RESUMEN
AIM: To describe in type 2 diabetes the 24-hour distribution of hypoglycaemia and compare the frequency of nocturnal events based on a predefined nocturnal window or an expanded interval, using illustrative data for two insulin glargine formulations. METHODS: Temporal distribution of hypoglycaemic events was assessed descriptively and by profile using participant-level data from three randomized trials comparing insulin glargine 300 U/mL (Gla-300) and 100 U/mL (Gla-100). Risk of hypoglycaemia and annualized event rates were compared for the predefined nocturnal interval (00:00 to 05:59h) and an expanded window (22:00h to the pre-breakfast glucose measurement). RESULTS: Confirmed (≤3.9mmol/L [≤70 mg/dL]) or severe hypoglycaemic events were reported most frequently between 06:00 and 10:00 h with both insulins. Nearly threefold more events were identified using the expanded nocturnal interval. Risk of ≥1 nocturnal event was 25% lower with Gla-300 than Gla-100 with the predefined, and 16% lower with the expanded interval; annualized event rates were 31% and 24% lower with the predefined and expanded window, respectively. The between-insulin difference in number of nocturnal events depended markedly on the chosen nocturnal interval (556 vs. 1145 fewer events with Gla-300 using the predefined vs. expanded interval). CONCLUSIONS: The predefined 00:00-05:59h nocturnal interval excluded many hypoglycaemic events occurring during the actual overnight interval. While Gla-300 reduced hypoglycaemic events versus Gla-100 (regardless of the interval considered), the results obtained using the expanded window better reflect the clinical experience of people treated with basal insulin.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/epidemiología , Hipoglucemia/prevención & control , Insulina Glargina/efectos adversos , Insulina Glargina/uso terapéutico , Anciano , Glucemia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
AIM: To explore if efficacy and safety findings for insulin glargine 300U/mL (Gla-300) versus insulin glargine 100U/mL (Gla-100), observed over 6 months in insulin-naïve people with type 2 diabetes, are maintained after 12 months. METHODS: EDITION 3 was a phase 3a, randomized, multicentre, open-label, parallel-group, treat-to-target study of once-daily Gla-300 versus Gla-100 (target fasting self-monitored plasma glucose, 4.4-5.6mmol/L [80-100mg/dL]). Participants completing the initial 6-month treatment phase continued their previously allocated basal insulin. RESULTS: Of 878 participants randomized, 337/439 (77%) and 314/439 (72%) assigned to Gla-300 and Gla-100, respectively, completed 12 months of treatment. Improved glycaemic control was sustained until 12 months in both treatment groups, with similar reductions in HbA1c from baseline to month 12 (difference: -0.08 [95% confidence interval (CI): -0.23 to 0.07] % or -0.9 [-2.5 to 0.8] mmol/mol). Relative risk of experiencing≥1 confirmed (≤3.9mmol/L [≤70mg/dL]) or severe hypoglycaemic event with Gla-300 versus Gla-100 was 0.86 (95% CI: 0.69 to 1.07) at night and 0.92 (0.82 to 1.03) at any time of day. For events with a glycaemic threshold of<3.0mmol/L (<54mg/dL) these numbers were 0.76 (0.49 to 1.19) and 0.66 (0.50 to 0.88). A similar pattern was seen for documented symptomatic events. No between-group differences in adverse events were identified. CONCLUSION: Over 12 months, Gla-300 treatment was as effective as Gla-100 in reducing HbA1c in insulin-naïve people with type 2 diabetes, with lower overall risk of hypoglycaemia at the<3.0mmol/L threshold.
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Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/uso terapéutico , Insulina Glargina/uso terapéutico , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipoglucemia/sangre , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina Glargina/administración & dosificación , Insulina Glargina/efectos adversos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina Aspart/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Glucemia , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Esquema de Medicación , Sustitución de Medicamentos , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Insulina Aspart/efectos adversos , Insulina Aspart/farmacología , Insulina de Acción Prolongada/efectos adversos , Insulina de Acción Prolongada/farmacología , Resultado del TratamientoRESUMEN
AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10-1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17-1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83-1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV-specific/all-cause death. CONCLUSIONS: Ongoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV-specific/all-cause death.
