RESUMEN
Galectins are a family of mammalian carbohydrate-binding proteins expressed by many cell types. Galectins can function intracellularly and can also be secreted to bind to cell surface glycoconjugate counterreceptors. Some galectins are made by immune cells, whereas other galectins are secreted by different cell types, such as endothelial or epithelial cells, and bind to immune cells to regulate immune responses. Galectin binding to a single glycan ligand is a low-affinity interaction, but the multivalency of galectins and the glycan ligands presented on cell surface glycoproteins results in high-avidity binding that can reversibly scaffold or cluster these glycoproteins. Galectin binding to a specific glycoprotein counterreceptor is regulated in part by the repertoire of glycosyltransferase enzymes (which make the glycan ligands) expressed by that cell, and the effect of galectin binding results from clustering or retention of specific glycoprotein counterreceptors bearing these specific ligands.
Asunto(s)
Galectinas/metabolismo , Glicosiltransferasas/metabolismo , Inmunidad , Animales , Carbohidratos/inmunología , Citoesqueleto , Galectinas/inmunología , Glicoproteínas/metabolismo , Humanos , Unión Proteica , Agregación de ReceptoresRESUMEN
ABP 959 is being developed as a biosimilar to Soliris® (eculizumab) reference product (RP), which was approved under orphan designation for a group of rare diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Development of biosimilars for therapeutics approved for rare disease indications must provide scientific rationale based on the totality of evidence (TOE). To support the TOE and the scientific justification for extrapolation to all approved indications for eculizumab RP, including but not limited to aHUS and NMOSD, we utilized simulated ex-vivo pharmacodynamic (PD) assessments to compare the complement component 5 (C5) inhibitory activity of ABP 959 and the RP. Hemolysis activity of CH50 and AH50, and Wieslab CP, AP, and LP endpoints represent the three complement activation pathways (classical, alternative, and lectin), all of which share the terminal pathway and require C5 for activity. These endpoints were evaluated in normal serum, simulated aHUS serum, and simulated NMOSD serum to provide a robust comparison. The results support the conclusion that ABP 959 and eculizumab RP exhibit highly similar inhibition of C5 function regardless of the type of serum used. This work presents a full comparison of the effect of C5 inhibition across five complement functional assays. Using this approach to confirm functional similarity of ABP 959 with eculizumab RP contributes to the TOE for biosimilarity and provides support for extrapolation based on inhibition of C5 function to other rare disease indications approved for eculizumab RP.
Asunto(s)
Síndrome Hemolítico Urémico Atípico , Biosimilares Farmacéuticos , Neuromielitis Óptica , Humanos , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Neuromielitis Óptica/tratamiento farmacológico , Enfermedades RarasRESUMEN
Surface plasmon resonance (SPR) analysis provides important binding characteristic information for an antibody to its binding partner, such as binding specificity and affinity (KD). In recent years, SPR has been increasingly used in biosimilar development as part of the comparative analytical similarity assessment. Although there is no systematic study describing how to qualify SPR assays, there are various SPR result types (outputs) that have been used for assay qualification in publicly available regulatory documents. The mixed usage of SPR output can cause confusion and can be misleading when comparing binding attributes among antibody molecules. In this report, using a recombinant huIgG1 (mAb 1) antibody as an example, we performed assay qualification strictly based on the nature of the biomolecular interaction. We recommend that KD should be used as the output of assay qualification when the KD can be measured accurately by SPR. When KD cannot be accurately determined in a SPR setting, sensorgram comparison and Parallel Line Analysis (PLA) can be used to qualify the assay. We emphasize the importance of setting up appropriate SPR assay conditions for target and/or Fc receptor interactions to ensure the assay qualification parameters, such as accuracy and repeatability, to meet the criteria acceptable for regulatory filings. With increasing numbers of biotherapeutics being developed, the methods and guidelines provided here can help to align SPR application between the drug development industry and regulatory authorities which will benefit the scientific communities involved in biotherapeutic drug development.
Asunto(s)
Anticuerpos , Resonancia por Plasmón de Superficie , Resonancia por Plasmón de Superficie/métodos , TecnologíaRESUMEN
BACKGROUND: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population. METHODS: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days. RESULTS: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%). CONCLUSIONS: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.
