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.

Insulinas análogas de ação rápida para Diabetes Mellitus Tipo 1 / Analogous Fast-acting Insulins for Type 1 Diabetes Mellitus

O Diabetes Mellitus Tipo 1 (DM1) refere-se a um conjunto de alterações metabólicas que se apresenta com hiperglicemia constante em função da deficiência na produção de insulina pelo pâncreas. Indivíduos com DM1 dependem da administração de insulinas exógenas para manter os níveis de glicose no sangue na faixa da normalidade. Quando não devidamente controlado, o DM1 pode provocar episódios graves de hipoglicemia e cetoacidose a curto prazo, assim como alterações micro e macrovasculares a longo prazo. Não há dados específicos sobre a prevalência de DM1 na população brasileira, mas estima-se que mais de 600.000 pessoas vivem hoje com esta condição. O Ministério da Saúde dispõe de linha de cuidado para DM, com o objetivo de controlar a glicemia e desenvolver o autocuidado nos pacientes. Parte da estratégia inclui a prescrição de insulinas em esquema intensivo. Estão à disposição a insulina humana NPH, para a manutenção basal da glicemia, e a insulina humana regular, de ação rápida, a ser administrada cerca de 30 minutos antes das refeições. Pergunta: O uso de insulinas análogas de ação rápida é eficaz, seguro e custo efetivo em pacientes com diabetes mellitus tipo 1 quando comparado à insulina humana regular? Evidências clínicas:A partir da evidência apresentada pelo demandante e avaliação suplementar conduzida pela Secretaria-Executiva da CONITEC, a melhor evidência atualmente disponível sobre o uso das insulinas análogas de ação rápida para pessoas com DM1 é baseada em estudos com alto risco de viés, pouco tempo de seguimento, acompanhamento de poucos pacientes e patrocínio das empresas produtoras das insulinas. Os resultados com superioridade estatística foram observados apenas em desfechos substitutos e com alta heterogeneidade. Não há evidência disponível para eventos micro e macrovasculares a longo prazo com utilização de insulinas análogas de ação rápida. Não foi observada superioridade das insulinas análogas de ação rápida para crianças e adolescentes em quaisquer desfechos comparadas à insulina humana regular. Identificou-se benefício superior apenas com a utilização da insulina lispro em adultos, na qual a incidência de episódios de hipoglicemia grave passou de 1 episódio de hipoglicemia grave a cada 10 meses para 1 episódio a cada 18 meses. Em crianças, as insulinas análogas apresentaram tanto menor quanto maior risco de episódios de hipoglicemia grave. Avaliação econômica: O demandante apresentou uma avaliação econômica de custo-utilidade comparando todo o grupo de insulinas análogas de ação rápida à insulina humana regular, na perspectiva do SUS, por meio de um modelo de árvore de decisão com três desfechos clínicos finais: sem hipoglicemias, hipoglicemias eventuais e hipoglicemias frequentes. A população-alvo incluía todos os pacientes com DM1, horizonte temporal de um ano e custos diretos apenas com a aquisição dos medicamentos. Os resultados da avaliação econômica variaram entre R$ 61.551,52 e R$ 170.045,37 por QALY ganho. Diante da não comprovação de superioridade dessas insulinas análogas, o adequado seria a condução de uma análise de custo-minimização, em que a intervenção de menor custo seria dominante em relação às demais. Avaliação de Impacto Orçamentário: O impacto orçamentário incremental em 5 anos estimado pelo método do demandante foi entre R$ 242 milhões e R$ 404 milhões, com a variação dependente da dose recomendada. A taxa de difusão utilizada foi de 30%, 40%, 60%, 80% e 100%, o que foi considerada subestimada, uma vez que se trata de medicamentos com longo tempo de mercado, grande experiência dos prescritores e expectativa dos pacientes. Também é importante apontar que a apresentação de 3 mL seria a mais adequada, uma vez que com a dose média praticada haveria desperdício de metade do frasco-ampola de 10 mL. Recomendação final: Os membros do Plenário da CONITEC, em sua 51ª reunião ordinária, deliberaram, por unanimidade, recomendar a incorporação de insulina análoga de ação rápida para o tratamento da Diabetes Mellitus Tipo 1, mediante negociação de preço e conforme protocolo estabelecido pelo Ministério da Saúde. Foi assinado o Registro de Deliberação nº 227/2016. Decisão: Incorporar insulina análoga de ação rápida para o tratamento da Diabetes MellitusTipo 1, no âmbito do Sistema Único de Saúde - SUS. A decisão foi dada pela Portaria SCTIE-MS nº 10 publicada no Diário Oficial da União (DOU) nº 38, de 22 de fevereiro de 2017.

