Insulinas análogas de ação prolongada comparadas à insulina NPH para tratamento de diabetes mellitus tipo 2 em adultos: revisão rápida / Long-acting basal insulin analogues compared to nph insulin for type 2 diabetes mellitus in adults: rapid review

Tecnologia: Insulinas análogas de liberação prolongada versus insulina NPH (protamina neutra de Hagedorn). Indicação: Tratamento de adultos com diabetes mellitus tipo 2. Pergunta: Há diferenças de efeito nos principais desfechos de eficácia e segurança entre insulinas análogas de liberação prolongada versus insulina NPH no tratamento de pacientes com DM2? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foi selecionada e incluída uma revisão sistemática. Conclusão: As insulinas análogas (glargina e detemir) não demonstraram superioridade nos desfechos de eficácia e segurança quando comparadas à insulina NPH, não demonstraram redução significativa em relação à mortalidade por todas as causas e complicações secundárias ao DM2. Quando comparadas à insulina NPH, foi observado redução na hipoglicemia confirmada e hipoglicemia noturna a favor das insulinas análogas e na hipoglicemia grave a favor da insulina detemir

Technology: Long-acting insulin analogues versus NPH insulin (human isophane insulin). Indication: Treatment of adults with type 2 diabetes mellitus. Question: Are there effect differences in key efficacy and safety outcomes between long-acting insulin analogues versus NPH insulin in the treatment of DM2 patients? Methods: Rapid review of evidence (overview) of systematic reviews, with a bibliographic survey carried out in the PUBMED database, using a structured search strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Results: A systematic review was selected and included. Conclusion: Analog insulins (glargine and detemir) did not demonstrate superiority in efficacy and safety outcomes when compared to NPH insulin, did not demonstrate a significant reduction in all-cause mortality and complications secondary to DM2. When compared to NPH insulin, a reduction in confirmed hypoglycemia and nocturnal hypoglycemia in favor of analogue insulins and in severe hypoglycemia in favor of insulin detemir was observed

Nueva generación de insulinas: glargina U300: Resumen de evidencia clínica / New generation of insulins: glargine U300. Summary of clinical evidence

La diabetes mellitus tipo 2 tiene evolución crónica y progresiva, prevalencia creciente y aún es diagnosticada tardíamente. Esto conlleva mayor incidencia de complicaciones crónicas, con incremento de costos en salud. Existe retraso en el inicio de insulinoterapia por causas relacionadas tanto al paciente como al médico. A pesar de los avances en su tratamiento, una baja proporción de enfermos logra control glucémico adecuado. La alta prevalencia de hipoglucemia en pacientes insulino-tratados, impulsó el desarrollo de una nueva generación de insulinas basales de acción prolongada, mayor estabilidad con menor variabilidad y riesgo de hipoglucemias. El programa EDITION evaluó la eficacia y seguridad de glargina U300 vs. glargina U100 en pacientes con diabetes tipo 1 y 2, en distintas etapas de la enfermedad. Glargina U300 es una nueva formulación de insulina glargina con perfil farmacocinético y farmacodinámico más estable y prolongado que glargina U100. Glargina U300 demostró eficacia y tolerabilidad comparable a glargina U100, con descenso significativo del riesgo de hipoglucemias nocturnas y en 24 horas, aportando mayor flexibilidad en el horario de inyección, con una ventana de 6 horas. Además, no se observó mayor aumento de peso que con glargina U100. El estudio Bright (2018) comparó glargina U300 vs. degludec U100, demostrando mayor beneficio en relación al riesgo de hipoglucemia con Gla-300 durante el período de titulación. Gla-300 es una insulina basal de última generación, disponible para mejorar el control metabólico, con menor riesgo de hipoglucemia.

Type 2 diabetes is a chronic, progressive disease with increasing prevalence and still late diagnostic. This leads to an increase in the incidence of chronic complications, with signifi cantly increasing health costs. There is also a delay in the onset of insulin therapy in patients with type 2 diabetes for causes related to both patients and physicians. Despite advances in treatment, a low proportion of patients achieve adequate glycemic control. The high hypoglycemia prevalence, consequence of insulin, has led to the development of a new generation long-acting basal insulins to achieve a more stable and prolonged action profile, reducing the variability and risk of hypoglycemia. The EDITION program evaluated the efficacy and safety of glargine U300 compared to glargine U100 in patients with type 1 and 2 diabetes at different stages of the disease. Gla-300 is a new formulation of insulin glargine which has a more stable and prolonged pharmacokinetic and pharmacodynamic profile. Gla-300 demonstrated efficacy and tolerability comparable to glargine U100, with a significant decrease in the risk of hypoglycemia, at night and in 24 hours, providing greater flexibility in the injection schedule, with a window of 6 hours. No increase in weight was observed compared to glargine U100. Bright study (2018) compared glargine U300 vs. degludec U100, demonstrating greater benefit in relation to the risk of hypoglycemia with Gla-300 during titration period. Gla-300 is a last-generation basal insulin, available to improve metabolic control, with a lower risk of hypoglycemia.

