ANALYSIS OF CLINICAL AND LABORATORY PARAMETERS CHILDREN WITH DIABETES MELLIUS TYPE 1 USING DIFFERENT TYPES OF INSULIN PREPARATIONS.

A comparative analysis of clinical and laboratory parameters was carried out in 49 children. The patients were divided into 3 groups depending on the type of insulin they received. Group 1 included 20 children who used Insulin human (Insulatard), group 2 included 15 children using insulin Glargine, and group 3 included 14 children using insulin Detemir. All children using Detemir and Glargine used short acting insulin Aspart. Those using Insulin human (Insulatard) used Human insulin (rDNA, Actrapid) in addition. In all children, blood glucose, glycohemoglobin and cholesterol were determined by laboratory methods. Statistical calculations were carried out using a statistical package at a confidence level of p＜0.05. A significant difference was found between the mean values of glycohemoglobin and glucose of Glargine users and patients with using Insulin human (Insulatard) (p≺0.05). These indicators were lower in Glargine users. There is a positive correlation between doses of Regular insulin and Insulin human (Insulatard) with body weight and height. There is a positive correlation between dose of Detemir and body mass. However, no such relationship between Glargine, body mass and height was recorded. It was a negative correlation between its dose Glargine with glycohemoglobin and also between glucose and cholesterol using Glargine.

Effectiveness, safety, initial optimal dose, and optimal maintenance dose range of basal insulin regimens for type 2 diabetes: A systematic review with meta-analysis.

AIMS: To investigate the effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins in insulin-naïve patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from January 2000 to February 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was adopted. The registration ID is CRD42022319078 in PROSPERO. RESULTS: Among 11 163 citations retrieved, 35 publications met the planned criteria. From meta-analyses and network meta-analyses, we found that when injecting basal insulin regimens at bedtime, the optimal choice in order of most to least effective might be glargine U-300 or degludec U-100, glargine U-100 or detemir, followed by neutral protamine hagedorn (NPH). Injecting glargine U-100 in the morning may be more effective (ie, more patients archiving glycated hemoglobin < 7.0%) and lead to fewer hypoglycemic events than injecting it at bedtime. The optimal starting dose for the initiation of any basal insulins can be 0.10-0.20 U/kg/day. There is no eligible evidence to investigate the optimal maintenance dose for basal insulins. CONCLUSIONS: The five basal insulins are effective for the target population. Glargine U-300, degludec U-100, glargine U-100, and detemir lead to fewer hypoglycemic events than NPH without compromising glycemic control.

Insulin degludec versus insulin detemir, both in combination with insulin aspart, in the treatment of pregnant women with type 1 diabetes (EXPECT): an open­label, multinational, randomised, controlled, non-inferiority trial.