Quality of life perception of type 1 diabetic patients treated with insulin analogs and receiving medication review with follow-up in a public health care service from Ponta Grossa-PR, Brazil

ABSTRACT Glycemic control in patients with diabetes mellitus type 1 (DM1) reduces the risk of complications but requires a rigorous health care routine. Thus, diabetes education is central to increasing treatment compliance and self-care practices. This study aimed to evaluate the quality of life (QoL) and glycemic control of DM1 patients being treated with insulin analogs and receiving medication review with follow-up. This was a transversal study that included 110 patients registered at the 3rd Health Regional of Ponta Grossa-PR, aged ≥ 18 years, and receiving pharmaceutical care for at least 1 year. The Diabetes Quality of Life Measure (DQOL)-Brazil was used to evaluate QoL. The data were statistically analyzed using SPSS version 17.0 with 95% confidence levels. Of the 110 patients, 58.2% were women. The average age was 33.7 years (±10.5), and the average glycated hemoglobin (HbA1c) value was 8% (±1.4). The mean total DQOL-Brazil score was 2.11 (95% confidence interval, 2.02 - 2.21). All DQOL-Brazil scores were lower in patients with HbA1c ≤ 8%, indicating a better QoL. Good glycemic control, thus, appears to have a positive influence on the QoL, and pharmaceutical interventions are able to contribute to the achievement of therapeutic targets.

Perception of diabetic patients regarding basal bolus insulin injections and outcome of its use

Objective: To assess the perceptions regarding basal bolus insulin injections and the changes in blood glucose levels and glycosylated hemoglobin [HbA1c] before and after 3 months of such treatment in diabetic patients. Study Design: Quasi-experimental study. Place and Duration of Study: Department of Endocrinology, Liaquat National Hospital, Karachi, from December 2014 to March 2015

Methodology: A total of 222 diabetic patients started on basal bolus insulin injection were enrolled and asked to answer 17 questions. Those with complications of diabetes were excluded. Fasting blood glucose [FBS], random blood glucose [RBS] and HbA1c levels were checked initially, and after 3 months of getting basal bolus insulin. Paired t-test and chi-square test were used for determining p-value with significance at p < 0.05

Results: Majority [n=217, 97.7%] of the patients were previously taking other insulins. Before starting this treatment, the mean FBS was 260.5 +/- 52.2 mg/dl, RBS was 385.5 +/- 47.61 mg/dl and HbA1c was 12.76 +/- 1.92%. After 3 months of treatment, FBS improved to 117.9 +/- 14.2 mg/dl, RBS was 156.7 +/- 17.09 mg/dl and HbA1c was 7.72 +/- 4.41% [p < 0.001]. Two hundred and sixteen [97.3%] patients believed that basal bolus insulin was started as their diabetes worsened; 157 [70.70%] thought that their blood glucose control would improve with the use of this form of insulin. One hundred and ninety four [87.4%] had fear of needle injections. Perceptions regarding hypoglycemia with this form of insulin were observed in 157 [70.7%]. One hundred and twenty seven [84.1%] of the females and 51 [71.8%] of the males thought that the basal bolus insulin regimen was too expensive [p=0.032]

Conclusion: There were many misconceptions in patients who were started on basal bolus insulin. Marked improvement in blood glucose levels and HbA1c were observed after the use of this regimen

The Effects of Anti-insulin Antibodies and Cross-reactivity with Human Recombinant Insulin Analogues in the E170 Insulin Immunometric Assay / 대한진단검사의학회지

BACKGROUND: Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. METHODS: Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. RESULTS: In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). CONCLUSIONS: IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for beta cell function assessment in diabetic patients undergoing insulin therapy.