Asunto(s)
Arteria Braquial/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Linagliptina/uso terapéutico , Microvasos/efectos de los fármacos , Compuestos de Sulfonilurea/uso terapéutico , Anciano , Biomarcadores/sangre , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/fisiopatología , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/enzimología , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/enzimología , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Quimioterapia Combinada , Endotelio Vascular/fisiopatología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Linagliptina/efectos adversos , Masculino , Metformina/uso terapéutico , Microcirculación/efectos de los fármacos , Microvasos/fisiopatología , Persona de Mediana Edad , Compuestos de Sulfonilurea/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vasodilatación/efectos de los fármacosRESUMEN
AIMS: The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. METHODS: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. RESULTS: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. CONCLUSIONS: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
Asunto(s)
Albuminuria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Hiperglucemia/inducido químicamente , Linagliptina/uso terapéutico , Insuficiencia Renal/tratamiento farmacológico , Anciano , Albuminuria/etiología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal/complicaciones , Insuficiencia Renal/epidemiología , Nivel de Atención , Resultado del TratamientoRESUMEN
During inflammation, dendritic cells emigrate from inflamed tissue across the lymphatic endothelium into the lymphatic vasculature and travel to regional lymph nodes to initiate immune responses. However, the processes that regulate dendritic cell tissue egress and migration across the lymphatic endothelium are not well defined. The mammalian lectin galectin-1 is highly expressed by vascular endothelial cells in inflamed tissue and has been shown to regulate immune cell tissue entry into inflamed tissue. Here, we show that galectin-1 is also highly expressed by human lymphatic endothelial cells, and deposition of galectin-1 in extracellular matrix selectively regulates migration of specific human dendritic cell subsets. The presence of galectin-1 inhibits migration of immunogenic dendritic cells through the extracellular matrix and across lymphatic endothelial cells, but it has no effect on migration of tolerogenic dendritic cells. The major galectin-1 counter-receptor on both dendritic cell populations is the cell surface mucin CD43; differential core 2 O-glycosylation of CD43 between immunogenic dendritic cells and tolerogenic dendritic cells appears to contribute to the differential effect of galectin-1 on migration. Binding of galectin-1 to immunogenic dendritic cells reduces phosphorylation and activity of the protein-tyrosine kinase Pyk2, an effect that may also contribute to reduced migration of this subset. In a murine lymphedema model, galectin-1(-/-) animals had increased numbers of migratory dendritic cells in draining lymph nodes, specifically dendritic cells with an immunogenic phenotype. These findings define a novel role for galectin-1 in inhibiting tissue emigration of immunogenic, but not tolerogenic, dendritic cells, providing an additional mechanism by which galectin-1 can dampen immune responses.
Asunto(s)
Movimiento Celular/inmunología , Células Dendríticas/inmunología , Células Endoteliales/inmunología , Galectina 1/inmunología , Animales , Línea Celular , Movimiento Celular/genética , Células Dendríticas/patología , Modelos Animales de Enfermedad , Células Endoteliales/patología , Matriz Extracelular/genética , Matriz Extracelular/inmunología , Quinasa 2 de Adhesión Focal/genética , Quinasa 2 de Adhesión Focal/inmunología , Galectina 1/genética , Glicosilación , Humanos , Leucosialina/genética , Leucosialina/inmunología , Linfedema/genética , Linfedema/inmunología , Linfedema/patología , Ratones , Ratones NoqueadosRESUMEN
Leukocyte entry from the blood into inflamed tissues, exit into the lymphatics, and migration to regional lymph nodes are all crucial processes for mounting an effective adaptive immune response. Leukocytes must cross two endothelial cell layers, the vascular and the lymphatic endothelial cell layers, during the journey from the blood to the lymph node. The proteins and cellular interactions which regulate leukocyte migration across the vascular endothelium are well studied; however, little is known about the factors that regulate leukocyte migration across the lymphatic endothelium. Here, we will summarize evidence for a role for galectins, a family of carbohydrate-binding proteins, in regulating leukocyte migration across the vascular endothelium and propose that galectins are also involved in leukocyte migration across the lymphatic endothelium.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Galectinas/metabolismo , Regulación de la Expresión Génica/inmunología , Inflamación/inmunología , Leucocitos/inmunología , Endotelio Linfático/inmunología , Endotelio Vascular/inmunología , Galectinas/farmacología , Humanos , Leucocitos/fisiologíaRESUMEN
