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Lifestyle modifications, metformin, and linagliptin reduce the incidence of type 2 diabetes (T2D) in people with prediabetes. The gut microbiota (GM) may enhance such interventions' efficacy. We determined the effect of linagliptin/metformin (LM) vs metformin (M) on GM composition and its relationship to insulin sensitivity (IS) and pancreatic ß-cell function (Pßf) in patients with prediabetes. A cross-sectional study was conducted at different times: basal, six, and twelve months in 167 Mexican adults with prediabetes. These treatments increased the abundance of GM SCFA-producing bacteria M (Fusicatenibacter and Blautia) and LM (Roseburia, Bifidobacterium, and [Eubacterium] hallii group). We performed a mediation analysis with structural equation models (SEM). In conclusion, M and LM therapies improve insulin sensitivity and Pßf in prediabetics. GM is partially associated with these improvements since the SEM models suggest a weak association between specific bacterial genera and improvements in IS and Pßf.
Assuntos
Microbioma Gastrointestinal , Linagliptina , Metformina , Estado Pré-Diabético , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Linagliptina/uso terapêutico , Linagliptina/farmacologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Adulto , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , IdosoRESUMO
Background: The control of diabetes mellitus is multifactorial, the different therapeutic options make it necessary to compare the effectiveness with previous therapeutic schemes. Objective: Analize the indicators of control of diabetes mellitus after incorporating liraglutide, sitagliptin/metformin, linagliptin, and sitagliptin. Methods: Observational, analytical, longitudinal study. Glucose, glycosylated hemoglobin, and blood pressure were compared after the inclusion of new cues in patients with diabetes mellitus; in addition to the control indicators reported in the unit in october, november, and december 2000, with those of 2021 in the same months. A descriptive analysis was performed, T for related samples and McNemar, a value of < .05 was considered significant, a confidence level of 95%, with the IBM-SPSS 24 software. Results: 352 files were analyzed, 59% women, aged 26 to 88 years, and the percentage of control decreased after the change of scheme (38.4% vs 35.8%) without a statistical difference (p .503). There was no statistical difference between the levels of glucose, glycated hemoglobin, weight, and blood pressure before and six months after the change. In the unit, the regimen glycemic control indicator improved in October, November, and December 2020 compared to the same months in 2021, it increased (from 17.2, 18.7, and 16.3, to 41.6, 47.2, and 46.5%). Blood pressure control went from 64.5, 66.7, and 67 to 82.4, 85.1, and 83.1%. Conclusions: The control indicators in the unit improved, however, the patients who used the new keys did not show any difference.
Introducción: el control de la diabetes mellitus es multifactorial, las diferentes opciones terapéuticas hacen necesario comparar la efectividad con esquemas terapéuticos previos. Objetivo: analizar los indicadores de control de diabetes mellitus posterior a incorporar liraglutida, sitagliptina/metformina, linagliptina y sitagliptina. Métodos: estudio observacional, analítico, longitudinal. Se compararon glucosa, hemoglobina glucosilada y presión arterial posterior a la inclusión de nuevas claves en pacientes con diabetes mellitus; además de los indicadores de control reportados en la unidad en los meses octubre, noviembre y diciembre 2020, con los del 2021 en los mismos meses. Se realizó un análisis descriptivo, T para muestras relacionadas y McNemar, se consideró un valor de p ≤ 0.05 como significativo, un nivel de confianza de 95%, con el programa informático IBM-SPSS 24. Resultados: se analizaron 352 expedientes, el 59% correspondía a mujeres, con edades de 26 a 88 años, el porcentaje de control disminuyó después del cambio de esquema (38.4% frente a 35.8%) sin diferencia estadística (p = 0.503). No hubo diferencia estadística entre los niveles de glucosa, hemoglobina glucosilada, peso y presión arterial previos y seis meses después del cambio de esquema. En la unidad, el indicador de control de glucemia en los meses de octubre, noviembre y diciembre 2020 comparados con los mismos meses en el 2021 incrementaron (17.2, 18.7 y 16.3, a 41.6, 47.2 y 46.5%). El control de presión arterial pasó del 64.5, 66.7 y 67 a 82.4, 85.1 y 83.1%. Conclusiones: los indicadores de control en la unidad mejoraron, sin embargo los pacientes que utilizaron las nuevas claves no mostraron diferencia.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Feminino , Masculino , Fosfato de Sitagliptina/uso terapêutico , Liraglutida/uso terapêutico , Linagliptina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos Longitudinais , Resultado do Tratamento , Metformina/uso terapêutico , Hemoglobinas Glicadas , Glucose/uso terapêutico , Quimioterapia Combinada , GlicemiaRESUMO
AIM: To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice. METHODS: Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups. RESULTS: The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining. CONCLUSION: Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.