Comparing effects of continuous insulin infusion with or without subcutaneous glargine insulin on glycemic control in diabetic patients undergoing coronary artery bypass graft [CABG]

Hyperglycemia is associated with increased morbidity and mortality in diabetic patients following coronary artery bypass grafting. Tight glycemic control in perioperative period can reduce these events. The goal of this study was to determine whether combination of continuous infusion and subcutaneous glargine as a basal insulin could improve glycemic control. Diabetic patients who were candidate for CABG were randomized to receive continuous insulin infusion with or without subcutaneous Glargine insulin for at least 72 hours which started 24 hours before surgery and continued for 48 hours after surgery. A total 84 subjects were required. In group A [n=45] continuous insulin infusion was used for glycemic control and in group B [n=39] we used continuous infusion with subcutaneous glargine insulin. Blood glucose level was significantly better in desirable range in group B in comparison to group A. Total mean blood glucose level in group A was 186.1 mg/dl and in group B was 174.3 mg/dl [P=0.008]. Frequency of hypoglycemia [blood glucose <70 mg/dl] was 0.66% in group A and 0.5% in group B that was similar [P=0.530]. The mean length of stay in the hospital was not different between two groups [P=0.288]. We found out that a combination of continuous insulin infusion and glargine insulin as main basal insulin can improve glycemic control in diabetic patients undergoing coronary artery bypass grafting

Valores normativos de resistencia a la insulina mediante HOMA-IR en adultos mayores de Santiago de Chile / Homeostasis model assessment (HOMA) values in Chilean elderly subjects

Background: The homeostasis assessment model for insulin resistance (HOMA-IR) estimates insulin resistance using basal insulin and glucose values and has a good concordance with values obtained with the euglycemic clamp. However it has a high variability that depends on environmental, genetic and physiologic factors. Therefore it is imperative to establish normal HOMA values in different populations. Aim: To report HOMA-IR values in Chilean elderly subjects and to determine the best cutoff point to diagnose insulin resistance. Material and methods: Cross sectional study of 1003 subjects older than 60 years of whom 803 (71 percent women) did not have diabetes. In 154 subjects, an oral glucose tolerance test was also performed. Insulin resistance (IR) was defined as the HOMA value corresponding to percentile 75 of subjects without over or underweight. The behavior of HOMA-IR in metabolic syndrome was studied and receiver operating curves (ROC) were calculated, using glucose intolerance defined as a blood glucose over 140 mg/dl and hyperinsulinemia, defined as a serum insulin over 60 µU/ml, two hours after the glucose load. Results: Median HOMA-IR values were 1.7. Percentile 75 in subjects without obesity or underweight was 2.57. The area under the ROC curve, when comparing HOMA-IR with glucose intolerance and hyperinsulinemia, was 0.8 (95 percent confidence values 0.72-0.87), with HOMA-IR values ranging from 2.04 to 2.33. Conclusions: HOMA-IR is a useful method to determine insulin resistance in epidemiological studies. The HOMA-IR cutoff point for insulin resistance defined in thi spopulation was 2.6.

Utilização da insulina glargina em crianças menores de oito anos de idade / Use of insulin glargine in type 1 diabetes children with less than eight years old

