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1.
Expert Opin Pharmacother ; 21(1): 121-130, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31689132

RESUMEN

Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs).Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone.Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues  (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were -0.76 ± 1.27% and -23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD.Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Hipoglucemiantes/administración & dosificación , Vildagliptina/administración & dosificación , Anciano , Glucemia/efectos de los fármacos , Estudios de Cohortes , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Quimioterapia Combinada , Femenino , Hemoglobina A Glucada/análisis , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/administración & dosificación , Insulina/uso terapéutico , Japón , Masculino , Metformina/administración & dosificación , Metformina/uso terapéutico , Persona de Mediana Edad , Vigilancia de Productos Comercializados , Compuestos de Sulfonilurea/uso terapéutico , Vildagliptina/efectos adversos
2.
PLoS Med ; 16(12): e1002999, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31877127

RESUMEN

BACKGROUND: Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication-including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)-can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. METHODS AND FINDINGS: We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367-2.963, p < 0.001; 2.352, 95% CI 2.123-2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071-1.340, p = 0.002; 1.496, 95% CI 1.342-1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099-1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776-1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915-1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. CONCLUSIONS: Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.


Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemia/mortalidad , Insulina/efectos adversos , Metformina/efectos adversos , Adulto , Anciano , Enfermedades Cardiovasculares/mortalidad , Estudios de Cohortes , Diabetes Mellitus Tipo 2/mortalidad , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Hipoglucemia/complicaciones , Hipoglucemiantes/efectos adversos , Incidencia , Insulina/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Compuestos de Sulfonilurea/efectos adversos , Tiazolidinedionas/uso terapéutico , Resultado del Tratamiento
3.
Diabetes Res Clin Pract ; 158: 107909, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31697992

RESUMEN

AIMS: To characterise the patterns of switching, adherence, and persistence among adults aged ≥18 years with diabetes prescribed dipeptidyl peptidase-4 inhibitors (DPP-4is) in Australia. METHODS: The analysis included 15,915 adults newly prescribed DPP-4is (sitagliptin = 9576; vildagliptin = 1130; saxagliptin = 1126; linagliptin = 3560; and alogliptin = 523). Multivariable logistic regression model was used to compare the non-adherence (proportion of days covered [PDC] <0.80) rates whereas Cox proportional hazards regression models were used to compare switching and non-persistence (≥90-day gap) among different DPP4-is over 12-months. RESULTS: Overall, 36.0% (5722/15,915) of DPP-4i users were non-adherent and 30.0% (4775/15,915) were non-persistent at 12-months. Compared to sitagliptin, vildagliptin, linagliptin, and alogliptin were not associated with higher non-adherence and non-persistence. However, saxagliptin was associated with a higher likelihood of being non-adherent (odds ratio 1.41, 95% confidence interval [CI] 1.23-1.60) or non-persistent (hazard ratio 1.27, 95% CI 1.15-1.42) compared to sitagliptin. Just 3.2% of people switched between different DPP-4is. Compared to sitagliptin, people initiated on vildagliptin, saxagliptin, alogliptin, and linagliptin were more likely to switch. CONCLUSIONS: We found no significant differences in the adherence and persistence rates between alogliptin, vildagliptin or linagliptin and sitagliptin. However, saxagliptin was associated with higher non-adherence and non-persistence compared to sitagliptin. Switching was lowest amongst users of sitagliptin.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Anciano , Estudios de Cohortes , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Femenino , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Life Sci ; 239: 117017, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31678284

RESUMEN

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Asunto(s)
Adamantano/análogos & derivados , Asma/tratamiento farmacológico , Dipéptidos/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , FN-kappa B/efectos de los fármacos , Receptor Toll-Like 4/efectos de los fármacos , Enfermedad Aguda , Adamantano/uso terapéutico , Animales , Asma/inducido químicamente , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Dexametasona/uso terapéutico , L-Lactato Deshidrogenasa/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Óxido Nítrico/metabolismo , Ovalbúmina , Peroxidasa/metabolismo
5.
Int Heart J ; 60(6): 1421-1429, 2019 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-31735774

RESUMEN

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE-/-) mice. Eight-week-old nondiabetic ApoE-/- mice fed a Western-type diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE-/- mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE-/- mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.


Asunto(s)
Aterosclerosis/prevención & control , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Vildagliptina/uso terapéutico , Animales , Apolipoproteínas E , Aterosclerosis/etiología , Aterosclerosis/patología , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Células Endoteliales/fisiología , Endotelio Vascular/patología , Ratones , Ratones Endogámicos C57BL , Molécula 1 de Adhesión Celular Vascular/sangre
7.
Metabolism ; 101: 154001, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31672448

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.


