone loss compared to the ligature, 5 mg/kg gliclazide, and 10 mg/kg gliclazide treatments. All concentrations of gliclazide increased bone volume/tissue volume (BV/TV) compared to the ligature group. Treatment with 1 mg/kg gliclazide reduced myeloperoxidase activity, malondialdehyde, IL-1ß, and TNF-α levels (p≤0.05), and resulted in weak staining for COX-2, cathepsin k, MMP-2, RANK, RANKL, SOD-1, GPx-1,MIF and PI3k. In addition, down-regulation of NF-κB p50, PI3k, AKT, and F4/80 were observed, and OPG staining was strong after the 1 mg/kg gliclazide treatment. CONCLUSIONS: This treatment decreased neutrophil and macrophage migration, decreased the inflammatory response, and decreased bone loss in rats with ligature-induced periodontitis.
Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Antioxidantes/farmacologia , Gliclazida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Periodontite/tratamento farmacológico , Perda do Osso Alveolar/patologia , Animais , Antioxidantes/uso terapêutico , Catepsina K/análise , Imunofluorescência , Gengiva/química , Gengiva/patologia , Gliclazida/uso terapêutico , Glutationa/análise , Imuno-Histoquímica , Interleucina-1beta/análise , Fatores Inibidores da Migração de Macrófagos/efeitos dos fármacos , Masculino , Malondialdeído/análise , Metaloproteinase 2 da Matriz/análise , Neutrófilos/efeitos dos fármacos , Periodontite/patologia , Peroxidase/análise , Ligante RANK/análise , Distribuição Aleatória , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/análise , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/análise , Microtomografia por Raio-XRESUMO
Abstract Objective The aim of this study was to evaluate the effects of gliclazide on oxidative stress, inflammation, and bone loss in an experimental periodontal disease model. Material and Methods Male albino Wistar rats were divided into no ligature, ligature, and ligature with 1, 5, and 10 mg/kg gliclazide groups. Maxillae were fixed and scanned using micro-computed tomography to quantify linear and bone volume/tissue volume (BV/TV) and volumetric bone loss. Histopathological, immunohistochemical and immunofluorescence analyses were conducted to examine matrix metalloproteinase-2 (MMP-2), cyclooxygenase 2 (COX-2), cathepsin K, members of the receptor activator of the nuclear factor kappa-Β ligand (RANKL), receptor activator of nuclear factor kappa-Β (RANK), osteoprotegerin (OPG) pathway, macrophage migration inhibitory factor (MIF), superoxide dismutase-1 (SOD-1), glutathione peroxidase-1 (GPx-1), NFKB p 50 (Cytoplasm), NFKB p50 NLS (nuclear localization signal), PI3 kinase and AKT staining. Myeloperoxidase activity, malondialdehyde and glutathione levels, while interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels were evaluated by spectroscopic ultraviolet-visible analysis. A quantitative reverse transcription polymerase chain reaction was used to quantify the gene expression of the nuclear factor kappa B p50 subunit (NF-κB p50), phosphoinositide 3-kinase (PI3k), protein kinase B (AKT), and F4/80. Results Micro-computed tomography showed that the 1 mg/kg gliclazide treatment reduced linear bone loss compared to the ligature, 5 mg/kg gliclazide, and 10 mg/kg gliclazide treatments. All concentrations of gliclazide increased bone volume/tissue volume (BV/TV) compared to the ligature group. Treatment with 1 mg/kg gliclazide reduced myeloperoxidase activity, malondialdehyde, IL-1β, and TNF-α levels (p≤0.05), and resulted in weak staining for COX-2, cathepsin k, MMP-2, RANK, RANKL, SOD-1, GPx-1,MIF and PI3k. In addition, down-regulation of NF-κB p50, PI3k, AKT, and F4/80 were observed, and OPG staining was strong after the 1 mg/kg gliclazide treatment. Conclusions This treatment decreased neutrophil and macrophage migration, decreased the inflammatory response, and decreased bone loss in rats with ligature-induced periodontitis.