OBJETIVOS: Avaliar prospectivamente a eficácia e a segurança da insulina glargina no controle metabólico de crianças com diabetes melito tipo 1 (DMT1) com menos de oito anos de idade. MÉTODOS: Foram avaliados 19 meninos e 11 meninas. Antes de iniciar a insulina glargina, todas as crianças foram colocadas em tratamento intensivo com insulina NPH e insulina asparte durante três meses. Posteriormente, os pacientes foram acompanhados por 12 meses para o tratamento com glargina. Todos os pacientes realizavam medidas da glicemia capilar 3-7 vezes ao dia. Desfechos principais: controle metabólico por meio da hemoglobina glicada (A1c); ocorrência de hipoglicemia leve (glicemia capilar < 60 mg/dL) e ocorrência de hipoglicemia grave (perda ou alteração na consciência, convulsão ou necessidade de intervenção médica). RESULTADOS: A1c média no início do estudo foi 8,68 por cento, semelhante ao valor obtido ao final dos 12 meses de tratamento com glargina (8,64 por cento; p = 0,82). A frequência de hipoglicemia leve às 3 horas da madrugada foi 1,43/3 meses por paciente com insulina NPH e de 0,28/3 meses por paciente com insulina glargina (p < 0,007). Em relação à hipoglicemia severa, houve uma diferença favorável à glargina: 0,008 versus 0,56 eventos/3 meses por paciente (p < 0,002). CONCLUSÕES: O uso da insulina glargina no tratamento de crianças com DMT1 foi considerado tão eficaz quanto o uso da NPH, apresentando, no entanto, melhor perfil de segurança caracterizado pelo menor risco de hipoglicemia noturna e severa.

OBJECTIVES: To evaluate prospectively the efficacy and safety of insulin glargine use for the metabolic control of type 1 diabetes mellitus (T1DM) children younger than eight years old. METHODS: Nineteen boys and 11 girls with T1DM were included. Before initiating insulin glargine, all children received intensive NPH and aspart insulins for three months. Afterwards, they were assisted for 12 more months for glargine treatment. All patients performed self blood glucose monitoring before and two hours after meals and in early morning (3:00 AM). Primary endpoints: metabolic control using A1C levels; frequency of mild hypoglycemia (capillary glycemia < 60 mg/dL); and frequency of severe hypoglycemia (loss or alteration of consciousness, seizures or need for medical intervention). RESULTS: Mean A1C at the study entry was 8.68 percent and after 12 months of glargine, was 8.64 percent (p = 0.82). Frequency of mild hypoglycemia at 3.00 AM was 1.43/3 months during the NPH period and 0.28/3 months during the glargine period (p < 0.007). Frequency of severe hypoglycemia was 0.56/3 months during the NPH period and 0.008/3 months during the glargine period (p < 0.002). CONCLUSIONS: The treatment of T1DM children with insulin glargine was considered as efficacious as with NPH. However, a better safety profile, disclosed by the lower incidence of nocturnal and severe hypoglycemia episodes, was observed for insulin glargine.

Hypoglycemia in diabetic - The role of new technologies

One common obstacle in the treatment of diabetics is hypoglycemia. Hypoglycemia in diabetic is unpredictable and life threatening. It is a consequence of either treatment or part of the natural history of diabetes. Therefore, many dietary and therapeutic maneuvers have been initiated to tackle such obstacle. Twenty-eight years old Bahraini male known diabetic since birth was suffering from frequent attacks of hypoglycemia mandating visits to the Accident and Emergency Department. His blood biochemistry parameters were normal except for the high HbA1c. His general examination was normal. Several treatment regimens were initiated to combat his hypoglycemia with little success. New insulin analogue was prescribed for the patient to reduce the magnitude and frequency of hypoglycemic attacks and improve the blood sugar control. This method of treatment combined with dietary interventions proved effective in reducing the hypoglycemic attacks in clinical trials

Análogos de la insulina, una nueva esperanza / Insulin analogs, a new hope

Después del descubrimiento de que la insulina mejora el pronóstico de vida de las personas con diabetes, sin embargo aún falta por alcanzar el control metabólico adecuado. Todos estamos de acuerdo en que, hasta el momento, para el tratamiento de las personas con diabetes se administra el medicamento inadecuado, en el momento inadecuado y a la dosis inadecuada. Tras la administración de insulina humana regular transcurre un período antes que comience su acción, lo que está condicionado por su estructura molecular en forma de hexámeros. Al modificar la estructura molecular mediante tecnología recombinante surgen los análogos de la insulina, los que tienen una mejor y más estable absorción. En esta revisión se describen los distintos análogos de la insulina, tanto de acción corta como prolongada. Se describe la farmacocinética de cada uno de ellos y se compara su acción con la de la insulina humana.