BACKGROUND: Insulin degludec (degludec) is a second-generation basal insulin with an improved pharmacokinetic-pharmacodynamic profile compared with first-generation basal insulins, but there are few data regarding its use during pregnancy. In this non-inferiority trial, we aimed to compare the efficacy and safety of degludec with insulin detemir (detemir), both in combination with insulin aspart (aspart), in pregnant women with type 1 diabetes. METHODS: This open-label, multinational, randomised, controlled, non-inferiority trial (EXPECT) was conducted at 56 sites (hospitals and medical centres) in 14 countries. Women aged at least 18 years with type 1 diabetes who were between gestational age 8 weeks (+0 days) and 13 weeks (+6 days) or planned to become pregnant were randomly assigned (1:1), via an interactive web response system, to degludec (100 U/mL) once daily or detemir (100 U/mL) once or twice daily, both with mealtime insulin aspart (100 U/mL), all via subcutaneous injection. Participants who were pregnant received the trial drug at randomisation, throughout pregnancy and until 28 days post-delivery (end of treatment). Participants not pregnant at randomisation initiated the trial drug before conception. The primary endpoint was the last planned HbA1c measurement before delivery (non-inferiority margin of 0·4% for degludec vs detemir). Secondary endpoints included efficacy, maternal safety, and pregnancy outcomes. The primary endpoint was assessed in all randomly assigned participants who were pregnant during the trial. Safety was assessed in all randomly assigned participants who were pregnant during the trial and exposed to at least one dose of trial drug. This study is registered with ClinicalTrials.gov, NCT03377699, and is now completed. FINDINGS: Between Nov 22, 2017, and Nov 8, 2019, from 296 women screened, 225 women were randomly assigned to degludec (n=111) or detemir (n=114). Mean HbA1c at pregnancy baseline was 6·6% (SD 0·6%; approximately 49 mmol/mol; SD 7 mmol/mol) in the degludec group and 6·5% (0·8%; approximately 48 mmol/mol; 9 mmol/mol) in the detemir group. Mean last planned HbA1c measurement before delivery was 6·2% (SE 0·07%; approximately 45 mmol/mol; SE 0·8 mmol/mol) in the degludec group and 6·3% (SE 0·07%; approximately 46 mmol/mol; SE 0·8 mmol/mol) in the detemir group (estimated treatment difference -0·11% [95% CI -0·31 to 0·08]; -1·2 mmol/mol [95% CI: -3·4 to 0·9]; pnon-inferiority<0·0001), confirming non-inferiority. Compared with detemir, no additional safety issues were observed with degludec. INTERPRETATION: In pregnant women with type 1 diabetes, degludec was found to be non-inferior to detemir. FUNDING: Novo Nordisk.

Detemir improves diabetic regulation in poorly controlled diabetic dogs with concurrent diseases.

OBJECTIVE: This study evaluated the use of detemir for treating diabetic dogs with comorbidities that were poorly controlled with intermediate-acting insulins. ANIMALS: 7 insulin-treated diabetic dogs. PROCEDURES: Retrospective pilot study. Dogs were treated with detemir for at least 3 months, and glycemia was assessed by the owners at home initially 2 to 4 times daily for 6 to 8 weeks and twice daily thereafter. Clinical evaluations occurred on days 7 to 14, day 30, and then every 60 to 90 days, and dosage adjustments of detemir occurred as needed to control glycemia. RESULTS: The mean, peak, nadir, morning, and evening preinsulin daily blood glucose concentrations were significantly lower after dosing with detemir for 1, 3, or 6 months and during the last month of treatment compared to the final month of treatment with intermediate-acting insulin. Intermediate-acting insulins resulted in significantly worse glycemic control than detemir in all 3 categories of control. The odds of a biochemical hypoglycemic measurement with detemir were not significantly different compared to intermediate-acting insulins. Clinical hypoglycemia did not occur following detemir treatment. When insulin was withheld because of low morning preinsulin blood glucose concentration < 6.7 mmol/L (≤ 120 mg/dL) and dogs were fed, mean blood glucose concentration was significantly higher 1 hour later. Glucose concentrations were also significantly higher 12 hours later on days when insulin was withheld in the morning or evening for either 1 or 12 hours. CLINICAL RELEVANCE: Detemir is useful in diabetic dogs with other comorbidities and can be considered an alternative treatment in poorly controlled diabetic dogs.

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

Alteração das Insulinas análogas de ação prolongada para o tratamento de diabetes mellitus tipo I / Alteration of long-acting insulin analogues for the treatment of type I diabetes mellitus

