[Pharmacological and clinical characteristics of Insulin Faster Aspart (Fiasp®)]. / Características farmacológicas y clínicas de Insulina Aspártica Más Rápida (Fiasp®).

Fast acting aspart insulin is a faster-acting formulation of aspart insulin, having nicotinamide and Larginine added to the molecule, in order to achieve a faster absorption through the subcutaneous cellular tissue. Pharmacokinetic and pharmacodynamic studies showed a left-shifted mean serum concentration-time profile compared to the conventional formulation. Its efficacy profile is highlighted in terms of early postprandial glycemic control. In addition, fast acting aspart insulin allows a more flexible treatment schedule, as it may be administrated at mealtime, immediately before or up to 20 minutes after; this schedule represents an advantage regarding quality of life in patients with diabetes treated with prandial insulin, especially in populations such as children, pregnant women or elderly subjects. The safety and tolerability profiles are comparable to conventional aspart insulin.

La insulina aspártica de acción rápida es una formulación más rápida de la insulina aspártica convencional, a la que se adicionan nicotinamida y L-arginina para lograr una absorción más rápida en el tejido celular subcutáneo. Estudios farmacocinéticos y farmacodinámicos demostraron un desplazamiento de las curvas de concentración sérica de insulina/tiempo hacia la izquierda en comparación con la formulación convencional. Su perfil de eficacia se destaca en términos del control de la glucemia posprandial temprana. Además, la insulina aspártica de acción rápida aporta flexibilidad al tratamiento, ya que puede aplicarse al momento de la comida, inmediatamente antes o hasta 20 minutos después, lo que constituye una ventaja en cuanto a calidad de vida en los pacientes con diabetes en tratamiento con insulina prandial, especialmente en poblaciones como los niños, las embarazadas o los ancianos. El patrón de seguridad y tolerabilidad es comparable al de la insulina aspártica convencional.

Análogo de insulina de acción rápida (Aspart) para el tratamiento de Diabetes mellitus Tipo 1 / Fast-acting insulin analogue (Aspart) for the treatment of Type 1 Diabetes mellitus

