The cost-effectiveness of insulin analogs and regular insulin for diabetes control: a case study in Iran.

PURPOSE: For years, traditional techniques have been used for diabetes treatment. There are two major types of insulin: insulin analogs and regular insulin. Insulin analogs are similar to regular insulin and lead to changes in pharmacokinetic and pharmacodynamic properties. The purpose of the present research was to determine the cost-effectiveness of insulin analogs versus regular insulin for diabetes control in Yazd Diabetes Center in 2017. DESIGN/METHODOLOGY/APPROACH: In this descriptive-analytical research, the cost-effectiveness index was used to compare insulin analogs and regular insulin (pen/vial) for treatment of diabetes. Data were analyzed in the TreeAge Software and a decision tree was constructed. A 10% discount rate was used for ICER sensitivity analysis. Cost-effectiveness was examined from a provider's perspective. FINDINGS: QALY was calculated to be 0.2 for diabetic patients using insulin analogs and 0.05 for those using regular insulin. The average cost was $3.228 for analog users and $1.826 for regular insulin users. An ICER of $0.093506/QALY was obtained. The present findings suggest that insulin analogs are more cost-effective than regular insulin. ORIGINALITY/VALUE: This study was conducted using a cost-effectiveness analysis to evaluate insulin analogs versus regular insulin in controlling diabetes. The results of study are helpful to the government to allocate more resources to apply the cost-effective method of the treatment and to protect patients with diabetes from the high cost of treatment.

Are newer insulin analogues better for people with Type 1 diabetes?

Achieving optimal blood glucose control in Type 1 diabetes is a delicate balance between ensuring tight glycaemic control and achieving this without the expense of hypoglycaemia and weight gain, two major factors impacting quality of life. This is a real challenge for people with Type 1 diabetes and underpins many of the struggles they face in self-managing on a day-to-day basis. The main goals of insulin delivery are to try to simulate the physiology of ß-cell insulin secretion as closely as possible and to overcome the challenges of peripheral insulin administration by achieving rapidity of onset with mealtime insulins and stability of the glucose-lowering effects of long-acting insulins. Since the early days of human insulin use, there have been many developments in insulin formulations that aim to achieve these goals as much as possible, thus contributing to better glycaemic control whilst minimizing hypoglycaemia. In the present review we discuss the currently available insulin analogues and the challenges of achieving glucose control using current analogues in those on multiple daily injections, and appraise the evidence base for newer-generation insulin analogues, such as insulin degludec, glargine U300, faster-acting insulin aspart and BioChaperone lispro. We also highlight new insulins in development and unmet needs in people with Type 1 diabetes.

Lixisenatide versus insulin glulisine on top of insulin glargine in patients with type 2 diabetes mellitus: a cost-per-responder analysis in China.

Objective: To compare the cost per responder of lixisenatide versus insulin glulisine once daily (basal-plus) and three times daily (basal-bolus) on top of basal insulin for the treatment of patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin in China.Methods: The cost per responder was estimated based on clinical data obtained from the GetGoal Duo-2 clinical trial and direct medical costs from the perspective of the Chinese healthcare system over a 52-week time horizon. The response was assessed at week 26 in the clinical trial, which was extrapolated to 52 weeks to estimate the annual cost per responder. Responders were primarily defined using a composite endpoint that based on an HbA1c ≤ 7.0% threshold AND no weight gain With or Without no documented symptomatic hypoglycemia. Composite endpoints with varied HbA1c thresholds were defined in secondary analyses.Results: For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain, the annual cost per responder results were 96,722 CNY, 122,552 CNY and 135,926 CNY (14,616, 18,520 and 20,541 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain AND no documented symptomatic hypoglycemia, the annual cost per responder results were 136,290 CNY, 231,487 CNY and 222,424 CNY (20,596, 34,982 and 33,612 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. The secondary analyses proved similar results.Conclusion: Lixisenatide combined with basal insulin is associated with a lower cost per responder compared with basal-plus and basal-bolus for T2DM patients inadequately controlled by basal insulin in China.

