Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications.

BACKGROUND: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. OBJECTIVE: We conducted a narrative review of low-cost OHMs. METHODS: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. RESULTS: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment. CONCLUSION: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

Bomba de infusão de insulina como adjuvante no tratamento de segunda linha de pacientes com diabetes mellitus tipo 1 / Insulin infusion pump as adjuvant in the second-line treatment of patients with type 1 diabetes mellitus

CONTEXTO: O tratamento do paciente acometido de 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. Tanto o sistema de infusão contínua de insulina como a terapia com múltiplas doses de insulina são meios utilizados para obter o controle glicêmico do paciente com diabetes tipo 1. TECNOLOGIA: Sistema de infusão contínua de insulina - SICI (ou bomba de infusão de insulina). PERGUNTA: O uso de bomba de infusão de insulina para o tratamento de segunda linha de pacientes com DM1 é eficaz, seguro e custo-efetivo, quando comparado à terapia com MDI? EVIDÊNCIAS CIENTÍFICAS: O demandante apresentou três estudos observacionais sobre o uso do SICI associado ao Accu-Chek® Combo comparado a terapia com MDI em pacientes com DM1. Os desfechos avaliados nestes estudos foram classificados com qualidade baixa, em geral apresentaram um pequeno número de participantes. Os resultados dos estudos incluídos não foram discutidos e apesar de utilizarem métodos para a avaliação da qualidade das evidencias, isso não foi ponderado nas conclusões. Portanto os resultados apresentados nestes estudos devem ser interpretados com cautela. Dessa forma, a Secretaria-Executiva da CONITEC realizou novas buscas na literatura, considerando todas as bombas de insulina disponíveis no mercado e não apenas a marca do demandante. Foram selecionados quatro estudos, dois deles apresentaram qualidade alta, um estudo de qualidade moderada e outro de baixa qualidade, conforme a ferramenta AMSTAR. Os desfechos avaliados foram os níveis de hemoglobina A glicosilada (HbA1c) e episódios de hipoglicemia. A redução dos níveis de HbA1c nos estudos selecionados variou de 0,18% a 0,55%. No entanto, este valor não é considerado clinicamente significante. Os eventos de hipoglicemia leve, grave e noturna não demonstraram diferenças significativas entre os grupos em uso da terapia SICI e MDI, em crianças e adultos com DM1. Não foram identificadas evidências suficientes em relação a eventos adversos, complicações tardias do diabetes e mortalidade. AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise econômica parcial, incluindo apenas uma descrição dos custos referentes às complicações relacionadas aos níveis de HbA1c. A população utilizada nesta análise incluiu apenas 80% dos pacientes que utilizavam o SICI e apresentavam controle glicêmico satisfatório, sem definição deste desfecho. No entanto, deve-se considerar que 20% dos pacientes em uso do SICI podem continuar sem atingir o controle glicêmico e estes não foram incluídos na análise econômica. O demandante considerou a média dos preços de todas as insulinas de ação rápida e de ação lenta, o adequado seria a utilização das insulinas regular e NPH, incluídas na Relação Nacional de Medicamentos Essenciais (RENAME). O demandante encontrou uma estimativa de redução anual de 26,00% no consumo de insulina, 92,13% no número de eventos hipoglicêmicos graves e 35,59% no número de complicações relacionadas a HbA1c. No entanto, devido às várias inconsistências identificadas, os resultados apresentados não refletem os custos e as consequências para saúde relacionados ao uso de SICI. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante realizou uma estimativa do impacto da incorporação do SICI através do sistema Accu-Chek® Combo para o tratamento de segunda linha de pacientes com DM1, para os próximos cinco anos. Foram identificadas algumas limitações nesta análise: o número de pacientes foi estimado a partir de uma projeção do demandante; não foi relatada a taxa de difusão da tecnologia após a incorporação; não foi apresentado uma descrição das estimativas dos custos do tratamento; o manual de uso do Accu-Chek® Combo recomenda que o paciente faça um seguro do equipamento, no entanto estes custos não foram considerados na análise. Considerando estas limitações, não se pode afirmar que o cálculo do impacto orçamentário seja uma representação fidedigna das consequências financeiras da incorporação desta tecnologia no SUS. CONSIDERAÇÕES: As evidências disponíveis não suportam a superioridade do SICI comparado a terapia com MDI. Os estudos selecionados neste relatório indicam uma discreta redução nos níveis de HbA1c, favorecendo o SICI comparado à terapia de MDI. No entanto, esta redução não é considerada clinicamente significante. Não há evidências suficientes em relação aos eventos adversos, eventos de hipoglicemia, complicações tardias do diabetes, mortalidade e custo-efetividade. De fato, ainda existem importantes lacunas no conhecimento em relação a capacidade relativa dessas tecnologias para alcançar um melhor controle glicêmico e reduzir o risco de hipoglicemia. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A CONITEC em sua 63ª reunião ordinária, no dia 31 de janeiro de 2018, recomendou a não incorporação no SUS do sistema de infusão contínua de insulina para o tratamento de pacientes com diabetes tipo 1 que falharam à terapia com múltiplas doses de insulina devido à ausência de evidências que comprovem os benefícios clínicos da terapia e as fragilidades dos estudos econômicos apresentados. CONSULTA PÚBLICA: Por meio da Consulta Pública nº 08/2018 entre os dias 28/02/2018 e 19/03/2018 foram recebidas 5.812 contribuições, sendo 696 pelo formulário para contribuições técnico-científicas e 5.116 pelo formulário para contribuições sobre experiência ou opinião. Ao todo foram anexados 429 documentos, que foram analisados quanto aos critérios de elegibilidade, destes 10 estudos foram incluídos. Após apreciação das contribuições encaminhadas pela Consulta Pública, o plenário discutiu as incertezas quanto à eficácia e efeito adverso em longo prazo; o risco de dano não avaliado nestes estudos; o não entendimento do funcionamento do equipamento e principalmente a grande incerteza nos relatos de melhora da qualidade de vida, pois apenas 89 participantes declaram ter alguma experiência com o equipamento. Portanto, apesar de existirem pontos casuais favorecendo o uso do SICI, o grau de incerteza ainda é muito alto. O plenário entendeu que as contribuições não agregaram evidências científicas suficientes para alterar a recomendação inicial. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes em sua 68ª reunião ordinária, no dia 04 de julho de 2018, deliberaram por maioria recomendar a não incorporação do sistema de infusão contínua de insulina como adjuvante no tratamento de pacientes com Diabetes Mellitus tipo 1, que falharam à terapia com múltiplas doses de insulina. Foi assinado o Registro de Deliberação nº 357/2018. A recomendação será encaminhada para decisão do Secretário da SCTIE. DECISÃO: Não incorporar o sistema de infusão contínua de insulina para tratamento de segunda linha de pacientes com diabetes mellitus tipo 1, no âmbito do Sistema Único de Saúde - SUS, dada pela Portaria nº 38 de 11 de setembro de 2018, publicada no DOU de 12/09/2018.

