Effect of Linagliptin versus Metformin on Insulin Secretion, Insulin Sensitivity and Glucose Control in Subjects with Impaired Glucose Tolerance / Efecto de la Linagliptina Frente a la Metformina en la Secreción de Insulina, Sensibilidad a la Insulina y Control de la Glucosa en Sujetos con Intolerancia a la Glucosa

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.

Comparative Cardiovascular Risks of Dipeptidyl Peptidase-4 Inhibitors: Analyses of Real-world Data in Korea

BACKGROUND AND OBJECTIVES: To compare cardiovascular disease (CVD) risk associated with 5 different dipeptidyl peptidase-4 inhibitors (DPP-4is) in people with type 2 diabetes. METHODS: We identified 534,327 people who were newly prescribed sitagliptin (n=167,157), vildagliptin (n=67,412), saxagliptin (n=29,479), linagliptin (n=220,672), or gemigliptin (n=49,607) between January 2013 and June 2015 using the claims database of the Korean National Health Insurance System. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for major CVD events (myocardial infarction, stroke, or death) among users of different DPP-4is. The model was adjusted for sex, age, duration of DPP-4i use, use of other glucose-lowering drugs, use of antiplatelet agents, hypertension, dyslipidemia, atrial fibrillation, chronic kidney disease, microvascular complications of diabetes, Charlson comorbidity index, and the calendar index year as potential confounders. RESULTS: Compared to sitagliptin users, the fully adjusted HRs for CVD events were 0.97 (95% confidence interval [CI], 0.94–1.01; p=0.163) for vildagliptin, 0.76 (95% CI, 0.71–0.81; p < 0.001) for saxagliptin, 0.95 (95% CI, 0.92–0.98; p < 0.001) for linagliptin, and 0.84 (95% CI, 0.80–0.88; p < 0.001) for gemigliptin. CONCLUSIONS: Compared to sitagliptin therapy, saxagliptin, linagliptin, and gemigliptin therapies were all associated with a lower risk of cardiovascular events.

Dipeptidyl Peptidase 4 Inhibitors and the Risk of Cardiovascular Disease in Patients with Type 2 Diabetes: A Tale of Three Studies

Dipeptidyl peptidase 4 (DPP4) inhibitors have been touted as promising antihyperglycemic agents due to their beneficial effects on glycemia without inducing hypoglycemia or body weight gain and their good tolerability. Beyond their glucose-lowering effects, numerous clinical trials and experimental studies have suggested that DPP4 inhibitors may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms or involving other substrates. Since 2008, regulatory agencies have required an assessment of cardiovascular disease (CVD) safety for the approval of all new anti-hyperglycemic agents, including incretin-based therapies. Three large prospective DPP4 inhibitor trials with cardiovascular (CV) outcomes have recently been published. According to the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) and EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) trials, DPP4 inhibitors, including saxagliptin and alogliptin, did not appear to increase the risk of CV events in patients with type 2 diabetes and established CVD or high risk factors. Unexpectedly, saxagliptin significantly increased the risk of hospitalization for heart failure by 27%, a finding that has not been explained and that requires further exploration. More recently, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial demonstrated the CV safety of sitagliptin, including assessments of the primary composite CV endpoint and hospitalization for heart failure in patients with type 2 diabetes and established CVD. The CV outcomes of an ongoing linagliptin trial are expected to provide new evidence about the CV effects of a DPP4-inhibitor in patients with type 2 diabetes.

A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy / 药学学报

Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.

Determination of yogliptin and its metabolite in Wistar rat plasma by liquid chromatography-tandem mass spectrometry / 药学学报

A rapid, sensitive and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the simultaneous determination of yogliptin and its metabolite in Wistar rat plasma. Linagliptin and dexamethasone were chosen as the internal standards of yogliptin and its metabolite, (R)-8-(3-hydroxypiperidine- -yl)-7-(but-2-yn-1-yl)-1-((5-fluorobenzo[d]thiazol-2-yl)methyl)-3-methyl- H-purine-2, 6 (3H, 7H)-dione, respectively. After a simple protein precipitation using acetonitrile as the precipitating solvent, both analytes and ISs were separated on a Grace Altima HP C18 column (2.1 mm x 50 mm, 5 microm) with gradient elution using methanol (containing 0.1% formic acid, 4 mmol x L(-1) ammonium acetate)-0.1% formic acid (containing 4 mmol x L(-1) ammonium acetate) as the mobile phase. A chromatographic total run time of 4.4 min was achieved. Mass spectrometric detection was conducted with electrospray ionization under positive-ion and multiple-reaction monitoring modes. Linear calibration curves for yogliptin and its metabolite were over the concentration range of 0.5 to 500 ng x mL(-1) with a lower limit of quantification of 0.5 ng x mL(-1). The intra- and inter- assay precisions were all below 14%, the accuracies were all in standard ranges. The method was used to determine the concentration of yogliptin and M1 in Wistar rat plasma after a single oral administration of yogliptin (27 mg x kg(-1)). The method was proved to be selective, sensitive and suitable for pharmacokinetic study of yogliptin and M1 in Wistar rat plasma.

Comparison of DPP-4 Inhibitors / 임상당뇨병

During past several years, a novel class of antihyperglycemic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors, has become one of the most important options in the management of type 2 diabetes. These agents have unique insulinotropic actions as well as other advantages such as lower hypoglycemia and a weight-neutral effect compared to traditional insulin secretagogues. To date, 6 different DPP-4 inhibitors have been introduced: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin and gemiglitin. This review provides a summary of the clinical data for each DPP-4 inhibitor, and discusses the similarities and differences between them.