Assuntos
Animais , Masculino , Periodontite/tratamento farmacológico , Perda do Osso Alveolar/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Gliclazida/farmacologia , Antioxidantes/farmacologia , Periodontite/patologia , Imuno-Histoquímica , Distribuição Aleatória , Reprodutibilidade dos Testes , Perda do Osso Alveolar/patologia , Imunofluorescência , Fatores Inibidores da Migração de Macrófagos/efeitos adversos , Fator de Necrose Tumoral alfa/análise , Ratos Wistar , Peroxidase/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Metaloproteinase 2 da Matriz/análise , Interleucina-1beta/análise , Ligante RANK/análise , Receptor Ativador de Fator Nuclear kappa-B/análise , Microtomografia por Raio-X , Catepsina K/análise , Gengiva/patologia , Gengiva/química , Gliclazida/uso terapêutico , Glutationa/análise , Malondialdeído/análise , Neutrófilos/efeitos dos fármacos , Antioxidantes/uso terapêuticoRESUMO
To determine the effects of combined therapy of gliclazide and bedtime insulin on glycemic control and C-peptide secretion, we studied 25 patients with type 2 diabetes and sulfonylurea secondary failure, aged 56.8 +/- 8.3 years, with a duration of diabetes of 10.6 +/- 6.6 years, fasting plasma glucose of 277.3 +/- 64.6 mg/dl and a body mass index of 27.4 +/- 4.8 kg/m2. Patients were submitted to three therapeutic regimens lasting 2 months each: 320 mg gliclazide (phase 1), 320 mg gliclazide and bedtime NPH insulin (phase 2), and insulin (phase 3). At the end of each period, glycemic and C-peptide curves in response to a mixed meal were determined. During combined therapy, there was a decrease in all glycemic curve values (P<0.01). Twelve patients (48%) reached fasting plasma glucose <140 mg/dl with a significant weight gain of 64.8 kg (43.1-98.8) vs 66.7 kg (42.8-101.4) (P<0.05), with no increase in C-peptide secretion or decrease in HbA1. C-Peptide glucose score (C-peptide/glucose x 100) increased from 0.9 (0.2-2.1) to 1.3 (0.2-4.7) during combined therapy (P<0.01). Despite a 50% increase in insulin doses in phase 3 (12 U (9-30) vs 18 U (11-60); P<0.01) only 3 patients who responded to combined therapy maintained fasting plasma glucose <140 mg/dl (P<0.02). A tendency to a higher absolute increase in C-peptide (0.99 (0.15-2.5) vs 0.6 (0-2.15); P = 0.08) and C-peptide incremental area (2.47 (0.22-6.2) vs 1.2 (0-3.35); P = 0.07) was observed among responders. We conclude that combined therapy resulted in a better glucose response to a mixed meal than insulin alone and should be tried in type 2 diabetic patients before starting insulin monotherapy, despite difficulties in predicting the response.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adulto , Idoso , Glicemia/análise , Peptídeo C/sangue , Peptídeo C/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Sulfonilureia/uso terapêutico , Falha de TratamentoRESUMO
To determine the effects of combined therapy of gliclazide and bedtime insulin on glycemic control and C-peptide secretion, we studied 25 patients with type 2 diabetes and sulfonylurea secondary failure, aged 56.8 + or - 8.3 years, with a duration of diabetes of 10.6 + or - 6.6 years, fasting plasma glucose of 277.3 + or - 64.6 mg/dl and a body mass index of 27.4 + or - 4.8 kg/m². Patients were submitted to three therapeutic regimens lasting 2 months each: 320 mg gliclazide (phase 1), 320 mg gliclazide and bedtime NPH insulin (phase 2), and insulin (phase 3). At the end of each period, glycemic and C-peptide curves in response to a mixed meal were determined. During combined therapy, there was a decrease in all glycemic curve values (P<0.01). Twelve patients (48 percent) reached fasting plasma glucose <140 mg/dl with a significant weight gain of 64.8 kg (43.1-98.8) vs 66.7 kg (42.8-101.4) (P<0.05), with no increase in C-peptide secretion