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Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Anciano , Canadá/epidemiología , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/mortalidad , Cardiomiopatías Diabéticas/epidemiología , Cardiomiopatías Diabéticas/mortalidad , Cardiomiopatías Diabéticas/prevención & control , Europa (Continente)/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/fisiopatología , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Japón/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mortalidad , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of 'normal' physiological insulin secretion, thereby controlling basal and meal-time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3-10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet ß cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day-to-day changes in insulin sensitivity. Physiologically, meal-time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal-time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day-to-day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer-to-average physiological meal-time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile.
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Diabetes Mellitus/sangre , Insulina/sangre , Glucemia/efectos de los fármacos , Glucemia/fisiología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/fisiopatología , Humanos , Hipoglucemiantes/administración & dosificación , Inyecciones Subcutáneas , Insulina/administración & dosificación , Sistemas de Infusión de Insulina , Comidas , Periodo Posprandial/fisiologíaRESUMEN
Biosimilar insulins are approved copies of insulins outside patent protection. Advantages may include greater market competition and potential cost reduction, but clinicians and users lack a clear perspective on 'biosimilarity' for insulins. The manufacturing processes for biosimilar insulins are manufacturer-specific and, although these are reviewed by regulators there are few public data available to allow independent assessment or review of issues such as intrinsic quality or batch-to-batch variation. Preclinical measures used to assess biosimilarity, such as tissue and cellular studies of metabolic activity, physico-chemical stability and animal studies of pharmacodynamics, pharmacokinetics and immunogenicity may be insufficiently sensitive to differences, and are often not formally published. Pharmacokinetic and pharmacodynamic studies (glucose clamps) with humans, although core assessments, have problems of precision which are relevant for accurate insulin dosing. Studies that assess clinical efficacy and safety and device compatibility are limited by current outcome measures, such as glycated haemoblobin levels and hypoglycaemia, which are insensitive to differences between insulins. To address these issues, we suggest that all comparative data are put in the public domain, and that systematic clinical studies are performed to address batch-to-batch variability, delivery devices, interchangeability in practice and long-term efficacy and safety. Despite these challenges biosimilar insulins are a welcome addition to diabetes therapy and, with a transparent approach, should provide useful benefit to insulin users.
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Biosimilares Farmacéuticos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Animales , Técnica de Clampeo de la Glucosa , HumanosRESUMEN
AIMS: To evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. METHODS: EDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. RESULTS: Of 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had ≥1 confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. CONCLUSION: During 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/administración & dosificación , Insulina Glargina/administración & dosificación , Insulina/administración & dosificación , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/métodos , Ayuno/sangre , Femenino , Hemoglobina Glucada/efectos de los fármacos , Humanos , Masculino , Comidas , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of glargine 100 U/ml (Gla-100) in insulin-naïve people with type 2 diabetes using oral glucose-lowering drugs. METHODS: The EDITION 3 study was a multicentre, open-label, parallel-group study. Participants were randomized to Gla-300 or Gla-100 once daily for 6 months, discontinuing sulphonylureas and glinides, with a dose titration aimed at achieving pre-breakfast plasma glucose concentrations of 4.4-5.6 mmol/l (80-100 mg/dl). The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to month 6. The main secondary endpoint was percentage of participants with ≥1 nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia from week 9 to month 6. Other measures of glycaemia and hypoglycaemia, weight change and insulin dose were assessed. RESULTS: Randomized participants (n = 878) had a mean (standard deviation) age of 57.7 (10.1) years, diabetes duration 9.8 (6.4) years, body mass index 33.0 (6.7) kg/m(2) and HbA1c 