Assuntos
Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Comportamento Alimentar , Linagliptina/uso terapêutico , Lipogênese , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Ingestão de Alimentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Jejum/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Insulina/sangue , Resistência à Insulina , Linagliptina/farmacologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Oxirredução , Perilipina-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
INTRODUCTION: Linagliptin is a high-cost oral antidiabetic that has been widely used, and studies on its effectiveness and safety for the treatment of type 2 diabetes mellitus (DM2) in the real world is rare and necessary. OBJECTIVE: To analyze the values of glycated hemoglobin (HbA1c) and adverse events before and after the use of linagliptin in the post-marketing context of a pilot study. METHODS: This is a descriptive observational and exploratory study with a retrospective longitudinal approach, conducted between January 2014 and December 2016. All patients who participated in the study were over 18 years of age, with DM2, assisted by the Brazilian Public Health System (Sistema Único de Saúde - SUS) and had been indicated for use of linagliptin. The users were followed up and the variables of interest were collected from a computerized health information system (sistema informatizado de saúde - SIS) and patient records. For effectiveness analysis, HbA1c before (T0) and after (T1) the use of linagliptin was considered in patients registered as having collected linagliptin at the pharmacy for at least three consecutive months. For safety analysis, registered adverse events (AE) were verified in patients' records. The sample was stratified according to the pharmacotherapeutic scheme of the users. To compare the means before (T0) and after (T1), a paired t-test (data with normal distribution) and Wilcoxon Signed Rank Sum test (non-normal distribution data) were performed. RESULTS: Considering the total population of the study, in a different pharmacotherapeutic regimen, a median reduction in HbA1c of -0.86% (p < 0.05) was observed. After stratification by pharmacotherapeutic regimen, the most significant reduction of HbA1c was -1.07% (p = 0.014) for the linagliptin group associated with insulins and oral antidiabetic agents (n = 13). On the other hand, patients taking linagliptin in monotherapy had the lowest HbA1c reduction, -0.48% (p > 0.05). AE occurred in 12 (36.4%) patients, and 16.7% were in monotherapy. CONCLUSION: Linagliptin did not presented, in real world, the desired performance as showed in randomized premarketing clinical trials and it should be carefully evaluated in public health services.
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PURPOSE: To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model. METHODS: Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet. RESULTS: HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel. CONCLUSIONS: The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.
Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/uso terapêutico , Obesidade/tratamento farmacológico , Gordura Subcutânea/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Adipócitos Marrons , Adiposidade , Animais , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Insulina/sangue , Linagliptina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/etiologia , Distribuição Aleatória , Gordura Subcutânea/citologia , Gordura Subcutânea/metabolismoRESUMO
ABSTRACT Aim: The aim of the study is to evaluate the effect of linagliptin versus metformin on insulin secretion, insulin sensitivity and glucose control in patients with impaired glucose tolerance (IGT). Patients and methods: A randomized, double-blind, clinical trial with parallel groups was per-formed on 16 adults with IGT. Lipid profile and haemoglobin (HbA1c) were evaluated prior to and after the intervention. Glucose and insulin were measured at 0, 30, 60, 90 and 120 minutes after a 75-g oral dextrose load. Eight patients received metformin (500 mg) twice a day before meals for three months. The remaining eight patients received placebo (500 mg) in the morning and linagliptin (5 mg) in the evening before meals. The area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. Results: After linagliptin administration, a significant decrease in glucose at 90 minutes (10.8 ± 2.6 vs 7.9 ± 2.2 mmol/L, p < 0.05), 120 minutes (8.8 ± 0.9 vs 6.5 ± 2.1 mmol/L, p < 0.05) and AUC of glucose (1168 ± 210 vs 953 ± 207 mmol/L, p < 0.05) were observed. Metformin administration decreased insulin significantly at 0 minutes (94.8 ± 25.8 vs 73.8 ± 24.6 pmol/L, p < 0.05). Conclusion: Three-month administration of linagliptin in patients with IGT decreased glucose at 90 and 120 minutes after a 75-g oral dextrose load and AUC of glucose. Metformin decreased insulin at 0 minutes.