INTRODUÇÃO: O diabetes mellitus tipo 1 (DM1) é um transtorno endócrino caracterizado por hiperglicemia devido à destruição de células beta, geralmente levando a deficiência absoluta de insulina. Trata-se de uma doença de grande relevância, principalmente porque o não tratamento ou o seu agravamento podem levar a desfechos graves como a morte e a complicações macro e microvasculares, oculares, renais e neurológicas. O tratamento do paciente acometido com DM1 consiste na reposição de insulina endógena através do uso de insulina de ação rápida ou ultrarrápida, associada a uma insulina de ação intermediária ou prolongada, além da monitorização da glicemia capilar pelo paciente e medidas de autocuidado dos pacientes. Como terapia medicamentosa, o SUS disponibiliza a insulina Regular, insulina NPH e insulinas análogas de ação rápida. Além das insulinas disponibilizadas pelo SUS, atualmente também se encontram disponíveis no mercado, as insulinas análogas de ação prolongada (glargina, detemir e degludeca), além de pré-misturas que contêm associações entre estas diversas opções. PERGUNTA DE PESQUISA: O objetivo do presente relatório é verificar e atualizar as evidências científicas sobre a eficácia, segurança e recalcular o impacto orçamentário das insulinas análogas de ação prolongada (glargina, detemir e degludeca). EVIDÊNCIAS CLÍNICAS: Dois novos estudos foram avaliados, no relatório original foram selecionadas sete revisões sistemáticas (RS) de risco de viés baixo a incerto, avaliadas pela ferramenta Risk of Bias in Systematic Reviews (ROBIS) e separadas por tipo de comparação. Insulina glargina vs NPH: foram incluídas quatro RS com metanálise, que demonstraram eficácia na redução dos níveis de HbA1c a favor da insulina glargina, variando entre 0,33 a 0,40%. Tricco et al. (2021), incluiu 65 estudos únicos com 14200 pacientes com diabetes tipo 1, as insulinas de ação prolongada se mostraram superiores para o controle da hipoglicemia noturna, superioridade na Redução hemoglobina glicada, glicemia de jejum, ganho de peso. Quanto aos episódios de hipoglicemia grave Dawoud et al. (2018) e Tricco et al. (2014) demonstraram que não houve diferença estatisticamente significante entre as insulinas, no entanto Marra et al. (2016) apresentaram uma estimativa da diferença da média do número de episódios de hipoglicemia grave a favor da insulina glargina em -0,58. Insulina detemir vs NPH: foram incluídas duas RS nesta comparação, na qual ambas demonstraram que a insulina detemir foi mais eficaz na redução dos níveis de HbA1c em relação à insulina NPH, uma diferença de 0,16% e 0,26%. A insulina detemir (utilizada uma ou duas vezes por dia) foi associada a um risco menor de episódios de hipoglicemia grave, de 0,25 , comparada a insulina NPH (utilizada uma ou duas vezes por dia). Insulina degludeca vs NPH: apenas Dawoud et al. (2018) avaliaram a eficácia e segurança da insulina degludeca comparada à insulina NPH, demonstrando que não houve nenhuma diferença estatisticamente significativa entre as insulinas na redução dos níveis de HbA1c e nas taxas de episódios de hipoglicemia grave. Insulina glargina vs detemir: foram incluídas três RS nesta comparação, na qual todas demonstraram que não houve diferença estatisticamente significante entre elas na redução dos níveis de HbA1c. Dawoud et al. (2018) não mostraram diferenças significativas ou clinicamente relevantes na taxa de hipoglicemia grave entre as insulinas glargina e detemir. Insulina glargina vs degludeca: foram incluídas três RS nesta comparação, na qual todas demonstraram que não houve diferença significante entre as insulinas na redução dos níveis de HbA1c. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise consistiu em uma atualização do impacto apresentado no Relatório de Recomendação da Conitec nº 440 de março de 2019, considerando o preço de aquisição da insulina NPH e as aquisições dos comparativos pelo BPS e Siasg. Foi considerada a dose diária definida estabelecida pela OMS para todas as tecnologias (40 UI). Os preços foram obtidos no Sistema Integrado de Administração de Serviços Gerais (SIASG). Foram feitos dois cenários populacionais, a partir de dados epidemiológicos e outro com dados de dispensação pelo SUS e pelo programa "Aqui Tem Farmácia Popular". Considerando o cenário epidemiológico estimado, o gasto previsto com incorporação de insulinas análogas de ação prolongada variou no primeiro ano entre cerca de R$ 195 mi e cerca de R$ 990 mi, de acordo