8.54 (1.06) % [69.8 (11.6) mmol/mol]. HbA1c levels decreased by equivalent amounts with the two treatments; the least squares mean difference in change from baseline was 0.04 [95% confidence interval (CI) -0.09 to 0.17] % or 0.4 (-1.0 to 1.9) mmol/mol. Numerically fewer participants reported ≥1 nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia from week 9 to month 6 [relative risk (RR) 0.89 (95% CI 0.66 to 1.20)] with Gla-300 versus Gla-100; a significantly lower risk of hypoglycaemia with this definition was found over the 6-month treatment period [RR 0.76 (95% CI 0.59 to 0.99)]. No between-treatment differences in adverse events were identified. CONCLUSIONS: Gla-300 is as effective as Gla-100 in reducing HbA1c in insulin-naïve people with type 2 diabetes, with lower hypoglycaemia risk.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Insulina Glargina/administración & dosificación , Administración Oral , Anciano , Glucemia/análisis , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Monitoreo de Drogas , Resistencia a Medicamentos , Europa (Continente)/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Inyecciones Subcutáneas , Insulina Glargina/efectos adversos , Insulina Glargina/uso terapéutico , Japón/epidemiología , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Riesgo , Aumento de Peso/efectos de los fármacosAsunto(s)
Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/epidemiología , Cardiomiopatías Diabéticas/epidemiología , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Neoplasias/epidemiología , Femenino , Humanos , MasculinoRESUMEN
AIMS: To investigate the efficacy and tolerability of albiglutide, a weekly glucagon-like peptide-1 receptor agonist, when added to metformin and glimepiride in a triple therapy regimen in people with type 2 diabetes mellitus. METHODS: This was a 156-week, randomized, double-blind, parallel-group, multicentre study. In the present paper we describe the primary results, namely those at 52 weeks. Adult participants (n = 685) were randomly assigned to albiglutide (30 mg/week), pioglitazone (30 mg/day) or placebo. If needed, blinded uptitration of albiglutide (to 50 mg/week) and pioglitazone (to 45 mg/day) was allowed. The participant's current dose of metformin (>1500 mg/day) was maintained throughout. The glimepiride dose (4 mg/day), standardized before randomization, could be decreased if persistent hypoglycaemia occurred. RESULTS: The week 52 model-adjusted difference in change of glycated haemoglobin (primary endpoint) for albiglutide versus placebo was -0.87 [95% confidence interval (CI) -1.07, -0.68]%-units (p < 0.001), and for albiglutide versus pioglitazone it was 0.25 (95% CI 0.10, 0.40)%-units; therefore, not non-inferior. In the albiglutide group only, fasting plasma glucose reduced rapidly in the first 2 weeks. Confirmed hypoglycaemia occurred in 14% of participants on albiglutide, 25% on pioglitazone and 14% on placebo. The mean (± standard error) weight change was -0.42 (±0.2) kg with albiglutide, +4.4 (±0.2) kg (p < 0.001) with pioglitazone, and -0.40 (±0.4) kg with placebo and serious adverse events occurred in 6.3, 9.0 and 6.1% of participants in the respective groups. Injection site reactions occurred in 13% of participants on albiglutide and resulted in treatment discontinuation for four participants (1.4%). CONCLUSIONS: Albiglutide, as part of triple therapy, provided effective glucose-lowering and was generally well tolerated.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Tiazolidinedionas/uso terapéutico , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/efectos adversos , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Pioglitazona , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/efectos adversos , Resultado del TratamientoRESUMEN
AIMS: To examine whether insulin glargine can lead to better control of glycated haemoglobin (HbA1c) than that achieved by neutral protamine Hagedorn (NPH) insulin, using a protocol designed to limit nocturnal hypoglycaemia. METHODS: The present study, the Least One Oral Antidiabetic Drug Treatment (LANCELOT) Study, was a 36-week, randomized, open-label, parallel-arm study conducted in Europe, Asia, the Middle East and South America. Participants were randomized (1:1) to begin glargine or NPH, on background of metformin with glimepiride. Weekly insulin titration aimed to achieve median prebreakfast and nocturnal plasma glucose levels ≤5.5 mmol/l, while limiting values ≤4.4 mmol/l. RESULTS: The efficacy population (n = 701) had a mean age of 57 years, a mean body mass index of 29.8 kg/m², a mean duration of diabetes of 9.2 years and a mean HbA1c level of 8.2% (66 mmol/mol). At treatment end, HbA1c values and the proportion of participants with HbA1c <7.0 % (<53 mmol/mol) were not significantly different for glargine [7.1 % (54 mmol/mol) and 50.3%] versus NPH [7.2 % (55 mmol/mol) and 44.3%]. The rate of symptomatic nocturnal hypoglycaemia, confirmed by plasma glucose ≤3.9 or ≤3.1 mmol/l, was 29 and 48% less with glargine than with NPH insulin. Other outcomes were similar between the groups. CONCLUSION: Insulin glargine was not superior to NPH insulin in improving glycaemic control. The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins. This study confirms, in a globally heterogeneous population, the reduction achieved in nocturnal hypoglycaemia while attaining good glycaemic control with insulin glargine compared with NPH, even when titrating basal insulin to prevent nocturnal hypoglycaemia rather than treating according to normal fasting glucose levels.