It has been discovered that insulin improves the prognosis of life of the persons suffering from diabetes; however, an adequate metabolic control has not been attained yet. We all agree that up to now diabetic patients have received the inadequate drug at the wrong time and at an inappropriate dose. Once the regular human insulin is administered, it takes a time to act due to its molecular structure in hexamerous form. On modifying the molecular structure by recombinant technology, the insulin analogs appear with a better and stabler absorption. The different insulin analogs of short and prolonged action are described in this review, as well as the pharmacokinetics of each of them. Their action is compared with that of human insulin.

Complicações hiperglicêmicas agudas no diabetes melito tipo 1 do jovem: [revisão] / Hyperglycemic acute crisis in type 1 diabetes mellitus in youth: [review]

A principal complicação hiperglicêmica no diabetes melito tipo 1 (DM1) é a cetoacidose diabética (CAD). Embora variações nos protocolos possam ocorrer, os princípios básicos que norteiam o tratamento devem ser os mesmos. A recuperação inicial da capacidade circulatória, com a infusão rápida de solução salina na dose de 20 mL/kg, que pode ser repetida, é o ponto de partida para o tratamento. A partir daí, a reposição de volume é relativamente lenta, e o objetivo principal é corrigir gradualmente os distúrbios metabólicos instalados, sem ocasionar variações muito intensas e muito rápidas na osmolalidade, fator de risco para complicações. Atenção ao desenvolvimento de edema cerebral que, uma vez suspeitado, deve ser imediatamente corrigido, sob pena de óbito ou seqüelas neurológicas. A administração de insulina ultra-rápida, por via subcutânea, mostra-se eficaz e simplifica o atendimento do paciente. A CAD é uma situação grave, ainda com alta mortalidade, e seu tratamento deve ser dirigido aos pontos principais que levaram ao quadro clínico, com correções graduais, sob risco de se agravar o quadro.

Diabetic ketoacidosis (DKA) is the main hyperglycemic complication in type 1 Diabetes Mellitus (DM1). The basic principles in treatment have to be followed carefully. The patient with DKA has a very deep volume depletion. To restore the circulatory capacity is the first step. From this point on, the restoration of the lost fluids is slow, around 1 percent per hour, aiming at the correction of the metabolic disturbance already on and avoiding great fluctuations in osmolality, which increases the risk of having complications. Attention to the development of cerebral edema, which, once suspected, deserves an urgent treatment plan, trying to avoid neurologic sequelae or even death. Subcutaneous ultra-rapid insulin has been demonstrated to be efficient and easier to use. As the perfusion gets improved and the levels of insulin increase, the lipolysis is blocked, as well as the generation of ketones and so the acidemia tends to be solved. DKA is still a high-mortality condition. And to be in a hurry frequently leads to neurologic sequelae and even to a fatal outcome.

A evolução da insulinoterapia no diabetes melito tipo 1: [revisão] / Insulin therapy for type 1 diabetes mellitus: past and present: [review]

A descoberta da insulina foi o grande marco da história do diabetes melito e a grande conquista para o seu tratamento. A primeira insulina disponibilizada foi a regular. Na seqüência, Hagedorn acrescentou a protamina à insulina, criando, assim, a insulina NPH. Na década de 1950 foi sintetizada uma insulina desprovida de protamina, denominada insulina lenta. Com o advento da biologia molecular, sintetizou-se, via DNA recombinante, a insulina humana sintética. Mais recentemente, foram disponibilizados vários tipos de análogos de insulina que permitiram o melhor controle metabólico dos pacientes. O tratamento do diabetes melito tipo 1, além do processo educacional, incluindo a prática regular de atividades físicas e orientações dietéticas, resume-se na substituição plena de insulina de longa e curta durações de ação, de maneira individualizada, de acordo com a experiência do médico-assistente. No diabetes melito tipo 1, a preferência é pelas insulinas de menor variabilidade, por meio do esquema basal/bólus ou pelas bombas de infusão contínua de insulina subcutânea com o objetivo de mimetizar a liberação fisiológica de insulina pelas células-beta.