INTRODUCCIÓN: Este documento técnico se realiza en el marco de la Elaboración de la Guía de Práctica Clínica para el diagnóstico y tratamiento con Diabetes mellitus Tipo 1; la pregunta PICO fue la siguiente: P: Adultos, adolescentes y niños mayor de un año de edad con diabetes mellitus tipo 1 con riesgo de hipoglicemia; I: Análogo de insulina de acción rápida (aspart); C: Insulina humana regular / otros análogos de insulina de acción rápida; O: Control glicémico: hemoglobina glicosilada A1c (HbA1c), Episodios hipoglicémicos moderados o graves, Complicaciones macrovasculares y microvasculares, Eventos adversos, Calidad de vida relacionada con la salud, Costos, Cambios en la Calidad de vida, Mortalidad. a. Cuadro clínico: La diabetes mellitus tipo 1 (DM-1) denominada diabetes mellitus insulinodependiente o juvenil, enfermedad metabólica caracterizada por hiperglicemia crónica, debida usualmente a una deficiencia absoluta de insulina ante la destrucción de las células ß del páncreas conduce a una deficiencia absoluta de insulina. Los síntomas incluyen excreción excesiva de orina (poliuria), sed (polidipsia), hambre constante, pérdida de peso, cambios en la visión y fatiga, estos síntomas pueden ocurrir repentinamente. En el 2021, alrededor de 8,4 (IC:95%: 8,1­8,8) millones de personas en todo el mundo había sido diagnosticada con diabetes tipo 1: de estos 1,5 millones (18%) eran menores de 20 años, 5,4 millones (64%) tenían entre 20 y 59 años y 1,6 millones (19%) tenían 60 años o más; la mayoría de ellos viven en países de ingresos altos. En la clasificación actual, la DM-1 se subdivide en dos subtipos: DM-1 A o autoinmune y DM-1 B o idiopática. b. Tecnología sanitária: Los análogos de insulina de acción rápida son insulina aspart fast, aspart, glulisina, y lispro, y tienen un inicio de la acción de 5 a 35 minutos, pico de acción 1 a 3 horas y duración de la acción de unas 3-5 horas. Con todas las dosis, altas y bajas, el inicio de la acción y el tiempo hasta el efecto pico es similar. Estos tipos de insulina cuenta con aprobación de la Food and Drug Administration (FDA) para DM1 en niños, adolescente y adultos. En Perú, el análogo de insulina de acción rápida aspart cuenta con varios registros sanitarios vigentes, sin embargo, no se cuenta en la lista del Petitorio Nacional Único de Medicamentos (PNUME). OBJETIVO; Describir la evidencia científica disponible sobre la eficacia y seguridad del análogo de insulina de acción rápida (aspart) para el tratamiento de la Diabetes mellitus Tipo 1. METODOLOGÍA: Búsqueda sistemática en Ovid Medline, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) y LILACS, complementada con la búsqueda en páginas de agencias gubernamentales y buscadores genéricos. Se priorizó la selección de ensayos clínicos aleatorizados controlados (ECA), revisiones sistemáticas (RS) con o sin metanálisis (MA) de ECA, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando AMSTAR 2 para RS, la herramienta de la colaboración Cochrane para ensayos clínicos y AGREE II para las GPC. RESULTADOS: Se identificaron seis revisiones sistemáticas, tres guías de práctica clínica y dos evaluaciones de tecnología sanitaria. La Revisión Sistemática de Norgaard et al.,2018 tuvo un nivel de confianza alta, la RS de Melo KFS et al.,2019 tuvo un nivel de confianza baja, mientras que la RS de Nicolucci A, et al., 2020, la RS de Wojciechowski P et al., 2015 y la RS de Rys P, et al., 2011 tuvieron un nivel de confianza críticamente baja. Las tres guías de práctica clínicas (GPC) incluidas obtuvieron un puntaje en la valoración global de calidad de 80,0 %, 79,2% y 71,6%. CONCLUSIONES: Los estudios analizados sugieren que los análogos de insulina de acción rápida (lispro y aspart) se deben usar preferentemente en lugar de la insulina humana regular (IHR) debido a que ambas insulinas tienen un inicio de acción más rápida, lo que permite que el paciente administre su insulina en el momento de la comida en lugar de 10-15 minutos antes de una comida. Esto proporciona un mejor control glucémico y ayuda a evitar los episodios de hipoglucemia en población adulta. Los niveles de hemoglobina A1c (HbA1c) se redujeron en 0,13% con análogo de insulina de acción rápida y el riesgo de hipoglicemia general (l7%), nocturna (45%) y severa (32%) en comparación con insulina humana regular (IHR). Los hallazgos demuestran que el tratamiento con análogo de insulina de acción rápida arpart (IAsp), en comparación con IHR, proporcionó una reducción promedio de la glucosa postprandial (PPG); y el IAsp en comparación con la insulina lispro, redujo los niveles de HbA1c cuando se utilizó con inyección diaria múltiple (IDM). La tasa de hipoglucemia total o grave no fue significativamente diferente entre los análogos de insulina de acción rápida (aspart o lispro) en comparación con la IHR, sin embargo, la frecuencia. de hipoglucemia nocturna fue menor con insulina aspart o insulina lispro en comparación con IHR. En población pediátrica, no se observó una reducción significativa en los niveles de hemoglobina glicosilada, ni en el riesgo de episodios de hipoglicemia debido a la alta heterogeneidad de los estudios primarios. La encuesta de satisfacción para el tratamiento de la diabetes que evalúa la flexibilidad del tratamiento mostró beneficios de IAsp en comparación con IHR. Las dos GPC de NICE recomiendan ofrecer análogos de insulina de acción rápida en lugar de insulina humana regular tanto para niños adolescentes y adultos. La GPC Canadiense (CDA) menciona que los pacientes que usan terapia basal con bolo o terapia con bomba de insulina, infusión subcutánea continua de insulina (ISCI), se debe usar análogos de insulina de acción rápida en lugar de insulina regular para mejorar los niveles de HbA1c, minimizar el riesgo de hipoglucemia y alcanzar los objetivos de glucemia postprandial. Dos Revisiones Sistemáticas (RS) fueron consideradas como nivel de confianza alta, una RS fue considerada como nivel de confianza baja y tres RS tuvieron un nivel de confianza críticamente baja. Las tres guías de práctica clínicas (GPC) incluidas obtuvieron un puntaje en la valoración global de calidad de 80,0 %, 79,2% y 71,6%. No se encontraron resultados para los desenlaces: complicaciones macrovasculares, microvasculares y mortalidad, ni resultados para población con riesgo de hipoglicemia.

Análogo de insulina de acción ultrarápida (Aspart fast) para el tratamiento de Diabetes mellitus Tipo 1 / Ultra-rapid-acting insulin analogue (Aspart fast) for the treatment of Type 1 Diabetes mellitus