Tratamiento farmacológico en diabetes mellitus tipo II / Pharmacological treatment in type II diabetes mellitus

INTRODUÇÃO: La Diabetes Mellitus es un desorden metabólico crónico caracterizado por niveles de glucosa en la sangre persistentemente elevados, debido a la alteración en la secreción y/o acción de la insulina. La Diabetes Mellitus tipo 2 (DMT2) se caracteriza por resistencia insulínica, que habitualmente se acompaña de un déficit relativo de insulina. La DMT2 es una enfermedad muy prevalente y está entre las primeras causas de morbi-mortalidad a nivel mundial. Para su tratamiento existen múltiples fármacos, qué junto con medidas higiénico-dietéticas y actividad física, pueden reducir significativamente la morbi-mortalidad prematura y mejorar la calidad de vida de estos pacientes. Siempre que no esté contraindicada, la metformina es el agente farmacológico inicial de elección mientras que otros hipoglucemiantes alternativos son utilizados en monoterapia cuando existe intolerancia a la metformina o combinados cuando no se logran alcanzar los objetivos de tratamiento. Entre los hipoglucemiantes alternativos se encuentran las sulfonilureas, las tiazolidinedionas, los inhibidores de la enzima dipeptidil-peptidasa 4, los inhibidores del cotransportador-2 de sodio-glucosa y los agonistas del receptor del péptido-1 símil glucagón, insulinas y análogos de insulina. OBJETIVO: El objetivo del presente informe es evaluar la eficacia, seguridad y costos de todos los tratamientos para DMT2. BÚSQUEDA BIBLIOGRÁFICA Se buscó en Pubmed, Lilacs, BRISA ­redetsa-, CRD (del inglés Centre for Reviews and Dissemination- University of York), Cochran

Are newer insulins always the better option?

PURPOSE OF REVIEW: Since its discovery almost a century ago, there have been numerous advancements in the formulations of insulin. The newer insulin analogs have structural modifications with the goal of altering pharmacokinetics to achieve either quick onset and offset of action (mealtime bolus analogs), or a prolonged steady action (basal analogs). These analogs offer many advantages over older human insulins but are several-fold more expensive. The aim of this review is to evaluate reasons for the exorbitant price of the newer insulins, to examine the evidence regarding their clinical advantages and to make value-based prescribing recommendations. RECENT FINDINGS: The higher cost of newer insulins cannot be justified based on drug development or manufacturing costs. Compared with older insulins, newer analogs do not offer significant advantage in achieving hemoglobin A1c targets, but they reduce risk of hypoglycemia. The reductions in hypoglycemia are relatively modest and most apparent in those with type 1 diabetes, possibly because these individuals are more prone to hypoglycemia. SUMMARY: When cost considerations are important, the older insulins (regular and NPH insulin) can be used safely and effectively for most individuals with type 2 diabetes who have a low risk of hypoglycemia.

Rapid Characterization of Insulin Modifications and Sequence Variations by Proteinase K Digestion and UHPLC-ESI-MS.

Discovery of novel insulin analogs as therapeutics has remained an active area of research. Compared with native human insulin, insulin analog molecules normally incorporate either covalent modifications or amino acid sequence variations. From the drug discovery and development perspective, methods for efficient and detailed characterization of these primary structural changes are very important. In this report, we demonstrate that proteinase K digestion coupled with UPLC-ESI-MS analysis provides a simple and rapid approach to characterize the modifications and sequence variations of insulin molecules. A commercially available proteinase K digestion kit was used to process recombinant human insulin (RHI), insulin glargine, and fluorescein isothiocynate-labeled recombinant human insulin (FITC-RHI) samples. The LC-MS data clearly showed that RHI and insulin glargine samples can be differentiated, and the FITC modifications in all three amine sites of the RHI molecule are well characterized. The end-to-end experiment and data interpretation was achieved within 60 min. This approach is fast and simple, and can be easily implemented in early drug discovery laboratories to facilitate research on more advanced insulin therapeutics. Graphical Abstract ᅟ.