The discovery of insulin can be considered the milestone of diabetes mellitus history and a great achievement for its treatment. The first insulin available was the regular. Afterwards, Hagedorn added the protamine to the insulin, thus, creating the NPH insulin. In the 1950s an insulin free of protamine was synthesized: the lente insulin. With the advent of molecular biology, synthetic human insulin was synthesized using recombinant DNA technology. Most recently several types of insulin analogues were available, providing the patients with better metabolic control. Type 1 diabetes mellitus treatment includes plain substitution and individualization for short-acting plus long-acting insulin according to the physician's assistance, besides regular practice of physical activities and diet orientations. In type 1 diabetes mellitus the insulin of low variability is the best choice since basal/bolus insulin therapy or continuous subcutaneous insulin infusion pump can mimetize the physiological release of insulin by beta cells.

Novas opções na terapia insulínica: [revisão] / New options in insulin therapy: [review]

OBJETIVO: Revisar as novas opções nas terapêuticas insulínicas para controlar o diabetes melito de crianças e adolescentes. FONTES DOS DADOS: Foram revisados artigos indexados no PubMed buscados conforme as palavras insulin analogs in children and adolescents e incluídas informações contidas nos consensos da American Diabetes Association e Sociedade Brasileira de Diabetes. SÍNTESE DOS DADOS: São apresentadas informações sobre os novos análogos da insulina e, para comparação, são também revisadas as outras diferentes modalidades de insulina que estão atualmente disponíveis, focalizando nas terapias insulínicas que tentam fornecer uma aproximação mais fisiológica das estratégias basal-bolos no tratamento. Com o objetivo de obter melhor controle metabólico, mais e mais crianças estão em regimes de múltiplas injeções diárias ou usando infusões subcutâneas contínuas de insulina. Atingir controle glicêmico ótimo nas crianças é difícil devido ao maior risco de hipoglicemia decorrente da grande variabilidade em hábitos de ingerir alimentos e em níveis de atividade física. Se aplicados em bolos, subcutâneos, no diabetes tipo 1, os análogos de ação rápida, comparados com insulina humana regular, geralmente reduzem os episódios de hipoglicemia e glicemia pós-prandial, enquanto os análogos basais tendem a reduzir particularmente a hipoglicemia noturna. CONCLUSÃO: Embora os benefícios nos desfechos individuais metabólicos e clínicos pareçam modestos, a maioria dos estudos demonstra benefícios quando são usados análogos de insulina no tratamento do diabetes tipo 1 ou 2.

OBJECTIVE:To review the new options in insulin therapy for controlling diabetes mellitus in children and adolescents. SOURCES: Articles indexed in PubMed were located using the search terms insulin analogs in children and adolescents and reviewed. Information was also obtained from American Diabetes Association and Sociedade Brasileira de Diabetes consensus documents. SUMMARY OF THE FINDINGS: Information is presented on new analogs of insulin and, for purposes of comparison, the other insulin modalities currently available are also reviewed, focusing on insulin therapies which attempt to approximate basal-bolus treatment strategies to physiology. With the objective of obtaining improved metabolic control, more and more children are being put on multiple daily injection regimes or using continuous subcutaneous insulin infusion. It is difficult to achieve optimum glycemic control in children due to the increased risk of hypoglycemia resulting from the great variability in dietary intake habits and in physical activity levels. With diabetes type 1, if rapid-acting analogs are given subcutaneously in bolus, they generally reduce hypoglycemia episodes and postprandial glycemia levels, compared with regular human insulin, while basal analogs tend to reduce particularly the number of episodes of nocturnal hypoglycemia. CONCLUSIONS: Although the benefits to individual metabolic and clinical outcomes appear modest, the majority of studies demonstrate benefits when insulin analogs are used in the treatment of diabetes type 1 or 2.