INTRODUCCIÓN: Este documento técnico se realiza en el marco de la Elaboración de la Guía de Práctica Clínica para el diagnóstico y tratamiento con Diabetes mellitus Tipo 1; la pregunta PICO fue la siguiente: P: Adultos, adolescentes y niños mayor de un año de edad con diabetes mellitus tipo 1 con riesgo de hipoglicemia; I: Análogo de insulina de acción ultrarápida (aspart fast); C: Insulina humana regular/ otros análogos de insulina de acción ultrarápida; O: Control glicémico: hemoglobina glicosilada A1c (HbA1c), Episodios hipoglicémicos moderados o graves, complicaciones macrovasculares y microvasculares, eventos adversos, calidad de vida relacionada con la salud, costos, mortalidad. a. Cuadro clínico La diabetes mellitus tipo 1 (DM-1) denominada diabetes mellitus insulinodependiente o juvenil, enfermedad metabólica caracterizada por hiperglicemia crónica, debida usualmente a una deficiencia absoluta de insulina ante la destrucción de las células ß del páncreas conduce a una deficiencia absoluta de insulina. Los síntomas incluyen excreción excesiva de orina (poliuria), sed (polidipsia), hambre constante, pérdida de peso, cambios en la visión y fatiga, estos síntomas pueden ocurrir repentinamente. En el 2021, alrededor de 8,4 (IC:95%: 8,1­8,8) millones de personas en todo el mundo había sido diagnosticada con diabetes tipo 1: de estos 1,5 millones (18%) eran menores de 20 años, 5,4 millones (64%) tenían entre 20 y 59 años y 1,6 millones (19%) tenían 60 años o más; la mayoría de ellos vive en países de ingresos altos. En la clasificación actual, la DM-1 se subdivide en dos subtipos: DM-1 A o autoinmune y DM-1 B o idiopática. b. Tecnología sanitária: Los análogos de insulina de acción rápida son insulina aspart, aspart fast, glulisina, y lispro, y tienen un inicio de la acción de 5 a 35 minutos, pico de acción 1 a 3 horas y duración de la acción de unas 3-5 horas. Con todas las dosis, grandes y pequeñas, el inicio de la acción y el tiempo hasta el efecto pico es similar. La duración de la acción de la insulina, sin embargo, se ve afectada por la dosis, así que unas pocas unidades pueden durar 4 horas o menos, mientras que 25 o 30 unidades pueden durar 5 a 6 horas. Como regla general, estas insulinas tienen una duración de la acción de 4 horas. Estos tipos de insulina cuenta con aprobación de la Food and Drug Administration (FDA) para DM1. En Perú, el análogo de insulina de acción ultrarrápida aspart fast no se cuenta en la lista del Petitorio Nacional Único de Medicamentos (PNUME). OBJETIVO: Describir la evidencia científica disponible sobre la eficacia y seguridad del análogo de insulina de acción ultrarápida (aspart fast/aspart faster) para el tratamiento de la Diabetes mellitus Tipo 1. METODOLOGÍA: Se realizo la búsqueda sistemática en Ovid Medline, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) y LILACS, complementada con la búsqueda en páginas de agencias gubernamentales y buscadores genéricos. Se priorizó la selección de ensayos clínicos aleatorizados controlados (ECA), revisiones sistemáticas (RS) con o sin metanálisis (MA) de ECA, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando AMSTAR 2 para RS(1), la herramienta de la colaboración Cochrane para ensayos clínicos y AGREE II para las GPC. RESULTADOS: Se identificó tres revisiones sistemáticas y tres guías de práctica clínica en la evaluación de tecnología. La Revisión Sistemática de Dutta D et al.,2022 y la RS de Avgerinos I et al.,2021 tuvieron un nivel de confianza alta, mientras que la RS de Pal R, et al., 2021, tuvo un nivel de confianza baja. Las tres guías de práctica clínicas (GPC) incluidas obtuvieron un puntaje en la valoración global de calidad de 77,0 %, 71,6% y 78,2%. El análogo de insulina aspart fast se asocia una reducción en los niveles de HbA1c, incremento de glucosa postpandrial (PPG) y episodios hipoglucémicos generales comparables con respecto a la insulina aspart en población adulta. Los resultados mostraron que los pacientes que usaron FIAsp tuvo un efecto similar en el cambio de los niveles de HbA1c, en comparación con las insulinas de acción rápida (DMP = -0,02 %, IC:95 %: -0,08 - 0,05, I2=61 % para pacientes con diabetes tipo 1. La insulina aspart fast se asoció con una reducción de la glucosa plasmática posprandial (PPG) 1 h/2 h después de la ingesta de comida en comparación con la insulina aspart en bomba de insulina se asoció con una reducción significativamente mayor a 1hPPG (diferencia de medias [DM], -1,35 mmol/L; IC95 %: (-1,72)­(-0,98); p< 0,01; I2=63 %) y 2hPPG (DM, -1,19 mmol/L; IC95 %: (-1,38)­(-1,00); p< 0,01; I2=0 %) en comparación con los controles. El tiempo en rango (TIR) fue comparable entre los grupos (DM, 1,06 %; IC95 %:(-3,84 a 5,96; p=0,67; I2=70 %). CONCLUSIONES: La insulina aspart de acción ultrarápida (FIAsp) tuvo un efecto similar en el cambio de los niveles de HbA1c, en comparación con las insulinas de acción rápida en población adulta, mientras que el uso de FIasp con bomba de insulina se asoció con una reducción significativa de la glucosa postpandrial (PPG) a 1h y 2h sin aumento de la hipoglucemia o la variabilidad glucémica. No se encontraron estudios que compararon el efecto de la FIAsp e Insulina Humana Regular (IHR). Los episodios hipoglucémicos postprandiales tempranos fueron mayores en la insulina de FIAsp; sin embargo, los episodios de hipoglucemia general y nocturna no fueron diferentes a la insulina aspart. La insulina de acción rápida debe inyectarse 30 minutos antes de la ingesta; mientras que la insulina de acción ultrarápida tienen la ventaja que se inyectan junto con las comidas. Por ello, son la mejor opción cuando se requiere administrar los bolos de insulina después de las comidas (lactantes y pre-escolares). En niños, adolescentes y adultos, con exposición temprana para la indicación de FIasp comparada con IAsp dentro de los 30 minutos posteriores a la dosificación, no tuvo una diferencia estadísticamente significativa. En adultos con diabetes tipo 1 que usan terapia de inyección de bolo basal o Infusión Continua de Insulina Subcutánea (ICIS), se deben usar análogos de insulina de acción rápida en lugar de insulina regular para mejorar la Hemoglobina glicosilada A1c (HbA1c) y minimizar el riesgo de hipoglucemia. No se evaluaron los desenlaces de complicaciones macrovasculares, microvasculares, ni mortalidad en pacientes con diabetes mellitus tipo 1.

Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines.

Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal-bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.

Effectiveness of Insulin Analogs Compared with Human Insulins in Pregnant Women with Diabetes Mellitus: Systematic Review and Meta-analysis.

Diabetes during pregnancy has been linked to unfavorable maternal-fetal outcomes. Human insulins are the first drug of choice because of the proven safety in their use. However, there are still questions about the use of insulin analogs during pregnancy. The objective of the present study was to determine the effectiveness of insulin analogs compared with human insulin in the treatment of pregnant women with diabetes through a systematic review with meta-analysis. The search comprised the period since the inception of each database until July 2017, and the following databases were used: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE and Google Scholar. We have selected 29 original articles: 11 were randomized clinical trials and 18 were observational studies. We have explored data from 6,382 participants. All of the articles were classified as having an intermediate to high risk of bias. The variable that showed favorable results for the use of insulin analogs was gestational age, with a mean difference of - 0.26 (95 % confidence interval [CI]: 0.03-0.49; p = 0.02), but with significant heterogeneity (Higgins test [I2] = 38%; chi-squared test [χ2] = 16.24; degree of freedom [DF] = 10; p = 0.09). This result, in the clinical practice, does not compromise the fetal well-being, since all babies were born at term. There was publication bias in the gestational age and neonatal weight variables. To date, the evidence analyzed has a moderate-to-high risk of bias and does not allow the conclusion that insulin analogs are more effective when compared with human insulin to treat diabetic pregnant women.

Diabetes durante a gestação tem sido relacionado a desfechos materno-fetais desfavoráveis. As insulinas humanas são a primeira escolha medicamentosa, devido à comprovada segurança no seu uso. Entretanto, ainda há questionamentos sobre o uso dos análogos da insulina na gestação. O objetivo do presente estudo foi determinar a efetividade dos análogos da insulina comparados às insulinas humanas no tratamento de gestantes com diabetes por meio de uma revisão sistemática com metanálise. A busca compreendeu desde o início de cada base de dados até julho de 2017, e foi realizada nos seguintes bancos de dados: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE e Google Scholar. Selecionamos 29 artigos originais, sendo 11 ensaios clínicos randomizados e 18 estudos observacionais. Exploramos dados de 6.382 participantes. Todos os artigos foram classificados como sendo de intermediário a alto risco de viés. A variável que demonstrou resultado favorável ao uso dos análogos da insulina foi idade gestacional, com uma diferença média de - 0.26 (95% índice de confiança [IC]: 0.03­0.49; p = 0.02), porém com heterogeneidade significativa (teste de Higgins [I2] = 38%; teste do qui quadrado [χ2] =16.24; graus de liberdade [GL] =10; p = 0.09). Esse resultado, na prática clínica, não compromete o bem-estar fetal, uma vez que todos os bebês nasceram a termo. Houve viés de publicação nas variáveis idade gestacional e peso neonatal. Até o momento, as evidências analisadas possuem um risco de viés moderado a elevado e não permitem concluir que os análogos da insulina sejam mais efetivos em comparação às insulinas humanas para tratar gestantes diabéticas.

Effectiveness of insulin analogs compared with human insulins in pregnant women with diabetes mellitus: systematic review and meta-analysis / Efetividade dos análogos da insulina comparados às insulinas humanas em gestantes com diabetes mellitus: Revisão sistemática com metanálise

Abstract Diabetes during pregnancy has been linked to unfavorable maternal-fetal outcomes. Human insulins are the first drug of choice because of the proven safety in their use. However, there are still questions about the use of insulin analogs during pregnancy. The objective of the present study was to determine the effectiveness of insulin analogs compared withhuman insulin in the treatment of pregnant women with diabetes througha systematic review withmeta-analysis. The search comprised the period since the inception of each database until July 2017, and the following databases were used:MEDLINE, CINAHL, EMBASE, ISIWeb of Science, LILACS, Scopus, SIGLE andGoogle Scholar.We have selected 29 original articles: 11 were randomized clinical trials and 18 were observational studies.We have explored data from 6,382 participants. All of the articles were classified as having an intermediate to high risk of bias. The variable that showed favorable results for the use of insulin analogs was gestational age, with a mean difference of - 0.26 (95 % confidence interval [CI]: 0.03-0.49; p = 0.02), but with significant heterogeneity (Higgins test [I2] = 38%; chi-squared test [χ2] = 16.24; degree of freedom [DF] = 10; p = 0.09). This result, in the clinical practice, does not compromise the fetal well-being, since all babies were born at term. There was publication bias in the gestational age and neonatal weight variables. To date, the evidence analyzed has a moderate-to-high risk of bias and does not allow the conclusion that insulin analogs are more effective when compared with human insulin to treat diabetic pregnant women.