Eficacia y seguridad de la insulina glargina 300 unidades ml versus insulina glargina 100 unidades ml en pacientes adultos con diabetes mellitus tipo 2 mal controlada en tratamiento basal-bolo con análogos de la insulina, que persisten con episodios de hipoglicemia severa a predominio nocturno / Efficacy and safety of insulin glargine 300 ml units versus insulin glargine 100 ml units in adult patients with type 2 diabetes mellitus poorly controlled in basal-bolus treatment with insulin analogues, which persist with episodes of severe hypoglycemia at nighttime prevalence

INTRODUCCIÓN: La Diabetes Mellitus tipo 2 (DM2) es una condición metabólica crónica caracterizada por la resistencia a la insulina y producción de insulina pancreática insuficiente, lo que resulta en altos niveles de glucosa en sangre (hiperglicemia). Está asociada con la obesidad, la poca actividad física y la mala alimentación; su morbimortalidad está determinada por las complicaciones microvasculares y macrovasculares. La DM2 representa entre el 90 y 95 % de todos los casos de Diabetes Mellitus (DM). En el Perú, la DM es la quinta causa de muerte entre todas las enfermedades. Además, en base a información actualizada al 2016, se estima que aproximadamente 932,531 peruanos se encuentran viviendo con DM, resultando en una prevalencia de 2,891.79 casos por cada 100,000 personas. En el contexto de EsSalud, se estima que aproximadamente 700,000 asegurados padecen de esta enfermedad, esto es, el 7 % de la población afiliada. TECNOLOGÍAS SANITARIA DE INTERÉS: Insulina Glargina: La actividad principal de la insulina, incluida la insulina glargina, es la regulación del metabolismo de la glucosa. La insulina y sus análogos reducen los niveles de glucosa en sangre, estimulan la captación de glucosa periférica, principalmente a través del músculo esquelético y la grasa, e inhiben la producción de la glucosa hepática. También inhiben la lipólisis y proteólisis, y aumentan la síntesis de proteínas (European Medicines Agency, 2018). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de Gla-300 versus Gla-100 en pacientes adultos con DM2 mal controlada en tratamiento basal-bolo con análogos de la insulina (Gla-100 y Lispro), que persisten con episodios de hipoglicemia severa a predominio nocturno. Se utilizó las bases de datos The Cochrane Library, Medline y TRIPDATABASE, priorizándose evidencia proveniente de revisiones sistemáticas o meta-análisis de ensayos clínicos. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica, incluyendo Scottish Medicines Consortium (SMC), The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH) y páginas web de organizaciones especializadas en diabetes. Se hizo una búsqueda adicional en la página web de clinicaltrials.gov , para poder identificar ensayos clínicos en curso o que no hayan sido publicados. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (tipo ensayos clínicos aleatorizados). RESULTADOS: Una de las complicaciones más frecuentemente asociada al tratamiento farmacológico de la DM2 es la hipoglicemia, que se define como una concentración de glucosa en sangre <70 mg/dL. Esta complicación puede producir síntomas autonómicos como sudoración, temblor y taquicardia, y síntomas neurológicos como pérdida del conocimiento, convulsiones y coma. La hipoglicemia ocurre con mayor frecuencia en pacientes con tratamiento intensivo con insulina, estimándose tasas de episodios/año en torno al 30 %, con un 2 % de episodios severos (estos últimos que requieren de asistencia de otra persona para ser tratada). En EsSalud, los pacientes con DM2 insulino-requiriente son tratados con las siguientes opciones: insulina regular, insulina NPH humana, insulina lispro e insulina glargina; todas en concentración de 100 unidades/ml. A pesar de esta variedad, los médicos especialistas solicitan la aprobación de uso de insulina glargina de 300 unidades/ml (Gla-300), no incluido en el Petitorio Farmacológico de EsSalud, considerando que este podría ofrecer un beneficio adicional respecto a insulina glargina de 100 unidades/ml (Gla-100) en pacientes adultos con DM2 insulino-requiriente, que persisten con episodios de hipoglicemia severa a predominio nocturno a pesar del uso de Gla-100. Tras nuestra búsqueda sistemática de literatura, se identificaron dos guías de práctica clínica (GPC) una elaborada por la Red Escocesa Intercolegiada sobre Directrices (SIGN, por sus siglas en inglés) y otra elaborada por la Diabetes Canada; una sinopsis de la evidencia publicado por el Instituto Nacional de Salud y Cuidados de Excelencia del Reino Unido (NICE, por sus siglas en inglés); y un ensayo clínico controlado aleatorizado (ECA) de fase III con un periodo de seguimiento de 6 meses (EDITION 1) y su extensión hasta los 12 meses. CONCLUSIONES: La única evidencia disponible a la actualidad que evalúa nuestra pregunta clínica en formato PICO proviene del estudio EDITION 1. Este estudio fue un ensayo clínico de no inferioridad y de etiqueta abierta que comparó la eficacia y seguridad de Gla-300 versus Gla-100 en pacientes con DM2 en tratamiento intensivo con insulina basal-bolo, con un periodo de seguimiento de 6 meses. El estudio EDITION 1 tuvo una serie de limitaciones metodológicas que afectaron la validez interna de sus resultados, incluyendo el diseño de etiqueta abierta del estudio (no ciego), la posible confusión por el ajuste de la dosis de insulina prandial, y el posible conflicto de interés. Este estudio no demostró que Gla-300 ofrezca un beneficio clínico en comparación con Gla-100 sobre la reducción del riesgo de hipoglicemia nocturna severa. Específicamente, no se reportaron diferencias estadísticamente significativas entre ambos grupos, esto pudo deberse a un tamaño de muestra insuficiente para detectar diferencias en este desenlace. Por otra parte, la reducción estadísticamente significativa de los eventos de hipoglicemia nocturna confirmada o severa con Gla-300, no se tradujo en un beneficio clínicamente importante. Otros desenlaces considerados de importancia para la presente evaluación, como el porcentaje de pacientes con HbA1c <7.0 %, la hipoglicemia severa en general y los EA, totales y serios, no mostraron diferencias significativas entre Gla-300 y Gla-100. En consecuencia, la evidencia científica disponible a la actualidad no permite sustentar un beneficio neto de Gla-300 respecto a Gla-100 en nuestra población de interés. Adicionalmente, se debe tener en cuenta que Gla-300 es un medicamento de alto costo, no solo en base a su costo unitario, sino también debido al gran número de pacientes con dicha condición (carga de la enfermedad) y la cronicidad de su uso. En ese sentido, la aprobación de uso de Gla-300 en EsSalud no es justificable al no haber demostrado un beneficio adicional respecto a las opciones terapéuticas disponibles en la institución, que a su vez son menos costosas. El IETSI no aprueba el uso de insulina glargina 300 unidades/ml en pacientes adultos con DM2 mal controlada en tratamiento basal-bolo con análogos de la insulina (Gla-100 y Lispro), que persisten con episodios de hipoglicemia severa a predominio nocturno.