Systematic Review of the Cost Effectiveness of Insulin Analogues in Type 1 and Type 2 Diabetes Mellitus.

BACKGROUND: Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required. OBJECTIVE: Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHODS: We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. RESULTS: Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses. CONCLUSION: Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin (HbA1c).

Eficacia y seguridad de liraglutida en pacientes con diabetes mellitus tipo 2 y sobrepeso, sin control metabolico adecuado (según HBA1C) a pesar de tratamiento bolo-basal con dosis altas de insulina / Efficacy and safety of liraglutide in patients with type 2 diabetes mellitus and overweight, without adequate metabolic control (according to HBA1C) despite bolus-basal treatment with high doses of insulin

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de Liraglutida en pacientes con diabetes melitus tipo 2 y sobrepeso, sin control metabólico adecuado (según HbA1c) a pesar de tratamiento bolo-basal con dosis altas de Insulina. Aspectos Generales: La diabetes melittus tipo 2 (conocida previamente como diabetes no insulino-dependiente o diabetes de inicio en el adulto) aparece por el uso inefectivo de la insulina por el organismo. Este tipo de diabetes incluyer a la mayoria de casos de diabetes en el mundo, y por contar con sintomas poco marcados o ausentes, puede no ser diagnosticada por varios años hasta la aparición de sus complicaciones. Tecnología Sanitaria de Interés: Los agonistas de receptores GLP-1 (Péptido similiar a1 glucagón tipo 1, por sus siglas en inglés) son un tipo de medicamentos antidiabéticos inyectables que pueden mejorar el control glicémico e inducir la disminución de peso. Estos medicamentos funcionan promoviendo la secreción de insulina dependiente de glucosa e inhibiendo la liberación promoviendo la secreción de insulina dependiente de glucosa e inhibiendo la liberación de glucagón. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de liraglutida en pacientes con diabetes mellitus tipo 2 y sobrepeso, sin control metabólico adecuado (según HbA1c) a pesar de tratamiento bolo-basal con dosis altas de insulina. Se dio preferencia a estudios de tipo meta-análisis, revisiones sistemáticas y ensayos clínicos aleatorizados; así como a guías de práctica clínica de grupos o instituciones relevantes al tema analizado. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda y revisión de la evidencia científica actual para la evaluación de la eficacia y seguridad de Liraglutida en pacientes con diabetes mellitus tipo 2 y sobrepeso, sin control metabólico adecuado a pesar de tratamiento bolo-basal con dosis altas de Insulina. Se presenta la información encontrada de acuerdo al tipo de evidencia revisada. CONCLUSIONES: La población de interés de la presente evaluación de tecnología sanitaria comprende los pacientes con diabetes mellitus tipo 2 y sobrepeso, sin control metabólico adecuado (según HbA1c) a pesar de tratamiento bolo-basal con dosis altas de Insulina. LOs ensayos clínicos revisados presentan un cambio significativo en los valores de HbA1c en pacientes que recibieron la intervención evaluada en comparación a los valores basales y al uso de insulina sola. Asimismo, se observa un resultado similar para el peso y dosis total de insulina diaria de los participantes. La frecuencia de efectos adversos severos asociados al uso de Liraglutida en combinación con Insulina bolo-basal es baja y el medicamento es bien tolerado. Las características de los GLP-1-RA los hacen útiles en casos en los que los pacientes reciben dosis altas de insulina y sus consecuentes efectos adversos. Se requiere la ejecución de estudios de costo-efectividad de uso de Liraglutida en combinación con insulina bolo-basal comparando dicho tratamiento con la Insulina bolo-basal sola para evaluar el impacto real de ambas terapias sobre los pacientes de interés. El Instituto de Evaluación de Tecnologías Sanitarias-IETSI, aprueba el uso de Liraglutida en apcientes con diabetes mellitus tipo 2 y sobrepeso, sin control metabólico adecuado a pesar de tratamiento bolo-basal con dosis altas de Insulina. El período de vigencia de este dictamen es de dos años y la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que se beneficien con dicho tratamiento y a nueva evidencia que pueda surgir en el tiempo.