Resumo Diabetes durante a gestação tem sido relacionado a desfechos materno-fetais desfavoráveis. As insulinas humanas são a primeira escolha medicamentosa, devido à comprovada segurança no seu uso. Entretanto, ainda há questionamentos sobre o uso dos análogos da insulina na gestação. O objetivo do presente estudo foi determinar a efetividade dos análogos da insulina comparados às insulinas humanas no tratamento de gestantes com diabetes por meio de uma revisão sistemática com metanálise. A busca compreendeu desde o início de cada base de dados até julho de 2017, e foi realizada nos seguintes bancos de dados: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE e Google Scholar. Selecionamos 29 artigos originais, sendo 11 ensaios clínicos randomizados e 18 estudos observacionais. Exploramos dados de 6.382 participantes. Todos os artigos foram classificados como sendo de intermediário a alto risco de viés. A variável que demonstrou resultado favorável ao uso dos análogos da insulina foi idade gestacional, com uma diferençamédia de - 0.26 (95% índice de confiança [IC]: 0.03-0.49; p = 0.02), porém com heterogeneidade significativa (teste de Higgins [I2] = 38%; teste do qui quadrado [χ2] =16.24; graus de liberdade [GL] =10; p = 0.09). Esse resultado, na prática clínica, não compromete o bem-estar fetal, uma vez que todos os bebês nasceram a termo. Houve viés de publicação nas variáveis idade gestacional e peso neonatal. Até o momento, as evidências analisadas possuem um risco de viés moderado a elevado e não permitem concluir que os análogos da insulina sejam mais efetivos em comparação às insulinas humanas para tratar gestantes diabéticas.

Physico-chemical properties of co-formulated fast-acting insulin with pramlintide.

Since the discovery of amylin its use has been discouraged by the inadequacy of the protocol involving multiple injections in addition to insulin. We aimed here to develop a combined fixed-dose formulation of pramlintide with fast-acting insulin. We have investigated the compatibility of regular and fast-acting insulin analogues (Aspart, AspB28, and LisPro, LysB28ProB29) with the amylin analogue pramlintide by using electrospray ionization - ion mobility spectrometry-mass spectrometry (ESI-IMS-MS), kinetic aggregation assays monitored by thioflavin T, and transmission electron microscopy (TEM) in the evaluation of the aggregation product. Insulin interacts with pramlintide, forming heterodimers as probed by ESI-IMS-MS. While their interaction is likely to delay the amyloid aggregation of pramlintide in phosphate-buffered solution pH 7.0, they do not prevent aggregation at this condition. At acidic sodium acetate solution pH 5.0, combination of pramlintide and the fast-acting insulin analogues become stable against amyloid aggregation. The co-formulated product at high concentration of both pramlintide (600 µg/mL,150 µM) and LisPro insulin (50 IU/mL, 300 µM) showed also stability against amyloid aggregation. These data indicate the physico-chemical short-term stability of the co-formulated preparation of LisPro insulin with pramlintide, which could bring benefits for the combined therapy.

Cost-effectiveness of insulin analogs from the perspective of the Brazilian public health system

ABSTRACT Human insulin is provided by the Brazilian Public Health System (BPHS) for the treatment of diabetes, however, legal proceedings to acquire insulin analogs have burdened the BPHS health system. The aim of this study was to perform a cost-effectiveness analysis to compare insulin analogs and human insulins. This is a pharmacoeconomic study of cost-effectiveness. The direct medical cost related to insulin extracted from the Ministry of Health drug price list was considered. The clinical results, i.e. reduction in glycated hemoglobin (HbA1c), were extracted by meta-analysis. Different scenarios were structured to measure the uncertainties regarding the costs and reduction in HbA1c. Decision tree was developed for sensitivity of Incremental Cost Effectiveness Ratio (ICER). A total of fifteen scenarios were structured. Given the best-case scenario for the insulin analogs, the insulins aspart, lispro, glargine and detemir showed an ICER of R$ 1,768.59; R$ 3,308.54; R$ 11,718.75 and R$ 2,685.22, respectively. In all scenarios in which the minimum effectiveness was proposed, lispro, glargine and detemir were dominant strategies. Sensitivity analysis showed that the aspart had R$ 3,066.98 [95 % CI: 2339.22; 4418.53] and detemir had R$ 6,163.97 [95% CI: 3919.29; 11401.57] for incremental costs. We concluded there was evidence that the insulin aspart is the most cost-effective.

The study of once- and twice-daily biphasic insulin aspart 30 (BIAsp 30) with sitagliptin, and twice-daily BIAsp 30 without sitagliptin, in patients with type 2 diabetes uncontrolled on sitagliptin and metformin-The Sit2Mix trial.