Trends in the use and cost of human and analogue insulins in a Colombian population, 2011-2015.

OBJECTIVES: Diabetes mellitus is a common disease among the general population and imposes considerable costs on health care systems. Insulin is used to treat type 1 diabetes mellitus and as an adjuvant to oral agents in advanced stages of type 2 diabetes mellitus. The objective was to describe the trends in use and cost of human and analogue insulins for Colombian patients. STUDY DESIGN: Descriptive retrospective analysis of prescriptions of human and analogue insulins on a monthly basis for the period from July 1, 2011 to February 2, 2015. METHODS: Information was collected for the database population of two insurance companies. Frequencies and proportions were calculated; estimated economic impact was expressed as net cost and cost per thousand inhabitants per day. RESULTS: During the observation period, there was continuous growth in use of insulin, mainly in analogue forms (34.0% growth). At the start of the study, 10.4% of subjects were using an analogue insulin; this figure was 62.6% at the end of the study. In 2012, the average cost per 1000 inhabitants/day was US$1.7 for analogue and US$0.8 for human insulins. At the end of the observation period these costs had risen to US$9.2 for analogue (441.1% increase) and fallen to US$0.5 for human insulin (58.3% decrease). CONCLUSIONS: There has been an increase in the unit cost and frequency of use of insulin analogues for anti-diabetic therapy in Colombian patients. Moreover, there is controversy over whether insulin analogues are a more cost-effective treatment than human insulins for the general diabetic population.