com o análogo de insulina. Considerando o cenário epidemiológico estimado, o gasto previsto com incorporação de insulinas análogas de ação prolongada variou no primeiro ano entre cerca de R$ 7,4 mi e cerca de R$ 907 mi, de acordo com o análogo de insulina. O gasto total ao final de cinco anos variou entre cerca de R$ 1.7 bi a cerca de R$ 9,5 bi, a depender do análogo de insulina. O impacto orçamentário incremental estimado, em relação à insulina humana NPH, variou entre R$ 108 mi e R$ 7,8 bi (Tabela 15). MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram considerados estudos clínicos de fases 3 ou 4 inscritos no ClinicalTrials, que testaram ou estão testando os medicamentos resultantes da busca supracitada. Os medicamentos com registro para a indicação clínica há mais de dois anos na Agência Nacional de Vigilância Sanitária (ANVISA), ou há mais de cinco anos na European Medicines Agency (EMA) ou na U.S. Food and Drug Administration (FDA) não foram considerados. Os dados da situação regulatória das tecnologias foram consultados nos sítios eletrônicos das referidas agências sanitárias. No horizonte considerado nesta análise, não foram detectadas tecnologias para o tratamento do diabetes mellitus tipo I. CONSIDERAÇÕES: As insulinas análogas de ação prolongada demonstram benefício clínico modesto, sendo o seu efeito mais proeminente para o controle da hipoglicemia grave e noturna. Seu uso como regime basal de insulina para DM1 parece beneficiar mais os pacientes que apresentam episódios recorrentes de hipoglicemia. No entanto, há de se ponderar a fragilidade em avaliar os eventos de hipoglicemia, devido às divergências nas definições deste desfecho. Na comparação entre insulinas análogas de ação prolongada não houve um consenso entre os autores sobre qual seria mais eficaz e segura. Além disso, desfechos importantes no diabetes, como complicações diabéticas, presença de eventos adversos e medidas da variabilidade glicêmica, não foram relatados nos estudos incluídos. Evidência clínica sobre a efetividade da insulina glargina com dados brasileiros demonstrou que um pequeno número de pacientes obtiveram o controle glicêmico e não foi identificada correlação entre o tipo de insulinoterapia e a qualidade de vida relacionada à saúde do paciente com DM1. Após abertura de licitação, nenhuma empresa conseguiu ofertar com o valor aprovado para incorporação. A nova análise de impacto orçamentário demonstra que o montante de recursos envolvidos numa potencial incorporação apesar de registrar resultado financeiro adicional, teve considerável redução em relação ao relatório de 2019. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 111ª Reunião Ordinária da Conitec, realizada no dia 04 de agosto de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar favorável à manutenção das insulinas análogas de ação prolongada com condicionante de custo de tratamento. CONSULTA PÚBLICA: As contribuições sobre experiência ou opinião, apresentaram 98% de concordância sobre a manutenção das insulinas. Destas 107 opiniões não continham informações complementares, 77% eram do sexo feminino, 47% entre 25 e 39 anos e 70% se autodeclaravam brancos. Ao reportar e sintetizar as opiniões, ficaram mais evidentes as falas de melhoria no controle da glicemia e comodidade para uso dos análogos de ação prolongada. Assim as contribuições recebidas na consulta pública sobre o relatório que avalia a proposta de à manutenção das insulinas análogas de ação prolongada com condicionante de custo de tratamento foram em sua maioria favoráveis a recomendação preliminar da Conitec, de incorporação. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário presentes na 114ª Reunião Ordinária da Conitec, realizada no dia 09 de novembro de 2022, deliberaram, por unanimidade, recomendar a não alteração da recomendação de incorporação das insulinas análogas de ação prolongada para o tratamento de diabetes mellitus tipo I, mantidos os termos da Portaria SCTIE/MS nº 19, de 27 de março de 2019. Foi assinado o registro de deliberação Nº 780/2022. DECISÃO: Não alterar, no âmbito do Sistema Único de Saúde - SUS, a incorporação das insulinas análogas de ação prolongada para o tratamento de diabetes mellitus tipo I, mantidos os termos da Portaria SCTIE/MS nº 19, de 27 de março de 2019, conforme protocolo estabelecido pelo Ministério da Saúde, conforme a Portaria nº 167, publicada no Diário Oficial da União nº 228, seção 1, página 81, em 6 de dezembro de 2022.