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Resistencia a Medicamentos , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Insulina Isófana/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Anciano , Asia , Automonitorización de la Glucosa Sanguínea , Ritmo Circadiano , Diabetes Mellitus Tipo 2/sangre , Cálculo de Dosificación de Drogas , Quimioterapia Combinada/efectos adversos , Europa (Continente) , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina Glargina , Insulina Isófana/efectos adversos , Insulina Isófana/uso terapéutico , Insulina de Acción Prolongada/efectos adversos , Insulina de Acción Prolongada/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Medio Oriente , Sudáfrica , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFß and IL1ß could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.
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Isoenzimas/metabolismo , Neoplasias Pulmonares/secundario , Proteína Quinasa C/metabolismo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Isoenzimas/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Trasplante de Neoplasias , Proteína Quinasa C/genéticaRESUMEN
AIM: To compare using propensity score analysis the outcome of beginning insulin therapy with basal, premix, mealtime + basal or mealtime insulin on the basis of data from 3031 people from the observational CREDIT (Cardiovascular Risk Evaluation in People with Type 2 Diabetes on Insulin Therapy) study. This approach overcomes likely confounding in baseline and unknown characteristics common to observational studies. METHODS: Efficacy and safety outcomes were collected at baseline and at 1 year in previously insulin-naïve people. Propensity score matched groups using all available baseline data were defined to compare outcomes by pairs of insulin regimens. RESULTS: From 2659 people with available data, propensity score matches were achieved for 686 people starting premix or basal insulin, 542 starting basal + mealtime or premix insulin and 400 starting basal or basal + mealtime. HbA1c reduction did not differ between the three pairs of insulin regimens. However, the relative risk of overall and nocturnal hypoglycaemia was lower (p = 0.010 to p < 0.001) with basal or basal + mealtime compared with premix insulin, and for nocturnal (p = 0.021) but not overall hypoglycaemia for basal compared to basal + mealtime insulin. Body weight increase was less for basal versus premix insulin [-1.3 (95% CI -2.1, -0.6) kg, p < 0.001] or versus basal + mealtime insulin [-1.4 (-2.5, -0.3) kg, p = 0.016], but did not differ between basal + mealtime and premix. Smaller groups matching mealtime insulin had some residual mismatching of HbA1c. CONCLUSION: Comparing insulin regimens between individuals matched by propensity scores indicated differences in hypoglycaemia and body weight change, despite similar HbA1c reductions. Our findings are consistent with those from randomized controlled trials.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulinas/administración & dosificación , Adulto , Anciano , Glucemia/metabolismo , Esquema de Medicación , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Resultado del TratamientoRESUMEN
AIMS: We investigated use and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in UK practice. METHODS: People starting a GLP-1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose-lowering agents were identified from The Health Information Network observational primary care database (2007-2011). Mean change in HbA1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics. RESULTS: Baseline characteristics of GLP-1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP-1 receptor agonist cohort was younger, had shorter diabetes duration and follow-up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose-lowering agents. Lower HbA1c reduction on GLP-1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference -1.4 (95% CI -4.1, 1.2) mmol/mol], except in the highest HbA1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference -17.8 (-28.6, -7.0) mmol/mol]. GLP-1 receptor agonist users lost weight [-4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6-month target reduction for GLP-1 receptor agonists of 11 mmol/mol (1.0%) HbA1c and 3% weight was reached by 24.9% of those continuing treatment. CONCLUSIONS: Those starting GLP-1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA1c reduction unless baseline HbA1c is very high. The UK 6-month GLP-1 receptor agonist target is usually not reached.