Insulina degludec en pacientes diabéticos tipo 1: observación a 18 meses / Degludec insulin in type 1 diabetic patients: 18 months of observation

Antecedentes: En el tratamiento de la diabetes se buscan insulinas de acción más prolongada y con menores tasas de hipoglicemias. Objetivo. Uso del análogo de insulina de acción ultralenta degludec en diabéticos tipo 1 (DM1) tratados previamente con glargina. Pacientes y método: Se observaron 230 DM1 durante 18 meses, promedio de edad 34 años y de diagnóstico 14 años, registrándose parámetros clínicos, bioquímicos, hipoglicemias y requerimientos de insulina (U/kg/peso), en régimen basal/bolo, con degludec y ultra-rápida precomidas. Degludec se ajustó quincenalmente. Resultados: A los 3 meses, la glicemia de ayunas disminuyó de 253mg/dl (243-270) a 180 mg/dl (172- 240), (p< 0,05); a los 6 meses a 156 mg/dl (137-180) (p< 0,05), a los 12 meses a 151 mg/dl (50-328) (p< 0,001) y a los 18 meses 150 (50-321) (p<0,001). La HbA1c, inicialmente de 10,6% (10,3-12,2) bajó a los 3 meses a 8,7% (8,2-11,1) (p< 0,05), a 6 meses a 8,3% (8,0-9,6) (p<0,05), a los 12 meses subió 9,0% (5,9-14,5) (p<0,001) y a los 18 meses 9,0% (5,9-14,6) (p<0,001). La dosis de degludec fue 0,5 U/kg/peso a los 18 meses. Hubo reducción de hipoglicemias: a los 3 meses 14 leves, 4 moderados 1 grave; a los 6 meses 8 leves, 2 moderados y ninguna grave; a los 12 meses 1 leve, y a los 18 meses 2 leves, 1 moderado y ninguna grave. Un 7,8% no presentó hipoglicemias. Conclusión: Degludec en DM1 mostró reducir las glicemias de ayunas y HbA1c, y menor número de hipoglicemias.

Background: In the treatment of diabetes, longer-acting insulins with lower rates of hypoglycaemia are sought. Objective. Use of ultralow-acting insulin analog degludec in type 1 diabetic patients (T1D) previously treated with glargine. Patients and method: 230 T1D patients were observed during 18 months, average of age 34 years and of diagnosis 14 years, registering clinical, biochemical, hypoglycemia and insulin requirements (U / kg / weight), in basal / bolus regimen, with degludec and ultra-fast pre-meals. Degludec adjusted himself fortnightly. Results: At 3 months, the fasting glycemia decreased from 253 mg / dl (243-270) to 180 mg / dl (172 - 240), (p <0.05); at 6 months at 156 mg / dl (137-180) (p <0.05), at 12 months at 151 mg / dl (50-328) (p <0.001) and at 18 months 150 (50-321) ;(p <0.001). HbA1c, initially of 10.6% (10.3-12.2), decreased after 3 months to 8.7% (8.2 - 11.1) (p <0.05), to 6 months to 8 months, 3% (8.0-9.6) (p <0.05), at 12 months it rose 9.0% (5.9-14.5) (p <0.001) and at 18 months 9.0 % (5.9-14.6) (p <0.001). The dose of degludec was 0.5 U / kg / weight at 18 months. There was reduction of hypoglycemia: at 3 months, 14 mild, 4 moderate, 1 severe; at 6 months 8 mild, 2 moderate and none serious; at 12 months 1 mild, and at 18 months 2 mild, 1 moderate and none serious. 7.8% did not present hypoglycemia. Conclusion: Degludec in T1D patients showed to reduce fasting glycemia and HbA1c, and lower number of hypoglycemia.