The majority (>95%) of thymocytes undergo apoptosis during selection in the thymus. Several mechanisms have been proposed to explain how apoptosis of thymocytes that are not positively selected occurs; however, it is unknown whether thymocytes die purely by "neglect" or whether signaling through a cell-surface receptor initiates an apoptotic pathway. We have previously demonstrated that on double positive thymocytes the ligation of CD8 in the absence of TCR engagement results in apoptosis and have postulated this is a mechanism to remove thymocytes that have failed positive selection. On mature single positive T cells CD8 acts as a co-receptor to augment signaling through the TCR that is dependent on the phosphorylation of the adaptor protein, linker for activation of T cells (LAT). Here, we show that during CD8-mediated apoptosis of double positive thymocytes there is an increase in the association of CD8 with LAT and an increase in LAT tyrosine phosphorylation. Decreasing LAT expression and mutation of tyrosine residues of LAT reduced apoptosis upon crosslinking of CD8. Our results identify novel functions for both CD8 and LAT that are independent of TCR signal transduction and suggest a mechanism for signal transduction leading to apoptosis upon CD8 crosslinking.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Apoptosis/inmunología , Antígenos CD8/fisiología , Linfocitos T CD8-positivos/fisiología , Proteínas de la Membrana/fisiología , Fosfoproteínas/fisiología , Transducción de Señal/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/genética , Interferencia de ARN , Receptores de Antígenos de Linfocitos T/fisiología , Tirosina/metabolismo , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
AIMS: To examine the safety and efficacy of linagliptin in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global clinical trials program. METHODS: Patient-level data were pooled from randomized, placebo-controlled clinical trials of linagliptin (5mg, monotherapy or combination therapy). Safety/efficacy analyses were conducted for patients with CAD and ≥12 and ≥24weeks of treatment, respectively. RESULTS: The safety analysis included 19 trials (linagliptin, n=451; placebo, n=272) and the efficacy analysis, 12 trials (linagliptin, n=328; placebo, n=198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo. Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24weeks, mean adjusted change (standard error) from baseline glycosylated hemoglobin was -0.64% (0.04) with linagliptin vs. -0.08% (0.05) with placebo (P<.001). CONCLUSIONS: This comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and was effective.
Asunto(s)
Enfermedad de la Arteria Coronaria/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Linagliptina/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population. METHODS: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.5%-12.0% received linagliptin/metformin or linagliptin monotherapy. Subgroups of baseline HbA1c, age, body-mass index (BMI), renal function, race, and ethnicity were evaluated, with efficacy measured by HbA1c change from baseline after 24 weeks. RESULTS: HbA1c reductions from baseline (mean 9.7%) at week 24 in the overall population were an adjusted mean -2.81% ± 0.12% with linagliptin/metformin (n = 132) and -2.02% ± 0.13% with linagliptin (n = 113); treatment difference -0.79% (95% CI -1.13 to -0.46, P < 0.0001). In patients with baseline HbA1c ≥9.5%, HbA1c reduction was -3.37% with linagliptin/metformin (n = 76) and -2.53% with linagliptin (n = 61); difference -0.84% (95% CI -1.32 to -0.35). In those with baseline HbA1c <9.5%, HbA1c reduction was -2.08% with linagliptin/metformin (n = 56) and -1.39% with linagliptin (n = 52); difference -0.69% (95% CI -1.23 to -0.15). Changes in HbA1c and treatment differences between the linagliptin/metformin and linagliptin groups were of similar magnitudes to the overall population across patient subgroups based on age, BMI, renal function, and race. Drug-related adverse events occurred in 8.8% and 5.7% of linagliptin/metformin and linagliptin patients, respectively; no severe hypoglycemia occurred. CONCLUSION: Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race. Thus, newly diagnosed, markedly hyperglycemic patients may be effectively treated by combinations of oral agents. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT01512979.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Linagliptina/uso terapéutico , Metformina/uso terapéutico , Adulto , Anciano , Glucemia , Índice de Masa Corporal , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Pruebas de Función Renal , Linagliptina/administración & dosificación , Linagliptina/efectos adversos , Masculino , Metformina/administración & dosificación , Metformina/efectos adversos , Persona de Mediana Edad , Grupos RacialesRESUMEN