Cost Effectiveness of IDegLira vs. Alternative Basal Insulin Intensification Therapies in Patients with Type 2 Diabetes Mellitus Uncontrolled on Basal Insulin in a UK Setting.

OBJECTIVES: Once-daily insulin degludec/liraglutide (IDegLira) is the first basal insulin and glucagon like peptide-1 receptor agonist combined in one delivery device. Our aim was to investigate the cost effectiveness of IDegLira vs. basal insulin intensification therapies for patients with type 2 diabetes mellitus uncontrolled on basal insulin (glycosylated haemoglobin; HbA1c >7.5 %; 58 mmol/mol) in a UK setting. RESEARCH DESIGN AND METHODS: Baseline cohort and clinical parameters were sourced from a pooled analysis comparing IDegLira with basal insulin plus liraglutide and basal-bolus therapy, and from the DUAL™ V trial comparing IDegLira with up-titrated insulin glargine (IGlar; Lantus(®)). The CORE Diabetes Model simulated lifetime costs and outcomes with IDegLira vs. these comparators from a UK healthcare payers' perspective. All costs were expressed in 2015 GBP. Sensitivity analyses were performed to assess the impact of key parameters in the model. RESULTS: Treatment with IDegLira resulted in mean increases in quality-adjusted life-years (QALYs) of 0.12, 0.41 and 0.24 vs. basal insulin plus liraglutide, basal-bolus therapy and up-titrated IGlar, respectively. IDegLira was associated with lower costs of £971 and £1698 vs. basal insulin plus liraglutide and basal-bolus therapy, respectively, and increased costs of £1441 vs. up-titrated IGlar. IDegLira was dominant, i.e., both more effective and less costly vs. basal insulin plus liraglutide and basal-bolus therapy, and highly cost effective vs. up-titrated IGlar with an incremental cost-effectiveness ratio of £6090/QALY gained. CONCLUSIONS: Once-daily IDegLira may be considered a cost-effective treatment option for prescribers, to improve glycaemic control for type 2 diabetes patients uncontrolled on basal insulin without an increased risk of hypoglycaemia or weight gain, and without adding to their injection burden.

Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics.

The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients' health-related quality of life; reviews relevant pharmacoeconomic data; and discusses recent advances in pump technology, including the development of closed-loop 'artificial pancreas' systems. © 2015 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.

Smartphone apps for calculating insulin dose: a systematic assessment.