AIMS: Investigate efficacy and tolerability of intensifying diabetes treatment with once- or twice-daily biphasic insulin aspart 30 (BIAsp 30) added to sitagliptin, and twice-daily BIAsp 30 without sitagliptin in patients with type 2 diabetes (T2D) inadequately controlled on sitagliptin. METHODS: Open-label, three-arm, 24-week trial; 582 insulin-naïve patients were randomized to twice-daily BIAsp 30+sitagliptin (BIAsp BID+Sit), once-daily BIAsp 30+sitagliptin (BIAsp QD+Sit) or twice-daily BIAsp 30 without sitagliptin (BIAsp BID), all with metformin. RESULTS: After 24 weeks, HbA1c reduction (%) was superior with BIAsp BID+Sit vs. BIAsp QD+Sit (BIAsp BID+Sit minus BIAsp QD+Sit difference: -0.36 [95% CI -0.54; -0.17], P<0.001) and BIAsp BID (BIAsp BID minus BIAsp BID+Sit difference: 0.24 [0.06; 0.43], P=0.01). Observed final HbA1c values were 6.9%, 7.2% and 7.1% (baseline 8.4%), and 59.8%, 46.5% and 49.7% of patients achieved HbA1c <7.0%, respectively. Confirmed hypoglycaemia was lower with BIAsp QD+Sit vs. BIAsp BID (P=0.015); rate: 1.17 (BIAsp QD+Sit), 1.50 (BIAsp BID+Sit) and 2.24 (BIAsp BID) episodes/patient-year. Difference in bodyweight change favoured BIAsp QD+Sit vs. both BID groups (P<0.001). CONCLUSIONS: Adding BIAsp 30 to patients with T2D poorly controlled with sitagliptin and metformin is efficacious and well tolerated; however, while BIAsp BID+Sit showed superior glycaemic control, BIAsp QD+Sit had a lower rate of hypoglycaemia and showed no weight gain.

Safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes switching from basal-bolus insulin regimens in the A1chieve study.

AIMS: Biphasic insulin aspart 30 allows fewer daily injections versus basal-bolus insulin regimens, which may improve adherence and treatment outcome. This sub-analysis of the observational A1chieve study assessed clinical safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes previously receiving basal-bolus insulin regimens. METHODS: A1chieve was an international, open-label, 24-week study in people with type 2 diabetes starting/switching to biphasic insulin aspart 30, insulin detemir or insulin aspart. This sub-analysis assessed patients switching from insulin glargine- or neutral protamine Hagedorn insulin-based basal-bolus insulin regimens to biphasic insulin aspart 30. RESULTS: 1024 patients were included. At 24 weeks, glycated haemoglobin and fasting plasma glucose were significantly reduced from baseline in both cohorts (all p<0.001). The proportion reporting any hypoglycaemia, major hypoglycaemia or nocturnal hypoglycaemia was significantly reduced after 24 weeks (all p<0.05). No serious adverse drug reactions were reported. Both cohorts had significantly improved health-related quality of life (HRQoL; p<0.001). CONCLUSIONS: 24 weeks after switching from basal-bolus insulin regimens to biphasic insulin aspart 30, glycaemic control and HRQoL were significantly improved, and hypoglycaemia was significantly reduced. This suggests that people with type 2 diabetes inadequately controlled on basal-bolus insulin regimens can consider biphasic insulin aspart 30.

Rheological properties of regular insulin and aspart insulin Langmuir monolayers at the air/water interface: condensing effect of Zn2+ in the subphase.

The interfacial behavior of regular insulin (Reg-insulin) and aspart insulin (Asp-insulin) was critically affected by the presence of Zn(2+) in the subphase. This cation induced a condensed-like behavior in the compression isotherms, especially apparent for Reg-insulin films when observed by Brewster angle microscopy. Immediately after spreading, Reg-insulin, but not Asp-insulin, showed bright patches that moved in a gaseous-like state. Moreover, Zn(2+) caused marked variations of the surface electrostatics of both insulin monolayers and considerable hysteresis of their molecular organization. By oscillatory compression-expansion cycles, we observed in all cases the development of a dilatational response to the surface perturbation, and both monolayers exhibited well-defined shear moduli in the presence of Zn(2+), which was higher for Reg-insulin. Development of a shear modulus indicates behavior resembling a nominal solid, more apparent for Reg-insulin than for Asp-insulin, suggesting the presence of viscoelastic networks at the surface.

Relação entre obesidade, insulina plasmática e posicionamento da falange distal em equinos da raça Crioula / Relationship between obesity, insulin and placement of plasma in equine distal phalanx of breed creole

Verificaram-se características radiográficas do posicionamento da falange distal em relação ao estojo córneo em equinos da raça Crioula e correlacionaram-se tais achados com sinais de obesidade e concentrações plasmáticas de insulina. Consideraram-se dois grupos com base no escore da condição corporal (ECC). A média de idade entre os grupos foi de 9,2±5,8 anos em indivíduos normais (ECC 5-7) e de 10,3±3,7 anos em obesos (ECC 8-9). Diferenças estatísticas entre grupos ocorreram para valores de peso, perímetro torácico, escore da condição corporal, escore da crista do pescoço, comprimento do pescoço, circunferência do pescoço em três regiões referentes a 25%, 50% e 75% do comprimento do pescoço e entre o posicionamento da falange distal em relação ao estojo córneo. O ângulo formado entre as superfícies dorsais de falange distal e casco (ângulo de rotação) correlacionou-se estatisticamente com ECC (r = 0,30; P=0,02) e com peso e perímetro torácico (r = 0,50; P<0,01). Quanto à concentração de insulina plasmática, foram encontradas correlações positivas com ECP (r = 0,40; P<0,01) e com ângulo de rotação (r = 0,23; P = 0,08), e correlação negativa com idade (r = -0,42; P<0,01). Em oito animais (27%) o ângulo de rotação foi maior que 2 graus; destes, 25% eram normais e 75%, obesos (P<0,05). Aparentemente, em equinos da raça Crioula, características morfométricas no casco diferiram dos padrões internacionais obtidos de outras raças. A obesidade interferiu na relação espacial da falange distal com o estojo córneo, indicando que os animais obesos dessa raça são mais propensos a desenvolver laminite.