Leukocyte migration from the bloodstream into tissues, and from tissues to lymph nodes, depends on expression of specific adhesion and signaling molecules by vascular endothelial cells and lymphatic endothelial cells. Tissue damage and microbial infection induce vascular endothelial cells to up-regulate expression of adhesion molecules to facilitate entry of several leukocyte populations from blood into tissues. Many of these cells then leave inflamed tissue and migrate to regional lymph nodes. A critical population that emigrates from inflamed tissue is dendritic cells. Dendritic cells in tissue have to migrate through extracellular matrix and across a layer of lymphatic endothelial cells to enter the lymphatic vasculature. Little is known about the adhesion molecules expressed by lymphatic endothelial cells or the processes required for the critical step of dendritic cell exit from tissues, specifically migration through the extracellular matrix and basal-to-apical migration across the lymphatic endothelial cell layer into lymphatic vasculature.Members of the galectin family of carbohydrate binding proteins are expressed in both vascular and lymphatic endothelial cells. Dynamic changes in galectin expression during inflammation are known to regulate leukocyte tissue entry during inflammation. However, the roles of galectin family members expressed by lymphatic endothelial cells in leukocyte tissue exit remain to be explored.Here, we describe an in vitro transmigration assay that mimics dendritic cell tissue exit in the presence and absence of galectin protein. Fluorescently labeled human dendritic cell migration through extracellular matrix and across human lymphatic endothelial cells is examined in the presence and absence of recombinant human galectin protein.
Asunto(s)
Movimiento Celular , Células Dendríticas/citología , Células Endoteliales/citología , Matriz Extracelular/metabolismo , Galectinas/metabolismo , Técnicas de Cultivo de Célula , Separación Celular , Fluoresceínas/metabolismo , Humanos , Membranas Artificiales , Proteínas Recombinantes/metabolismo , Coloración y Etiquetado , Succinimidas/metabolismoRESUMEN
Sulphonylureas (SUs) are antidiabetic agents widely used in patients with Type 2 Diabetes Mellitus (T2DM). Observational retrospective studies have raised concerns regarding the cardiovascular (CV) safety of this class of drugs, and data from observational and registry studies are conflicting. To address the SU controversy, this review looked at longer-term RCTs, where SUs were compared in a head-to-head fashion with active comparators. An analysis of 18 studies did not find any increase in the incidence of CV events with SU therapy. However, the available data are limited and most importantly, there is a lack of prospective, adequately powered, formal head-to-head CV outcome trials. Since SUs are still being used as second-line therapy in combination with metformin and in some cases as first-line treatment of T2DM, there is a definite need for CV safety data from a prospective RCT. The CAROLINA(®) study is currently the largest CV outcome study with a direct comparison of an SU and a dipeptidyl peptidase-4 inhibitor (DPP-4). Based on the study design and statistical power of CAROLINA(®), its results will provide a unique perspective regarding CV outcomes of these 2 commonly used agents.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Compuestos de Sulfonilurea/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Quimioterapia Combinada , Humanos , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Compuestos de Sulfonilurea/administración & dosificaciónRESUMEN
INTRODUCTION: The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naïve patients with type 2 diabetes. METHODS: Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks. RESULTS: At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups. CONCLUSION: Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day. FUNDING: Boehringer Ingelheim.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Linagliptina/uso terapéutico , Metformina/uso terapéutico , Adulto , Anciano , Glucemia , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Linagliptina/administración & dosificación , Linagliptina/efectos adversos , Masculino , Metformina/administración & dosificación , Metformina/efectos adversos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents. RESEARCH DESIGN AND METHODS: A total of 1,261 patients (HbA1c ≥7.0% [53 mmol/mol] to ≤10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators' discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks. RESULTS: At week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by -0.6% (-6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference -0.65% [95% CI -0.74 to -0.55] [-7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin -0.30 kg, placebo -0.04 kg). CONCLUSIONS: Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.