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Complicaciones de la Diabetes/terapia , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Sobrepeso/complicaciones , Pautas de la Práctica en Medicina , Receptores de Glucagón/antagonistas & inhibidores , Anciano , Índice de Masa Corporal , Estudios de Cohortes , Diabetes Mellitus/sangre , Prescripciones de Medicamentos , Registros Electrónicos de Salud , Femenino , Estudios de Seguimiento , Receptor del Péptido 1 Similar al Glucagón , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/prevención & control , Masculino , Persona de Mediana Edad , Sobrepeso/terapia , Atención Primaria de Salud , Reino Unido , Pérdida de Peso/efectos de los fármacosRESUMEN
AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.
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Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Neoplasias/mortalidad , Adulto , Anciano , Complicaciones de la Diabetes/complicaciones , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
AIM: To use baseline characteristics of the Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy study population to identify factors that could explain the choice of insulin therapy when beginning insulin. METHODS: The source, non-interventional, longitudinal, long-term study involves 314 centres in 12 countries in five regions. People were enrolled having started any insulin regimen in the previous 12 months. To identify factors associated with the choice of insulin regimen, multivariable backward logistic regression was performed on eligible physician and participant explanatory variables. RESULTS: Participants (N = 3031) had mean age 62 years, diabetes duration 11 years, body mass index 29.3 kg/m² and an HbA1c of 9.5%. Participants in Japan had less hypertension, smoked more and used fewer concomitant medications than those of other regions. Only physician location (rural or urban) influenced the choice of insulin in Japan. In the other four-regions-combined, physician location, specialty, sex and practice type influenced choice of insulin as did participant location, baseline HbA1c, use of glucose-lowering therapies and prior insulin secretagogue use. CONCLUSION: Choice of initial insulin regimen was influenced by several physician and participant characteristics in Canada and Europe, but only by physician location in Japan.
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Antihipertensivos/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Índice de Masa Corporal , Canadá/epidemiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Comparación Transcultural , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Europa (Continente)/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipertensión/epidemiología , Hipertensión/prevención & control , Japón/epidemiología , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Factores de RiesgoRESUMEN
Postprandial glucose excursions can inhibit achievement of good glycaemic control, and possibly have a specific effect on the risk of vascular comorbidities. Rapid-acting analogues control these excursions better than human insulin because their pharmacokinetic/pharmacodynamic (PK/PD) profile is closer to that of meal-time endogenous insulin secretion. Review of the findings of PK/PD studies and clinical trials suggests that the three marketed rapid-acting analogues--insulin lispro, insulin aspart and insulin glulisine--are equally efficacious and safe. In comparison with human insulin when using the same basal insulin, they provide comparable glycaemic control with a reduced risk of hypoglycaemia, although the combination of rapid-acting and basal analogues reduces glycated haemoglobin (HbA(1c)) more than human meal-time insulin combined with neutral protamine Hagedorn (NPH) insulin. Some studies have suggested that insulin glulisine has a slightly faster onset of action compared with insulin lispro or insulin aspart, but this has not been translated into demonstrable clinical benefit. Treatment satisfaction in patients with diabetes has been higher when therapy with a rapid-acting analogue is used instead of human insulin, perhaps due to differences in advised timing of injection. The largest benefits in efficacy, hypoglycaemia incidence, treatment satisfaction and quality of life have occurred when patients receive an all-analogue meal-time plus basal regimen as compared with an all-human insulin regimen. No new safety issues have been identified with the marketed rapid-acting analogues, and their insulin-like growth factor 1 receptor affinity and mitogenic activity are comparable to human insulin.