Asunto(s)
Hígado Graso/tratamiento farmacológico , Hipoglucemiantes/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Pioglitazona/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico
10.
J Assoc Physicians India ; 67(10): 14-19, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31571445

RESUMEN

Background: Teneligliptin is widely prescribed dipeptidyl peptidase-4 inhibitor (DPP-4i) in India because of its economical pricing. However, there is no headto-head trial comparing teneligliptin with any other DPP-4i in Indian setting. We evaluated the efficacy and safety of teneligliptin versus sitagliptin as add-on to metformin and/or sulfonylureas in patients with type 2 diabetes mellitus (T2DM). Methods: This prospective, open-label, randomized, active-controlled study enrolled 76 patients (1:1) at 2 centres. Patients received teneligliptin 20 mg or sitagliptin 100 mg orally once daily for 12 weeks as add-on to ongoing metformin or sulfonylurea therapy. Primary endpoint was mean change in glycosylated hemoglobin (HbA1c) from baseline at week 12. Results: Both arms were comparable (p>0.05) at baseline in terms of age, gender, metformin daily dose, sulfonylurea use, HbA1c, fasting and postprandial blood glucose (FBG and PPBG). At the end of 12 weeks, statistically significant reductions were observed in both teneligliptin and sitagliptin arms in HbA1c (-1.19 ± 1.16% p<0.0001 and -0.92 ± 0.95%, p<0.0001), in FBG (-28.3 ± 63.0 mg/dL, p= 0.01 and -22.9 ± 47.4 mg/dL, p=0.006) and PPBG (-41.3 ± 85.4 mg/dL, p=0.006 and -54.7 ± 85.6 mg/dL, p=0.0005). The reductions in all glycemic parameters were similar between the arms. Both gliptins were well-tolerated with no difference in the number of adverse events. There was no change in QT/QTc intervals or other ECG parameters at week 12 in both arms. In post-hoc comparison, percentage of patients achieving target HbA1c <7% (as per American Diabetes Association guidelines) at week 12 favored teneligliptin arm over sitagliptin arm (33.3% vs. 19.4% patients). Conclusion: Teneligliptin provided similar glycemic control as compared to sitagliptin and reduced HbA1c, FBG and PPBG values significantly within 12 weeks of treatment. Both gliptins were found to be safe and well-tolerated in Indian patients with T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Pirazoles/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Tiazolidinas/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Humanos , India , Estudios Prospectivos
11.
J Assoc Physicians India ; 67(8): 60-62, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31562719

RESUMEN

Aim: To evaluate the efficacy of DPP-4 inhibitors (DPP-4i) as the fourth drug in Asian Indian type2 DM patients uncontrolled inspite of using at least 3 oral anti diabetic drugs. Methods: A retrospective analysis of 7858 T2DM patients, who received a DPP-4i (Sitagliptin, Vildagliptin, Teneligliptin, Linagliptin and Saxagliptin) as the fourth drug to achieve glycemic control was undertaken. Patients with inadequate glycaemic control despite receiving optimum doses of at least any other three OADs were included in this analysis. Results: Patients were subdivided into 5 groups, based on the DPP-4i used for treatment: Sitagliptin (n=4787), Vildagliptin (n=2205), Teneligliptin (n=775), Linagliptin (n=64) and Saxagliptin (n=27). The mean fasting blood glucose (FPG) was 160.9 ± 20.4 mg/dl and mean post prandial glucose (PPG) was 227.8 ± 26.3 mg/dl. The mean baseline HbA1c was 8.2 ± 1.5 %. The mean duration required to control diabetes with all DPP-4i was 8.2 weeks with significantly lesser time with Sitagliptin (6.8 weeks, p<0.001). 81.5% of the total cases responded to treatment with a DPP-4i (P <0.05). At the end of the monitoring period, there was significant reduction in mean FPG by-28.1 ± 16.1 mg/dL(P=0.001), mean PPG by -55.3 ± 17.0 mg/dL(P=0.001), and mean HbA1c by -1.2 ± 0.7 (P= 0.001). There was no significant difference between the groups with respect to reduction in PPG and HbA1c. Conclusion: DPP-4 inhibitors are effective in achieving desired glycaemic goals even when used as a fourth drug in patients with inadequate glycaemic control despite receiving an optimum dose of at least 3 OADs.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Glucemia , Hemoglobina A Glucada , Humanos , Hipoglucemiantes , India , Estudios Retrospectivos , Fosfato de Sitagliptina , Resultado del Tratamiento
12.
Diabetes Res Clin Pract ; 156: 107832, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31513823