The radiographic relationship of the distal phalanx with the hoof capsule was verified in Creole breed horses and these findings correlated with signs of obesity and insulin blood levels. Horses were divided in two groups based on their body score condition (ECC). The average age was 9.2±5.8 years in normal (ECC 5-7) and 10.3±3.7 years in the obese group (ECC 8-9). Statistical differences between groups (P<0.05) were detected for values of weight, thoracic girth, body score condition, neck score (ECP), neck length, neck circumference into three regions based on 25% (P25), 50% (P50) and 75% (P75) of the length of the neck and phalanx and hoof capsule relationship. The angle between the dorsal aspects of distal phalanx and hoof wall (rotation angle) statistically correlated with ECC (r = 0.30; P=0.02) and with weight and thoracic girth (r = 0.50; P<0.01). Plasma insulin concentrations positively correlated with ECP (r = 0.40, P <0.01) and rotation angle (r = 0.23, P = 0.08) and negatively with age (r = -0.42, P <.01). In eight animals (27%) rotation angle was greater than 2 degrees, of which 25% were normal and obese 75% (P <0.05). Apparently in Creole horses, morphometric characteristics of the hoof differ from international standards obtained from other breeds. Obesity interfered with the spatial relationship of the distal phalanx with the hoof capsule, indicating that obese animals of this breed are more likely to develop laminitis.

Relação entre obesidade, insulina plasmática e posicionamento da falange distal em equinos da raça Crioula / Relationship between obesity, insulin and placement of plasma in equine distal phalanx of breed creole

Verificaram-se características radiográficas do posicionamento da falange distal em relação ao estojo córneo em equinos da raça Crioula e correlacionaram-se tais achados com sinais de obesidade e concentrações plasmáticas de insulina. Consideraram-se dois grupos com base no escore da condição corporal (ECC). A média de idade entre os grupos foi de 9,2±5,8 anos em indivíduos normais (ECC 5-7) e de 10,3±3,7 anos em obesos (ECC 8-9). Diferenças estatísticas entre grupos ocorreram para valores de peso, perímetro torácico, escore da condição corporal, escore da crista do pescoço, comprimento do pescoço, circunferência do pescoço em três regiões referentes a 25%, 50% e 75% do comprimento do pescoço e entre o posicionamento da falange distal em relação ao estojo córneo. O ângulo formado entre as superfícies dorsais de falange distal e casco (ângulo de rotação) correlacionou-se estatisticamente com ECC (r = 0,30; P=0,02) e com peso e perímetro torácico (r = 0,50; P<0,01). Quanto à concentração de insulina plasmática, foram encontradas correlações positivas com ECP (r = 0,40; P<0,01) e com ângulo de rotação (r = 0,23; P = 0,08), e correlação negativa com idade (r = -0,42; P<0,01). Em oito animais (27%) o ângulo de rotação foi maior que 2 graus; destes, 25% eram normais e 75%, obesos (P<0,05). Aparentemente, em equinos da raça Crioula, características morfométricas no casco diferiram dos padrões internacionais obtidos de outras raças. A obesidade interferiu na relação espacial da falange distal com o estojo córneo, indicando que os animais obesos dessa raça são mais propensos a desenvolver laminite.(AU)

The radiographic relationship of the distal phalanx with the hoof capsule was verified in Creole breed horses and these findings correlated with signs of obesity and insulin blood levels. Horses were divided in two groups based on their body score condition (ECC). The average age was 9.2±5.8 years in normal (ECC 5-7) and 10.3±3.7 years in the obese group (ECC 8-9). Statistical differences between groups (P<0.05) were detected for values of weight, thoracic girth, body score condition, neck score (ECP), neck length, neck circumference into three regions based on 25% (P25), 50% (P50) and 75% (P75) of the length of the neck and phalanx and hoof capsule relationship. The angle between the dorsal aspects of distal phalanx and hoof wall (rotation angle) statistically correlated with ECC (r = 0.30; P=0.02) and with weight and thoracic girth (r = 0.50; P<0.01). Plasma insulin concentrations positively correlated with ECP (r = 0.40, P <0.01) and rotation angle (r = 0.23, P = 0.08) and negatively with age (r = -0.42, P <.01). In eight animals (27%) rotation angle was greater than 2 degrees, of which 25% were normal and obese 75% (P <0.05). Apparently in Creole horses, morphometric characteristics of the hoof differ from international standards obtained from other breeds. Obesity interfered with the spatial relationship of the distal phalanx with the hoof capsule, indicating that obese animals of this breed are more likely to develop laminitis.(AU)

A T3R3 hexamer of the human insulin variant B28Asp.