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Insulina/análogos & derivados , Área Bajo la Curva , Humanos , Hipoglucemia/inducido químicamente , Insulina/farmacocinética , Insulina/farmacología , Insulina Aspart/farmacocinética , Insulina Aspart/farmacología , Insulina Lispro/farmacocinética , Insulina Lispro/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
AIMS: The efficacy and safety of insulin degludec (degludec), a new-generation ultra-long-acting basal insulin, was compared with insulin glargine (glargine) in people with Type 1 diabetes mellitus in a 16-week, open-label, randomized trial. Health status, an important aspect of effective diabetes management, was also assessed. METHODS: Degludec (n = 59) or glargine (n = 59) were injected once daily, with insulin aspart at mealtimes. Health status assessment utilized the validated Short Form 36 Health Survey, version 2, which has two summary component scores for mental and physical well-being, each comprising four domains. RESULTS: At study end, HbA(1c) reductions were comparable between groups, but confirmed nocturnal hypoglycaemia was significantly less frequent with degludec [relative rate 0.42 (95% CI 0.25-0.69)], and overall hypoglycaemia numerically less frequent [relative rate 0.72 (95% CI 0.52-1.00)]. After 16 weeks, a significant improvement in Short Form 36 Health Survey mental component score of +3.01 (95% CI 0.32-5.70) was obtained for degludec against glargine, attributable to significant differences in the social functioning [+8.04 (95% CI 1.89-14.18)] and mental health domains [+2.46 (95% CI 0.10-4.82)]. For mental component score, Cohen's effect size was 0.42, indicating a small-to-medium clinically meaningful difference. The physical component score [+0.66 (95% CI -2.30 to 3.62)] and remaining domains were not significantly different between degludec and glargine. CONCLUSIONS: In the context of comparable overall glycaemic control with glargine, degludec improved mental well-being as measured using the mental component score of the Short Form 36 Health Survey. The improvements in overall mental component score and the underlying social functioning and mental health domains with degludec compared with glargine may relate to the observed reduction in hypoglycaemic events.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Adolescente , Adulto , Anciano , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Esquema de Medicación , Femenino , Hemoglobina Glucada/efectos de los fármacos , Encuestas Epidemiológicas , Humanos , Inyecciones Subcutáneas , Insulina Glargina , Masculino , Persona de Mediana Edad , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: We investigated whether differences in duration of first insulin use in type 2 diabetes remain after adjustment for potential confounders, and what factors are associated with longer use. METHODS: People prescribed a first insulin (2000-2007) after 2-3 non-insulin glucose lowering treatments (OGLD) were identified from the THIN UK primary care database and grouped by insulin, detemir (n=165), glargine (n=1011) or NPH (n=420). Time from beginning insulin to the prescription of another insulin type or a glucagon-like peptide was compared between insulins in a Cox model adjusting for: demographics, HbA1c, history of vascular complications and cardiovascular risk factors. The strength of association between duration of use and these variables was investigated. RESULTS: The adjusted hazard ratios compared to glargine for treatment change were 1.58 (95% CI 1.25, 2.00) for detemir and 1.49 (1.25, 1.78) for NPH. Lower mean treatment HbA(1c) correlated with longer time to a different insulin regimen (Spearman rank correlation -0.30, p<0.01) as were continuing OGLDs, older age, longer time from diagnosis, lower body mass index, lower HbA(1c), and no heart failure at baseline. CONCLUSIONS: People who began treatment with glargine and those with better on-treatment HbA(1c) remained on their first insulin for longer than those who began detemir or NPH.