RESUMEN

AIMS: Dipeptidyl peptidase 4 inhibitors (DPP4Is) can increase sympathetic activity. We aimed to evaluate the direct association between serum DPP4 activity and sympathetic activity in humans. METHODS: Fasting serum DPP4 activity and plasma levels of catecholamines and their metabolites were measured in 211 patients with type 2 diabetes mellitus (T2DM) treated with DPP4I (n = 146) or non-DPP4I therapy (n = 65) and in healthy control subjects (n = 30). RESULTS: Although there were no differences in plasma levels of catecholamines and their metabolites between the DPP4I and non-DPP4I groups, the levels in both of these groups were lower than those in the healthy control group. In DPP4I-treated patients, serum DPP4 activity showed an inverse correlation with plasma levels of norepinephrine (NE) (r = -0.339, p < 0.01), metanephrine (MET) (r = -0.251, p < 0.01) and normetanephrine (r = -0.312, p < 0.001). In addition, plasma MET level showed a weak inverse correlation with serum DPP4 activity in the combined T2DM group. In DPP4I-treated patients, the inverse correlation between DPP4 activity and plasma NE remained significant even after multiple adjustments. CONCLUSIONS: Our results suggest that although sympathetic activity is lower in patients with T2DM, the greater the suppression of DPP4 activity by DPP4I therapy, the greater the increase in sympathetic activity is, which may have clinical implications in high risk T2DM patients.


Asunto(s)
Catecolaminas/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Adulto , Anciano , Estudios Transversales , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad
13.
Arch Med Res ; 50(3): 133-141, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-31495390

RESUMEN

BACKGROUND: Myocardial infarction (MI) is one of the most important diseases that has stimulated interest in understanding cardiac function recovery. SDF-1 is a chemotactic factor and a pro-angiogenic molecule; SDF-1 degradation is inhibited by dipeptidyl peptidase-4 (DPP4) inhibitors, such as vildagliptin. We investigated whether vildagliptin affects angiogenesis in MI and improves cardiac function recovery. METHODS: We established a therapeutic strategy using vildagliptin and G-CSF treatment to improve cardiac function recovery after MI in mice. RESULTS: Vildagliptin treatment increased the myocardial homing of circulating CXCR4+ stem cells and angiogenesis. The combination of vildagliptin and G-CSF treatment attenuated cardiac remodeling and improved survival and cardiac function after MI. Vildagliptin treatment induced active SDF-1, which preserved the cardiac SDF-1-CXCR4 homing axis for MI injury. CONCLUSION: Vildagliptin and G-CSF induced stem cell mobilization and increased angiogenesis as a therapeutic strategy for improving survival and cardiac function after MI.


Asunto(s)
Quimiocina CXCL12/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Vildagliptina/uso terapéutico , Animales , Dipeptidil Peptidasa 4/metabolismo , Modelos Animales de Enfermedad , Corazón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Receptores CXCR4/metabolismo , Células Madre
14.
Ann Acad Med Singapore ; 48(7): 217-223, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31495867

RESUMEN

INTRODUCTION: The risk for diabetes progression varies greatly in individuals with type 2 diabetes mellitus (T2DM). We aimed to study the clinical determinants of diabetes progression in multiethnic Asians with T2DM. MATERIALS AND METHODS: A total of 2057 outpatients with T2DM from a secondary-level Singapore hospital were recruited for the study. Diabetes progression was defined as transition from non-insulin use to requiring sustained insulin treatment or glycated haemoglobin (HbA1c) ≥8.5% when treated with 2 or more oral hypoglycaemic medications. Multivariable logistic regression (LR) was used to study the clinical and biochemical variables that were independently associated with diabetes progression. Forward LR was then used to select variables for a parsimonious model. RESULTS: A total of 940 participants with no insulin use or indication for insulin treatment were analysed. In 3.2 ± 0.4 (mean ± SD) years' follow-up, 163 (17%) participants experienced diabetes progression. Multivariable LR revealed that age at T2DM diagnosis (odds ratio [95% confidence interval], 0.96 [0.94-0.98]), Malay ethnicity (1.94 [1.19-3.19]), baseline HbA1c (2.22 [1.80-2.72]), body mass index (0.96 [0.92-1.00]) and number of oral glucose-lowering medications (1.87 [1.39-2.51]) were independently associated with diabetes progression. Area under receiver operating characteristic curve of the parsimonious model selected by forward LR (age at T2DM diagnosis, Malay ethnicity, HbA1c and number of glucose-lowering medication) was 0.76 (95% CI, 0.72-0.80). CONCLUSION: Young age at T2DM diagnosis, high baseline HbA1c and Malay ethnicity are independent determinants of diabetes progression in Asians with T2DM. Further mechanistic studies are needed to elucidate the pathophysiology underpinning progressive loss of glycaemic control in patients with T2DM.