Comparative efficacy and safety of basal insulins: A review.

BACKGROUND AND AIM: To provide an update on the usefulness of basal insulin in patients with type 2 diabetes mellitus. METHODS: We conducted a literature search using PubMed and MEDLINE, BIOSIS, Scopus, EMBASE, ClinicalTrials.gov, Google Scholar, and Springer Online Archives Collection until June 2021. RESULTS: All basal insulins are similar in efficacy, with only small differences among them in terms of the risk of hypoglycemia. CONCLUSIONS: For type 2 diabetes mellitus, all basal insulins have a similar efficacy, with some advantage of Glar-300 and Deg-100 in reducing the risk of hypoglycemia compared to Glar-100.

Detemir vs neutral protamine Hagedorn insulin for diabetes mellitus in pregnancy: a comparative effectiveness, randomized controlled trial.

BACKGROUND: Insulin detemir, being used increasingly during pregnancy, may have pharmacologic benefits compared with neutral protamine Hagedorn. OBJECTIVE: We evaluated the probability that compared with treatment with neutral protamine Hagedorn, treatment with insulin detemir reduces the risk for adverse neonatal outcome among individuals with type 2 or overt type 2 diabetes mellitus (gestational diabetes mellitus diagnosed at <20 weeks' gestation). STUDY DESIGN: We performed a multiclinic randomized controlled trial (September 2018 to January 2020), which included women with singleton gestation with type 2 or overt type 2 diabetes mellitus who sought obstetrical care at ≤21 weeks' gestation. Participants were randomized to receive either insulin detemir or neutral protamine Hagedorn by a clinic-stratified scheme. The primary outcome was a composite of adverse neonatal outcomes, including shoulder dystocia, large for gestational age, neonatal intensive care unit admission, respiratory distress (defined as the need of at least 4 hours of respiratory support with supplemental oxygen, continuous positive airway pressure or ventilation at the first 24 hours of life), or hypoglycemia. The secondary neonatal outcomes included gestational age at delivery, small for gestational age, 5-minute Apgar score of <7, lowest glucose level, need for intravenous glucose, respiratory distress syndrome, need for mechanical ventilation or continuous positive airway pressure, neonatal jaundice requiring therapy, brachial plexus injury, and hospital length of stay. The secondary maternal outcomes included hypoglycemic events, hospital admission for glucose control, hypertensive disorder of pregnancy, maternal weight gain, cesarean delivery, and postpartum complications. We used the Bayesian statistics to estimate a sample size of 108 to have >75% probability of any reduction in the primary outcome, assuming 80% power and a hypothesized effect of 33% reduction with insulin detemir. All analyses were intent to treat under a Bayesian framework with neutral priors (a priori assumed a 50:50 likelihood of either intervention being better; National Clinical Trial identifier 03620890). RESULTS: There were 108 women randomized in this trial (57 in insulin detemir and 51 in neutral protamine Hagedorn), and 103 women were available for analysis of the primary outcome (n=5 for pregnancy loss before 24 weeks' gestation). Bayesian analysis indicated an 87% posterior probability of reduced primary outcome with insulin detemir compared with neutral protamine Hagedorn (posterior adjusted relative risk, 0.88; 95% credible interval, 0.61-1.12). Bayesian analyses for secondary outcomes showed consistent findings of lower adverse maternal outcomes with the use of insulin detemir vs neutral protamine Hagedorn: for example, maternal hypoglycemic events (97% probability of benefit; posterior adjusted relative risk, 0.59; 95% credible interval, 0.29-1.08) and hypertensive disorders (88% probability of benefit; posterior adjusted relative risk, 0.81; 95% credible interval, 0.54-1.16). CONCLUSION: In our comparative effectiveness trial involving individuals with type 2 or overt type 2 diabetes mellitus, use of insulin detemir resulted in lower rates of adverse neonatal and maternal outcomes compared with neutral protamine Hagedorn.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

(Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus.