Consensus on Bridges for Barriers to Insulin Therapy.

INTRODUCTION: Insulin is an effective, safe and well-tolerated drug for glycaemic control. However, there are significant barriers to its use. OBJECTIVE: This consensus statement aims to define these barriers and suggest bridges to overcome them. METHODS: The consensus statements are based upon deliberations of a meeting held at New Delhi, India on 20 August 2016. The expert group committee reviewed various barriers to insulin use and categorized them into various categories: patient/community-related, physician-related and drug-related. The committee further proposed recommendations, based on published literature and their clinical experience, to address each of these barriers. RESULTS: Barriers (and bridges) can be classified as patient/community, physician/provider, and drug/device. Patient and physician barriers can further be categorized as those related to perceived inadequacy, perceived high cost, and perceived lack of benefit. Drug and device barriers can similarly be classified as those linked with perceived inadequacy, perceived high cost, and perceived lack of tolerability. Such a classification allows diabetes care providers to build appropriate bridges, which in turn facilitate timely insulin usage. Patient related barriers can be bridged by education, support and counselling. Use of modern insulin regimes and social marketing can address barriers related to perceived cost and lack of benefit. Physician related barriers can be resolved by training on various aspects of diabetes care. This will also help to break drug and device barriers, by ensuring appropriate choice of regimes, preparations and delivery devices. CONCLUSIONS: The consensus statements provide an easily understandable taxonomic structure of barriers to insulin use. By using a reader-friendly rubric, and by focusing on bridges (rather than barriers alone), it promotes a proactive and positive approach to diabetes management. The consensus statement should serve as a useful pedagogic and clinical tool for diabetes care professionals, and facilitate good diabetes care across the world.

Insulin-From its Discovery to the Industrial Synthesis of Modern Insulin Analogues.

After the discovery of insulin as a drug for diabetes, the pharmaceutical companies were faced with the challenge to meet the demand for insulin with the highest possible degree of purity in the required quantities from animal sources. The observation of an immune reaction of patients to insulin from animal pancreatic extracts made the availability of human insulin of highest priority. Only the enzyme-catalyzed semisynthesis at the C-terminus of the insulin B-chain led to a commercial process, but it depended on porcine insulin and was aggravated by supply concerns. The advent of rDNA technology allowed the commercial preparation of human insulin by biosynthesis in virtually unlimited quantities. An increased chemical diversity was only envisaged through chemical synthesis, which was simplified by advances in solid-phase peptide synthesis and chemical ligation. Single-chain insulin precursors are now being synthesized that should enable fast screening of insulin analogues for improved biophysical, biological, and thus promising new therapeutic properties, as well as for the industrial manufacture of insulin analogues not accessible by biosynthesis.

Evaluating drug cost per responder and number needed to treat associated with lixisenatide on top of glargine when compared to rapid-acting insulin intensification regimens on top of glargine, in patients with type 2 diabetes in the UK, Italy, and Spain.