Insulin shows a complex equilibrium between monomers and hexamers, involving varying conformers and association states. We sought to perform a structural characterization of the fast-acting human insulin variant B28Asp ("aspart"). Small-angle X-ray scattering measurements reveal similar globular behavior in both the aspart and regular human insulin, with a Rg of 19Å and a Dmax of approximately 50Å, indicating similar mean quaternary assembly distribution. Crystallographic assays revealed a T3R3 assembly of the aspart insulin formed by the TR dimer in the asymmetric unit, with all the first 8 residues of the B chain in the R-state monomer in helical conformation and the participation of its B3Asn in the stabilization of the hexamer. Our data provide access to novel structural information on aspart insulin such as an aspart insulin dimer in solution, the aspart insulin in T conformation and a pure R-state conformer establishing a T3R3 assembly, providing further insight on the stepwise conformational transition and assembly of this fast-insulin.

Targeting blood glucose management in school improves glycemic control in children with poorly controlled type 1 diabetes mellitus.

We hypothesized that school nurse supervision of glucose and insulin-dose adjustment significantly improves the hemoglobinA(1c) (HbA(1c)) level in pediatric patients with poorly controlled type 1 diabetes mellitus (HbA(1c) > or = 9%). A total of 36 subjects were enrolled and 18 subjects were randomized to receive the 3-month intervention. Their average HbA(1c) was lowered by 1.6%, suggesting that this intervention helps this difficult group of patients.

[Biphasic insulin aspart for the management of diabetic patients with unsatisfactory metabolic control]. / Tratamiento con insulina aspártica bifásica en pacientes con diabetes en mal control metabólico: experiencia clínica programada.

BACKGROUND: Biophasic insulin aspart (InAsBi) is a mixture of 30% of rapid acting soluble aspart insulin and 70% aspart insulin retarded with protamine. The soluble portion reduces postprandial serum glucose rises and the retarded portion reduces basal glucose levels. AIM: To assess the efficacy of biphasic insulin aspart in diabetics with a bad metabolic control. MATERIAL AND METHODS: Multicentríc study that included diabetic patients with a glycosilated hemoglobin over 7% that were transferred to treatment with InAsBi, given in one to three daily doses, according to glycemic control and followed for 12 weeks. At the end of follow up, glycosilated hemoglobin levels (HbA1c) were measured again. RESULTS: One hundred ninety six patients were enrolled and 154, age 59+/- 12 (84 females), completed the follow up. HbA 1 c levels decreased in at least 1% in 96 and increased in eight cases. In the total group HbA1c decreased from 10.1+/- 1.7 to 8.4+/-1.4% (p <0.01). Those with higher initial values and with oral therapy, had the greatest reductions. At the end of the observation period, 29 patients received one daily dose of InAsBi, 114 two doses and 11 three doses. Two patients had allergy, one systemic and one in the injection site. CONCLUSIONS: In this group of diabetic patients with a bad metabolic control, the use of InAsBi was associated with a significant reduction of glycosilated hemoglobin levels.

[Insulin analogues: searching for a physiological replacement]. / Análogos de insulina: en búsqueda del reemplazo fisiológico.

Insulin analogues, developed by molecular engineering, have structural changes in the A and B insulin chains. These modifications change their action profile, rendering insulin replacement closer to physiology. Rapid acting analogues like lispro, aspart and glulisine, are absorbed rapidly from the subcutaneous tissue to the circulation. In addition, two long acting insulin analogues have been developed: glargine and detemir. The combination of a long acting insulin, to maintain baseline levels, and multiple daily doses of a rapid acting analogue are the mainstay of basal-bolus therapy. Multiples studies have compared human insulin (NPH and regular) with insulin analogues in patients with type 1 or 2 diabetes mellitus, showing an improvement in the metabolic control, fewer hypoglycemic events and better quality of life. In summary, insulin analogues offer new therapeutic options and allow an individualized intensive treatment.

Insulin analogues. A critical review.

Multiple and important technological innovations in the field of insulin therapy have appeared in the last decade. Insulin analogues with novel pharmacokinetics have been developed. The first of these analogues to appear in the market was insulin lispro. We believe that the most part of the stu-dies carried out with this molecule in comparison with regular insulin were unfair as long as its short duration of action was ignored, since in many of these studies it was administered with meals and with only one dose of intermediate insulin given at night. Several studies done mainly by Italian investigators have proven this concept being true in studies with adequate baseline insulin coverage. Insulin aspart has appeared recently in the market in the United States with very similar effects to lispro. The FDA has recently approved a new ultralong acting analogue. The main advantages are its long, peakless action with better effects during down hours and a lower incidence of hypoglycaemia. We also review other approaches with novel insulin molecules attached to thyroxin or fatty acids in order to create a bridge for binding to plasmatic proteins. These molecules have longer effects and some of them more selective sites of action. Finally we included a brief review of other routes of insulin administration.