Comportamiento de hemoglobina glicosilada y frecuencia de hipoglicemias en diabéticos tipo 2 tratados con insulina glargina o NPH / Glycosylated hemoglobin behavior and frequency of hypoglycemia in type 2 diabetics treated with insulin glargine or NPH

Objetivo: Evaluar comportamiento de hemoglobina glicosilada (HbA1c) y frecuencia de hipoglicemias sintomáticas con esquema basal con insulina NPH comparado con insulina glargina en diabéticos tipo 2 (DM2), atendidos en un programa de riesgo cardiovascular. Materiales y métodos: Estudio observacional de cohorte retrospectivo. Se revisaron 613 historias clínicas de pacientes con DM2 manejados con esquema basal con insulina NPH o glargina, de los cuales 76 cumplieron los criterios de inclusión. Se revisó historia clínica al momento de inclusión (consulta No. 1), a los seis (consulta No. 2) y a los doce meses (consulta No. 3). Resultados: Se analizaron 13 pacientes del grupo glargina y 63 del grupo NPH (edad 64,9 [± 10,9 años], 54 porciento mujeres). En la consulta No. 1 el promedio de HbA1c fue 7.8 porciento en grupo con NPH y 7.5 porciento en grupo glargina. Al final del seguimiento los niveles de HbA1c fueron 7.5 porciento en grupo NPH y 7.9 porciento en grupo glargina (p= 0.4). Los eventos de hipoglucemia fueron 3 en la primera consulta y 4 en la tercera, todos recibían NPH. En la segunda consulta se presentaron 5 eventos en pacientes con NPH y 1 caso con glargina (p=0.9). Las variables más fuertemente asociadas con niveles bajos de HbA1c fueron enfermedad renal crónica y sexo femenino. Conclusiones: Los pacientes con DM2 de este estudio no presentaron diferencia estadísticamente significativa en valores de HbA1c de acuerdo al tipo de insulina recibida.Se observó menor frecuencia de hipoglucemias en pacientes que utilizaban insulina glargina sin encontrarse diferencia estadísticamente significativa.

To evaluate performance of glycosylated hemoglobin (HbA1c) and frequencyof symptomatic hypoglycemia scheme with basal insulin glargine compared toNPH insulin in type 2 diabetics (DM2), served in a program of cardiovascularrisk. Materials and methods: Observational retrospective cohort. 613 medicalrecords of patients with DM2 managed scheme with basal insulin NPHor glargine, of which 76 met the inclusion criteria were reviewed. medicalrecords were reviewed at the time of inclusion (see No. 1), six (see No. 2)and twelve months (see No. 3). Results: 13 patients in the glargine group and63 in the NPH group (age 64.9 [± 10.9 years], 54% female) were analyzed.The consultation No. 1 mean HbA1c was 7.8% with NPH group and 7.5% inglargine group. At follow-up HbA1c levels were 7.5% in NPH group and 7.9%in glargine group (p = 0.4). Hypoglycemic events were 3 in the first visit and 4in the third, all received NPH. In the second consultation five events occurredin patients with NPH and 1 case with glargine (p = 0.9). The variables moststrongly associated with low levels of HbA1c were chronic kidney disease andwomen. Conclusions: Patients with DM2 of this study showed no statisticallysignificant difference in HbA1c values according to the type of insulinreceived. Lower frequency of hypoglycemia in patients using insulin glargineno statistically significant difference was observed.

Resultados do estudo ORIGIN: implicações práticas para cardiologistas / Results of the study ORIGIN: pratical approach for cardiologists

Há grande debate em relação aos potenciais efeitos cardiovasculares da insulinoterapia concentrado em duas hipóteses conflitantes: seriam eles resultantes da administração exógena da insulina ou da própria condição de insulinorresistência que justificou o tratamento insulínico? O estudo ORIGIN testou a hipótese de que a normalização da glicemia, utilizando insulina exógena suficiente, reduziria eventos cardiovasculares em pacientes com pré-diabetes ou com diabetes tipo 2 recém-diagnosticado e, também, portadores de outro fator de risco cardiovascular. Este estudo incluiu 12.537 participantes com pré-diabetes ou DM2 de início recente, com idade média de 63,5 anos, portadores de fatores de risco cardiovascular, seguidos por sete anos. Os pacientes do grupo tratado receberam insulina glargina titulada para uma meta glicêmica de <95 mmg/dL, enquanto o grupo-controle recebeu tratamento convencional. Os resultados do estudo mostraram redução significativa da glicemia de jejum e, também, da hemoglobina glicada. A incidência de efeitos cardiovasculares foi semelhante entre os dois grupos. Houve redução significativa da conversão para o diabetes no grupo pré-diabético tratado com glargina. Um aumento da frequência de hipoglicemia foi detectado no grupo da insulina glargina, embora tenha atingido apenas 1,0 episódio/100 pacientes/ano. Não houve qualquer diferença estatística entre os dois grupos em relação à incidência de câncer. No subestudo ORIGIN-GRACE se observou que o tratamento insulínico promoveu modesta redução na velocidade de progressão do espessamento da camada média íntima dos segmentos proximais da carótida.

[New insulin types in type 1 diabetes mellitus]. / Nuevas insulinas en la diabetes tipo 1.

Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development.

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.