or decrease in HbA1. C-Peptide glucose score (C-peptide/glucose x 100) increased from 0.9 (0.2-2.1) to 1.3 (0.2-4.7) during combined therapy (P<0.01). Despite a 50 percent increase in insulin doses in phase 3 (12 U (9-30) vs 18 U (11-60); P<0.01) only 3 patients who responded to combined therapy maintained fasting plasma glucose <140 mg/dl (P<0.02). A tendency to a higher absolute increase in C-peptide (0.99 (0.15-2.5) vs 0.6 (0-2.15); P = 0.08) and C-peptide incremental area (2.47 (0.22-6.2) vs 1.2 (0-3.35); P = 0.07) was observed among responders. We conclude that combined therapy resulted in a better glucose response to a mixed meal than insulin alone and should be tried in type 2 diabetic patients before starting insulin monotherapy, despite difficulties in predicting the response
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Glicemia/análise , Peptídeo C/sangue , Peptídeo C/metabolismo , Quimioterapia Combinada , Fatores de Tempo , Falha de TratamentoRESUMO
Five male non-obese newly diagnosed NIDDM and 5 age-, sex- and body mass index (BMI) matched healthy controls without a family history of diabetes were submitted to a frequently sampled intravenous (i.v.) glucose tolerance test modified by exogenous insulin administration for estimation of insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) with Bergman's minimal model computer analysis of glucose kinetics. The tests were repeated after 3 months treatment with a second generation sulfonylurea, gliclazide, in the diabetics subjects. SI and SG were markedly reduced before gliclazide therapy in the diabetics in comparison to the paired controls. After gliclazide, despite significantly lower (almost normal) plasma glucose, normalization of glycosylated hemoglobin and increased fasting insulin levels, there was a slight but significant increase in SI while SG showed a further reduction, the improvement in glucose control being also associated to the significant increased first and 2nd phase insulin release for the first 20 min after glucose infusion.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/uso terapêutico , Insulina/farmacologia , Adulto , Jejum , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina Regular de Porco , Masculino , Pessoa de Meia-IdadeRESUMO
Se estudiaron en total noventa y seis pacientes diabéticos tipo II, en su mayoría recién diagnosticados. Fueron suguidos durante un lapso de tres meses de tratamiento con gliclazida, después de un período de dieta de un mes sin obtener resultados satisfactorios en el control de la diabetes. La gliclazida se administró en la dosis de 80 a 240 mg. La glicemia en ayunas fue determinada al inicio del período de dieta, al comenzar el tratamiento con gliclazida, a las dos semanas (para reajustar la dosis) y luego al mes, dos y tres meses se seguir esta medicación. La hemoglobina glicosilada total se midío al inicio y al final del tratamiento. En ambos parámetros se encuentra un descenso significativo de los valores, lo cual muestra un resultado satisfactorio sobre el control de la diabetes. En las curvas de glicemia e insulinemia no se encuentran diferencias significativas antes y despues del período de dieta. En cambio, hay una mejoría importante de la tolerancia a la glucosa a los tres meses del tratamiento con la gliclazida. Hay también a los tres meses un incremento de la secreción de isulina estimulada por glucosa a los 15, 30 y 90 minutos, con valores prácticamente iguales en las tres etapas del estudio (ates de la dieta, antes de iniciar la gliclazida y a los tres meses de su administración) a las dos horas de la sobrecarga con glucosa. En lo que respecta a los lípidos plasmáticos, hay pocas variaciones con el tratamiento en los niveles de colestrol, colesterol-HDL y triglicéridos. Hubo buena tolerancia del medicamento