OBJECTIVES: This study investigated the cost per responder and number needed to treat (NNT) in type 2 diabetes mellitus (T2DM) patients for lixisenatide compared to insulin intensification regimens using composite endpoints in the UK, Italy, and Spain. METHODS: Efficacy and safety outcomes were obtained from GetGoal Duo-2, a 26-week phase 3 trial comparing lixisenatide vs insulin glulisine (IG) once daily (QD) and three times daily (TID). Response at week 26 was extrapolated to 52 weeks, assuming a maintained treatment effect, based on long-term evidence in other T2DM populations. Responders were defined using composite end-points, based on an HbA1c threshold and/or no weight gain and/or no hypoglycemia. The HbA1c threshold was varied in sensitivity analyses. Annual treatment costs were estimated in euros (1 GBP = 1.26 EUR), including drug acquisition and resource use costs. Cost per responder was computed by dividing annual treatment costs per patient by the proportion of responders. RESULTS: Lixisenatide was associated with the lowest cost per responder for all composite end-points that included a weight-related component. For the main composite end-point of HbA1c ≤7.5% AND no weight gain AND no symptomatic hypoglycemia, cost per responder results were: UK: 6,867€, 8,746€, and 12,410€; Italy: 7,057€, 9,160€, and 12,844€; Spain: 8,370€, 11,365€, and 17,038€, for lixisenatide, IG QD, and TID, respectively. The NNT analysis showed that, for every 6.85 and 5.86 patients treated with lixisenatide, there was approximately one additional responder compared to IG QD and TID, respectively. LIMITATIONS: A limitation of the clinical inputs is the lack of 52-week trial data from GetGoal Duo-2, which led to the assumption of a maintained treatment effect from week 26 to 52. CONCLUSIONS: This analysis suggests lixisenatide is an efficient economic resource allocation in the UK, Italy, and Spain.

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.

Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included.

BIOSIMILARS AND NEW INSULIN VERSIONS.

OBJECTIVE: To provide clinicians with an overview of similar biologic products including biosimilars and new insulin versions available in the U.S. and of key issues associated with such products, including differences in manufacturing and regulatory approaches and their impact on clinical use. METHODS: We reviewed the relevant clinical and regulatory literature. RESULTS: Patent protections for many biologics including several insulin preparations have or will expire shortly. This opens the door for new insulin versions to enter the U.S. and global marketplace. The development, manufacturing, and approval process for similar biologic products is more complex than for generic versions of small molecules. Most similar biologic products in the U.S. will be submitted for approval under section 351(k), a newly created biosimilar regulatory pathway. However, some biologics, including new insulin versions, will be submitted via the existing 505(b)(2) regulatory pathway. These regulatory pathways have implications for how such products may be labeled, how they may be dispensed, and how patients may perceive them. The immunogenicity of biologics can affect safety and efficacy and can be altered through subtle changes in manufacturing. With the arrival of new insulin versions, health care providers will need to understand the implications of interchangeability, therapeutic equivalence, substitution, switching, and new delivery devices. CONCLUSION: An understanding of the above topics will be important as physicians, payers, and patients choose between similar versions of a reference listed biologic product.

Comparative efficacy and safety of insulin analogs in hospitalized adults.

PURPOSE: The comparative efficacy, safety, and cost-effectiveness of rapid and long-acting insulin analogs compared with regular or neutral protamine Hagedorn nonanalog insulins or with oral antidiabetic agents in hospitalized adults were evaluated. METHODS: A literature search was conducted to identify studies that compared the effects of rapid-acting, long-acting, or mixed insulin analogs with short- or intermediate-acting insulin or any other oral antidiabetic medication. RESULTS: Twenty-three primary studies were included in the review. Rapid-acting analogs and basal-bolus analog regimens were found to reduce the duration of hospital stay by approximately one day compared with regular insulin and basal-bolus nonanalog regimens. One large cohort study found an adjusted 48% relative risk reduction in mortality with rapid-acting analogs versus regular insulin in a heterogeneous hospitalized hyperglycemic population. A randomized controlled trial found a significant reduction in postoperative complications with basal-bolus analogs compared with basal-bolus nonanalog insulin. When compared with regular sliding-scale insulin (SSI), fixed-dose insulin glargine with or without insulin glulisine was found to reduce the blood glucose concentration in patients with type 2 diabetes and reduce postoperative complications in surgical patients with diabetes. The quality of evidence was primarily very low or low for most outcomes. CONCLUSION: A systematic literature review revealed a very low or low quality of evidence, suggesting that, compared with nonanalog regimens, rapid-acting insulin analogs reduce the duration of hospital stay and mortality rates and that basal- bolus analog regimens may reduce the duration of hospital stay and postoperative complications. There is also a low quality of evidence to suggest that a fixed-dose analog regimen of insulin glargine with or without insulin glulisine is more effective than regular SSI for reducing blood glucose concentrations and postoperative complications.