BACKGROUND: Medical apps are widely available, increasingly used by patients and clinicians, and are being actively promoted for use in routine care. However, there is little systematic evidence exploring possible risks associated with apps intended for patient use. Because self-medication errors are a recognized source of avoidable harm, apps that affect medication use, such as dose calculators, deserve particular scrutiny. We explored the accuracy and clinical suitability of apps for calculating medication doses, focusing on insulin calculators for patients with diabetes as a representative use for a prevalent long-term condition. METHODS: We performed a systematic assessment of all English-language rapid/short-acting insulin dose calculators available for iOS and Android. RESULTS: Searches identified 46 calculators that performed simple mathematical operations using planned carbohydrate intake and measured blood glucose. While 59% (n = 27/46) of apps included a clinical disclaimer, only 30% (n = 14/46) documented the calculation formula. 91% (n = 42/46) lacked numeric input validation, 59% (n = 27/46) allowed calculation when one or more values were missing, 48% (n = 22/46) used ambiguous terminology, 9% (n = 4/46) did not use adequate numeric precision and 4% (n = 2/46) did not store parameters faithfully. 67% (n = 31/46) of apps carried a risk of inappropriate output dose recommendation that either violated basic clinical assumptions (48%, n = 22/46) or did not match a stated formula (14%, n = 3/21) or correctly update in response to changing user inputs (37%, n = 17/46). Only one app, for iOS, was issue-free according to our criteria. No significant differences were observed in issue prevalence by payment model or platform. CONCLUSIONS: The majority of insulin dose calculator apps provide no protection against, and may actively contribute to, incorrect or inappropriate dose recommendations that put current users at risk of both catastrophic overdose and more subtle harms resulting from suboptimal glucose control. Healthcare professionals should exercise substantial caution in recommending unregulated dose calculators to patients and address app safety as part of self-management education. The prevalence of errors attributable to incorrect interpretation of medical principles underlines the importance of clinical input during app design. Systemic issues affecting the safety and suitability of higher-risk apps may require coordinated surveillance and action at national and international levels involving regulators, health agencies and app stores.

The effect of insulin intensification in children and young persons with Type 1 diabetes differs in relation to ethnic group; a prospective observational study.

AIMS: We prospectively evaluated the effect of insulin intensification on glycaemic control and lipid levels in children and young persons with Type 1 diabetes in relation to ethnicity. METHODS: In the first 2 years of a 3-year observation period, as part of routine clinical care, 231 children and young persons (40% white, 28% South Asian, 32% black) from a single clinic were offered intensive insulin therapy. After 2 years, 222 were on intensive therapy and their data were compared between ethnic groups at the end of year 3. RESULTS: We observed ethnic differences in HbA(1c) levels during the study [study beginning and end: white children and young persons 77 and 70 mmol/mol (9.2 and 8.6%) vs. South Asian 72 and 68 mmol/mol (8.7 and 8.4%) vs. black 83 and 79 mmol/mol (9.7 and 9.4%), P-value for ANCOVA = 0.007]. By study end, South Asians had the lowest HDL cholesterol (2.0 vs. 1.4 vs. 1.6 mmol/l, P-value = 0.03) and highest triglyceride levels (0.9 vs. 1.8 vs. 1.0 mmol/l, P-value = 0.001). In linear mixed modelling, after adjustment for socio-economic deprivation and other covariates: (1) black ethnicity was associated with poorer glycaemic control (P < 0.001) and (2) South Asian ethnicity was associated with higher triglyceride levels (P < 0.001), independent of HbA(1c). CONCLUSIONS: The effect of insulin intensification on glycaemic control and lipid profile in children and young persons with Type 1 diabetes differs in relation to ethnic group.

Deprivation and ethnicity impact on diabetes control and use of treatment regimen.

AIMS: Deprivation and/or ethnicity impact on care delivery. We have assessed how these factors influence diabetes care in a paediatric clinic. METHODS: We related access to care [type of insulin treatment regimen-twice daily, multiple daily injections and insulin pump therapy (continuous subcutaneous insulin infusion)], measures of care process (HbA(1c)) and an approximate measure of satisfaction with the service (clinic attendance rate) in 325 (170 male) children and young people with Type 1 diabetes (mean age 10.6 years, mean duration of diabetes of 4.5 years), with indices of deprivation and ethnicity. RESULTS: Of the 325 children and young people, 2.7% received twice-daily insulin, 48.4% multiple daily injections and 48.9% continuous subcutaneous insulin infusion. Median clinic HbA(1c) was 62 mmol/mol (7.8%) and those receiving the insulin pump therapy had the lowest HbA(1c). Four ethnic groups were represented; White British 81.6%, Asian non-Indian 6.5%, African 8.1% and Asian Indian 3.8%. Mean deprivation score was 21.06. White British and Asian Indian groups were more likely to receive insulin pump therapy (χ(2) = 50.3; P < 0.001). Attendance rates were 94.1% and did not differ across ethnic groups. Deprivation was related to ethnicity and HbA(1c) (R(2) = 0.02; P = 0.02). There was no relationship between clinic attendance and deprivation. Insulin regimen and ethnicity were associated with HbA(1c) (R(2) = 0.096; P < 0.001). Similar findings were obtained when analysis was confined to the White British population. CONCLUSIONS: These data suggest that deprivation and ethnicity influence diabetes control and how intensive insulin therapy is utilized. A better consideration of the needs of different ethnic groups is required to ensure equitable care delivery in paediatric diabetes.