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

Background: Biophasic insulin aspart (InAsBi) is a mixture of 30 percent of rapid acting soluble aspart insulin and 70 percent 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 percent 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 íeast 1 percent in 96 and increased in eight cases. In the total group HbA1c decreased from 10.1± 1.7 to 8.4±1.4 percent (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.

Substituição da insulina NPH por insulina glargina em uma coorte de pacientes diabéticos: estudo observacional / Switching of NPH insulin to glargine therapy in a cohort of poorly controlled diabetic patients: observational study

Este estudo avaliou o impacto da introdução da insulina glargina na terapia basal/bólus em pacientes com diabetes mellitus do tipo 1 (DM1) e do tipo 2 (DM2), com controle inadequado (A1c > 6,9 por cento) em uso prévio de insulina basal NPH. Foi realizado um estudo retrospectivo, não-controlado, com 49 pacientes (28F/21M), idade média 24,7 ± 16,5 anos, tempo de diabetes de 13,2 ± 10,1, sendo 93,1 por cento dos pacientes com DM1, que receberam insulina glargina combinada com insulina ultra-rápida (aspart/lispro) pré-refeições, durante 90 dias de seguimento. Foram analisados dose total de insulina, incidência de hipoglicemias, crises convulsivas, complicações hiperglicêmicas (cetoacidose) e níveis de A1c antes e após três meses do uso da insulina glargina. Os valores de A1c foram determinados pelo método HPLC, com valores de referência de 4,3 por cento a 6,9 por cento. Após 3 meses da modificação do esquema basal para insulina glargina, observou-se redução significativa dos níveis de A1c (10,2 ± 2,0 vs. 9,1 ± 1,8 por cento; p= 0,019). Além disso, verificou-se redução de 0,11 U/kg/dia na dose total de insulina utilizada (NPH: 0,75 U/kg para 0,64 U/kg de insulina glargina; p< 0,05). O uso da insulina glargina associou-se com redução das crises hipoglicêmicas (p= 0,02), crises convulsivas por hipoglicemia grave (p= 0,023) e nenhum caso de cetoacidose (p= 0,001). Este estudo corrobora a eficácia da introdução da insulina glargina em pacientes diabéticos mal controlados, em uso prévio de insulina NPH, com redução importante dos níveis de A1c. Estima-se uma melhora da qualidade de vida desses pacientes, marcada pela redução de eventos hipoglicêmicos (inclusive os graves), episódios de cetoacidose e utilização de menor dose diária de insulina, com provável impacto em políticas de saúde pública.

This study examined the impact of insulin glargine introduction in basal-bolus therapy in type 1 and type 2 diabetic patients with inadequate metabolic control (A1c > 6.9 percent) using previous NPH insulin regime. In this uncontrolled, retrospective study, 49 patients (28F/21M), average age 24.7 ± 16.5, mean duration of DM 13.2 ± 10.1 yrs., 93.1 percent DM1 patients, received insulin glargine plus mealtime rapid-acting insulin (lispro or aspart) followed by 90-day treatment. We analyzed mean total insulin dose, incidence of hypoglycemic events, convulsive crisis, hyperglycemic complications and A1c levels before and after three months of introduction of glargine therapy. A1c values were determined using the HPLC instrument, with a normal range of 4.3 percent to 6.9 percent. After switching to insulin glargine therapy, mean A1c dropped from 10.2 ± 2.0 to 9.1 ± 1.8 percent, with significant impact (p= 0.019). We observed a significant reduction of 0.11U/kg/day in total insulin dose, dropped from 0.75U/kg of NPH to 0.64U/kg of glargine, with significant correlation (p< 0.05). The introduction of glargine therapy was coincident with a decrease of hypoglycemic crisis (p= 0.02), convulsive events due to hypoglycemia (severe hypoglycemic crisis) (p= 0.023) and ketosis (p= 0.001) switching MDI-treated patients with improvement of metabolic control (reduction of A1c levels). This therapy improved quality of life in these patients due to a significant reduction of hypoglycemic (including severe) events, ketosis episodes and total daily insulin dose, with important impact on health public services.