RESUMEN Objetivo: El objetivo del estudio es evaluar el efecto de la linagliptina frente a la metformina en la secreción de insulina, la sensibilidad a la insulina, y el control de la glucosa en pacientes con intolerancia a la glucosa (IG). Pacientes y métodos: Se realizó un ensayo clínico aleatorio de doble ciego con grupos paralelos a 16 adultos con IG. El perfil lipídico y la hemoglobina (Hba1C) se evaluaron antes y después de la intervención. La glucosa y la insulina se midieron a los 0, 30, 60, 90 y 120 minutos después de un carga oral de 75-g dextrosa. Ocho pacientes recibieron metformina (500 mg) dos veces al día antes de las comidas por tres meses. Los ocho pacientes restantes recibieron placebo (500 mg) por la mañana y linagliptina (5 mg) por la noche antes de las comidas. El área bajo la curva (ABC) de la glucosa y la insulina, la secreción total de insulina, la primera fase de la secreción de insulina, y la sensibilidad a la insulina, fueron evaluadas. Resultados: Luego de la administración de la linagliptina, se observó una disminución significativa de la glucosa a los 90 minutos (10.8 ± 2.6 vs 7.9 ± 2.2 mmol/L, p < 0.05), 120 minutos (8.8 ± 0.9 mmol/L p < 0.05) y el ABC de la glucosa (1168 ± 210 vs 953 ± 207 mmol/L, p < 0.05). La administración de metformina redujo significativamente la insulina a los 0 minutos (94.8 ± 25.8 vs 73.8 ± 24.6 pmol/L, p < 0.05). Conclusión: Tres meses de administración de linagliptina en pacientes con IG disminuyó la glucosa a los 90 y 120 minutos después de una carga oral de dextrosa de 75-g y el ABC de la glucosa. La metformina disminuyó la insulina en 0 minutos.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Glicemia/efeitos dos fármacos , Linagliptina/farmacologia , Metformina/farmacologia , Método Duplo-Cego , Sensibilidade e Especificidade , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Insulina/metabolismoRESUMO
BACKGROUND: Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. MATERIAL AND METHODS: A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann-Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. RESULTS: Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 ± 0.9 vs. 6.9 ± 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. CONCLUSION: Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups.
Assuntos
Glicemia/análise , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Metformina/uso terapêutico , Adulto , Automonitorização da Glicemia , Método Duplo-Cego , Feminino , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Hemoglobinas Glicadas , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The prevalence of type 2 diabetes in black/African Americans from North and South America is high; yet data evaluating antidiabetic agents in this population is scarce. To address this gap, we pooled data from the clinical development program for linagliptin. METHODS: A retrospective pooled analysis of eight completed randomized, placebo-controlled Phase III trials of linagliptin identified 336 patients with type 2 diabetes who self-identified their ethnicity as black or African American. Participants received linagliptin (n = 173, 5 mg/day) or placebo (n = 163) as monotherapy, or as add-on to other antidiabetic agents, including insulin. The primary end point was the change in glycated hemoglobin (HbA1c) from baseline to week 18 or 24. RESULTS: The placebo-adjusted mean change (95% confidence interval [CI]) in HbA1c from baseline was -0.69% (-0.92 to -0.46; p < 0.0001) at week 18 (eight trials), and -0.64% (-0.90 to -0.39; p < 0.0001) at week 24 (six trials). The placebo-adjusted mean change (95% CI) in fasting plasma glucose from baseline was -11.7 mg/dL (-23.1 to -0.3; p = 0.0446) at week 18 and -14.7 mg/dL (-25.7 to -3.8; p = 0.0087) at week 24. Incidence of investigator-defined hypoglycemia was similar between the two groups (linagliptin, 12.1%; placebo, 11.7%). Overall, the safety profile of linagliptin in this patient group was comparable to that of placebo, with comparable incidence of adverse events; linagliptin was weight-neutral in this patient population. CONCLUSION: Linagliptin provided clinically significant improvements in glycemic control without increased risk of hypoglycemia and without weight gain, representing a useful type 2 diabetes therapy option for the black/African American population.