BACKGROUND: Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer insulin analogues may result in fewer macrovascular and microvascular events. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues (insulin glargine U100 and U300, insulin detemir and insulin degludec) with NPH (neutral protamine Hagedorn) insulin (human isophane insulin) in adults with type 2 diabetes mellitus. SEARCH METHODS: For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting insulin analogues to NPH in adults with type 2 diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. MAIN RESULTS: We identified 24 RCTs. Of these, 16 trials compared insulin glargine to NPH insulin and eight trials compared insulin detemir to NPH insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to insulin glargine and 1321 people to insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing insulin glargine to NPH insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing insulin detemir to NPH insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Changes in HbA1c were comparable for long-acting insulin analogues and NPH insulin. Insulin glargine compared to NPH insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with insulin detemir compared to NPH insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between insulin-analogues and NPH insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting insulin glargine U300 or insulin degludec with NPH insulin. AUTHORS' CONCLUSIONS: While the effects on HbA1c were comparable, treatment with insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Treatment with insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.

Newly-onset type 1 diabetes mellitus precipitated by COVID-19 in an 8-month-old infant.

Type 1 diabetes mellitus (T1DM) is rare in infants and toddlers and is usually associated with a relatively high mortality when complicated with diabetic ketoacidosis (DKA). In infants, the classical symptoms of DKA are atypical and therefore many infants with DKA are mistreated for infections. We report a case of DKA precipitated by COVID-19 in an 8-month-old infant with newly diagnosed diabetes mellitus. This case is reported in view of its rarity and originality. The relation between T1DM and COVID19 infection is discussed.

Comparison of Hypoglycemia and Safety Outcomes With Long-Acting Insulins Versus Insulin NPH in Pregestational and Gestational Diabetes.

Background: Current guidelines from the American College of Obstetricians and Gynecologists recommend insulin as the standard therapy for treatment of pregestational and gestational diabetes (PGDM and GDM). However, the guidelines do not specify which type(s) of insulin to utilize. Additionally, there are limited published data regarding safety parameters of insulin in this population. Objective: To evaluate if insulin glargine or detemir (long-acting insulin) results in less hypoglycemia, hospitalizations, or delivery complications compared with intermediate-acting insulin neutral protamine Hagedorn (NPH) in PGDM and GDM. Methods: This single-center, retrospective, observational cohort study included pregnant women who were 18 years or older with PGDM or GDM and received insulin therapy during pregnancy at an outpatient obstetric clinic. The primary outcome was the frequency of hypoglycemia (BG < 60 mg/dL). Secondary outcomes included emergency department visits and hospitalizations, delivery complications, and the duration of time at glycemic targets during pregnancy. Results: A total of 63 patients were included for evaluation. There was no significant difference in the frequency of hypoglycemia between the long-acting and NPH groups (4.4 vs 6.2 events per patient, respectively; P = 0.361). Patients receiving long-acting insulin had significantly more encounters with diabetes education (10.6 vs 5.1 visits per patient, P = 0.002) and more consistently provided glucose readings at their appointments (8.3 vs 4.8, P = 0.043). There was no difference in hospitalizations or maternal and neonatal complications. Conclusion and Relevance: Long-acting insulins did not reduce the frequency of hypoglycemia compared with NPH. The results of this study confirm the need for additional investigations with larger populations.

Basal Insulin Analogs versus Neutral Protamine Hagedorn for Type 2 Diabetics.