Asunto(s)
Grupo de Ascendencia Continental Asiática , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina A Glucada/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Metformina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Adulto , Edad de Inicio , Anciano , Área Bajo la Curva , China , Estudios de Cohortes , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Progresión de la Enfermedad , Quimioterapia Combinada , Grupos Étnicos , Femenino , Humanos , India , Modelos Logísticos , Estudios Longitudinales , Malasia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Singapur , Tiazolidinedionas/uso terapéutico
15.
J Korean Med Sci ; 34(35): e224, 2019 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-31496139

RESUMEN

BACKGROUND: There have been equivocal results in studies of the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i) on fractures. In this study, we analyzed the effect of DPP-4i on bone fracture risk in a Korean population. METHODS: We extracted subjects (n = 11,164) aged 50 years or older from the National Health Insurance Service-National Sample Cohort 2.0 from 2009 to 2014. Our control group included subjects without diabetes (n = 5,582), and our treatment groups with diabetes included DPP-4i users (n = 1,410) and DPP-4i non-users (n = 4,172). The primary endpoint was the incidence of a composite outcome consisting of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures. The secondary endpoint was the incidence of each individual component of the composite outcome. Survival analysis was performed with adjustment for age, gender, diabetes complications severity index, Charlson comorbidity index, hypertension medication, and dyslipidemia treatment. RESULTS: The incidence of the composite outcome per 1,000 person-years was 0.089 in DPP-4i users, 0.099 in DPP-4i non-users, and 0.095 in controls. There was no significant difference in fracture risk between DPP-4i users and DPP-4i non-users or controls after the adjustments (P > 0.05). The incidences of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures were not significantly different between DPP-4i users and non-users. The results of subgroup analyses by gender and age were consistent. CONCLUSION: DPP-4i had no significant effect on the risk of fractures in a Korean population.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Fracturas Óseas/diagnóstico , Hipoglucemiantes/efectos adversos , Anciano , Estudios de Cohortes , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Femenino , Fracturas Óseas/epidemiología , Fracturas Óseas/etiología , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico , Osteoporosis/epidemiología , Osteoporosis/etiología , República de Corea/epidemiología , Factores de Riesgo
16.
Life Sci ; 234: 116738, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31398418

RESUMEN

AIMS: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. MAIN METHODS: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. KEY FINDINGS: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SIGNIFICANCE: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Glomérulos Renales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfato de Sitagliptina/uso terapéutico , Animales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratas , Ratas Wistar , Fosfato de Sitagliptina/farmacología
17.
Prog Cardiovasc Dis ; 62(4): 342-348, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31442511

RESUMEN

Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Péptido 1 Similar al Glucagón/administración & dosificación , Seguridad del Paciente/estadística & datos numéricos , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Ensayos Clínicos Fase IV como Asunto , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Estudios de Seguimiento , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Medición de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación
18.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-31434198

RESUMEN

Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin's administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1bright. Significant reduction in Aß42 level has been associated with the use of linagliptin implying potential application in Alzheimer's disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron's survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1α/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1α/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Linagliptina/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Proliferación Celular/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Masculino , Óxido Nítrico/metabolismo , Sirtuina 1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
19.
Life Sci ; 234: 116776, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31425698

RESUMEN

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.


Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Animales , Diabetes Mellitus/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/metabolismo , Estrés Oxidativo/efectos de los fármacos
20.
Artículo en Inglés | MEDLINE | ID: mdl-31366085

RESUMEN

Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially associated with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiology, its treatment is varied and based upon a multitude of pharmacologic agents aiming to tackle the many aspects of the disease pathophysiology (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or "gliptins") represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biological activity of the "incretin" hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiological problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/clasificación , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/fisiopatología , Humanos
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