OBJECTIVE: To determine whether basal insulin analogs reduce the rate of composite neonatal morbidity compared with neutral protamine Hagedorn (NPH) in women with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a retrospective cohort study of women with T2DM and singleton pregnancy at a single tertiary center. Primary outcome was a composite neonatal morbidity of any of the following: shoulder dystocia, large for gestational age, neonatal intensive care unit admission, neonatal hypoglycemia, or respiratory distress syndrome. Secondary outcomes were rates of maternal hypoglycemic events, hypertensive disorders, preterm birth, and primary cesarean delivery. Adjusted relative risk (aRR) and 95% confidence intervals (CI) were calculated. RESULTS: Of 233 women with T2DM that met the inclusion criteria, 114 (49%) were treated with basal insulin analogs and 119 (51%) with NPH. The rate of composite neonatal morbidity was similar between groups (73 vs. 60%; aRR: 1.18; 95% CI: 0.92-1.51). There were no differences in the rates of maternal adverse outcomes between the groups. Basal insulin analog was associated with a lower rate of primary cesarean delivery as compared with NPH (21 vs. 36%; aRR: 0.44; 95% CI: 0.25-0.78). CONCLUSION: Among pregnant women with T2DM managed with either basal or NPH insulin regimen, the rates of composite neonatal morbidity and maternal complications were similar.

A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.

AIMS: To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). METHODS: We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. RESULTS: The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. CONCLUSIONS: In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.

Cost analysis of insulin degludec in comparison with insulin detemir in treatment of children and adolescents with type 1 diabetes in the UK.

Objective: With healthcare systems under increasing financial pressure from costs associated with diabetes care, it is important to assess which treatments provide clinical benefits and represent best value. This study evaluated the annual costs of insulin degludec (degludec) versus insulin detemir (IDet) in children and adolescents with type 1 diabetes (T1D) in the UK. Research design and methods: Using data from a randomized, treat-to-target, non-inferiority trial-BEGIN YOUNG 1-annual costs with degludec versus IDet in children and adolescents aged 1-17 years with T1D were estimated, as costs of these insulins and hyperglycemia with ketosis events. Analyses by age group (1-5, 6-11 and 12-17 years) and scenario (no ketosis benefit, no dose benefit, hyperglycemia with ketones >0.6 and >3.0 mmol/L and the additional costs of twice-daily IDet in 64% of patients) were also performed. Results: The mean annual cost per patient was estimated as £235.16 for degludec vs £382.91 for IDet, resulting in an annual saving of £147.75 per patient. These substantial cost savings were driven by relative reductions in the frequency of hyperglycemia with ketosis and basal insulin dose with degludec versus IDet. Annual savings in favor of degludec were observed across each age group (£122.63, £140.59 and £172.50 for 1-5, 6-11 and 12-17 years age groups, respectively). Five scenario analyses further demonstrated the robustness of the results, which included no ketosis or dose benefits in favor of degludec. Conclusions: Degludec provides appreciable annual cost savings compared with IDet in children and adolescents with T1D in a UK setting. While a cost-effectiveness analysis could incorporate the health impact of treatment complications better than the present cost analysis, the strong generalizability of the data from this study suggests that degludec can help healthcare providers to maximize health outcomes despite increasingly stringent budgets.

Comparison between the effect of regular human insulin and NPH with novo-rapid and levemir insulin in glycemic control in gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is one of the prevalent adverse conditions among pregnant women which needs delicate monitoring and control. GDM is a state in which the pregnant women's blood glucose level exceeds the normal range. Our goal was to determine the best therapeutic method to control the blood glucose level among GDM patients by comparing of the efficacy between two Insulin consisting, Novo-rapid + Levemir Insulin and Regular + NPH Insulin. METHOD: In this double-blind, randomized clinical trial study, we enrolled 100 women with GDM as an inpatient. In group A, patients underwent treating with Regular + NPH Insulin, and in group B, patients underwent treating with Novo-rapid + Levemir Insulin. Patient's demographic and clinical information gathered by specified several times during the study and analysis performed by SPSS21. RESULTS: Despite significant changes in the two groups patient's blood glucose levels; we could not find any remarkable differences between the two groups. In the case of patient and health care system satisfaction and the length of the hospitalization group, B was better than group A. CONCLUSION: Altogether, The Novo-rapid and Levemir Insulin in comparing with the Regular and NPH Insulin were practically advantageous due to the simple using method and short hospitalization period of the patient. Thus, we prefer and suggest this beneficial method (using Novo-rapid and Levemir Insulin) to reach therapeutic goals.