Custo-efetividade da empagliflozina em pacientes com diabetes mellitus do tipo 2 com alto risco cardiovascular na perspectiva da saúde suplementar / Cost-effectiveness of empagliflozin in patients with type 2 diabetes mellitus with high cardiovascular risk in the Brazilian private healthcare system perspective

Objetivo: Avaliar a custo-efetividade da empagliflozina adicionada ao cuidado usual para tratamento de diabetes mellitus tipo 2 (DM2) no cenário da saúde suplementar brasileira. Métodos: Foi utilizada simulação de eventos discretos, com dados de efetividade baseados no estudo EMPA-REG OUTCOME. Foram incluídos pacientes com DM2 e alto risco cardiovascular (histórico de cardiopatia isquêmica, acidente vascular cerebral ou doença vascular periférica). O horizonte temporal foi o tempo de vida; a taxa de desconto foi de 5% ao ano. Os dados de utilidade foram predominantemente de estudos brasileiros. Para estimar os custos de eventos/condições com diferença estatisticamente significativa no EMPA-REG OUTCOME (insuficiência cardíaca, diálise, morte cardiovascular), foi feita uma revisão sistemática, que identificou estudos com dados da saúde suplementar. O limiar de disposição a pagar utilizado foi 1 produto interno bruto (PIB) per capita (2017: R$ 31.587). Foram conduzidas análises de sensibilidade determinísticas e probabilísticas. Resultados: No caso-base, a empagliflozina gerou ganho de 0,66 ano de vida ajustado para qualidade (QALY) na comparação com o cuidado usual, com acréscimo de R$ 12.630 e relação de custo-efetividade incremental (RCEI) de R$ 18.895/QALY. Na análise determinística, nenhuma variação de parâmetro resultou em RCEI acima do limiar. A análise probabilística teve RCEI média de R$ 19.878/QALY (intervalo de credibilidade de 2,5% a 97,5%: R$ 5.237-R$ 36.451). Considerando 1 PIB per capita, 50% das simulações seriam custo-efetivas; para 2 PIB per capita, o percentual ultrapassaria 90%. Conclusão: Considerando o limiar de custo-efetividade adotado, de 1 PIB per capita, a empagliflozina se mostrou custo-efetiva em relação ao cuidado usual na perspectiva da saúde suplementar brasileira.

Objective: To evaluate the cost-effectiveness of empagliflozin added to usual care in type 2 diabetes mellitus (T2DM) in the private healthcare sector. Methods: We used a discrete events simulation model with effectiveness data based on the EMPA-REG OUTCOME trial. The population included patients with T2DM at high cardiovascular risk (history of ischemic heart disease, stroke, or peripheral vascular disease). A lifetime horizon and a 5% annual discount rate were used. The utility data used were predominantly from Brazilian studies. To estimate the cost of events/conditions with statistically significant difference in the EMPA-REG OUTCOME trial (heart failure, dialysis, cardiovascular death), a systematic review was performed to identify studies with data from the private healthcare system. A willingness-to-pay threshold of 1 GDP per capita (2017: R$ 31,587) was considered. Deterministic sensitivity analysis and a probabilistic sensitivity analysis were performed. Results: In the base case, empagliflozin generated incremental 0.66 QALY as compared to usual care, with an added cost of R$ 12,630 and incremental cost-effectiveness ratio (ICER) of R$ 18,895/QALY. None of the parameter variations evaluated by deterministic analysis generated ICERs above the cost-effectiveness threshold. Probabilistic sensitivity analysis revealed mean ICER of R$ 19,878/QALY (credibility interval 2.5% to 97.5%: R$ 5,237 to R$ 36,451). Considering 1 GDP per capita, 50% of the simulations would be cost-effective; considering 2 GDP per capita, over 90% would be cost-effective. Conclusion: Considering a threshold of 1 GDP per capita, the study shows that empagliflozin was cost-effective from the perspective of the Brazilian private healthcare sector.

Normoglucemiantes orales y riesgo cardiovascular / Oral glucose-lowering drugs and cardiovascular risk

Resumen Introducción: la enfermedad cardiovascular es la principal causa de muerte en el mundo, así como la primera causa de morbilidad y mortalidad en pacientes con diabetes mellitus; por tanto, es importante conocer los diferentes medicamentos que existen hoy para el manejo de la diabetes mellitus y sus efectos, tanto positivos como negativos a nivel cardiovascular. De ahí que las diferentes sociedades y asociaciones científicas del mundo hayan emitido la recomendación de que todos los medicamentos para el tratamiento de la diabetes mellitus tipo 2 deben ser evaluados y certificados como seguros a nivel cardiovascular. Metodología: se hizo una búsqueda ampliada de la literatura existente acerca de los antidiabéticos actuales y sus efectos cardiovasculares. Resultados: existen diferentes tipos de medicamentos que se han relacionado con disminución o aumento del riesgo cardiovascular. En la actualidad hay evidencia que relaciona la metformina (biguanida), la empagliflozina (inhibidor del cotransportador sodio- glucosa 2) y la liraglutide (análogo de péptido similar al glucagón) con menos muerte cardiovascular y eventos cardiovasculares en pacientes con enfermedad cardiovascular establecida. Conclusión: los pacientes con enfermedad cardiovascular conocida pueden tener un beneficio adicional seleccionando medicamentos hipoglucemiantes con un mejor perfil de seguridad cardiovascular.

Abstract Introduction: Cardiovascular disease is the main cause of death worldwide, as well as the first cause of morbidity and mortality in patients with diabetes mellitus. For these reasons it is important to know the different drugs currently available to manage diabetes mellitus and their positive and negative effects at cardiovascular level. Hence, different scientific societies and associations of the world have issued the recommendation that all drugs for the treatment of type 2 diabetes mellitus must be evaluated and certified as safe at cardiovascular level. Methodology: An extensive search was carried out on the existing literature on current antidiabetic drugs and their cardiovascular effects. Results: There are different types of drugs that are associated with a decrease or increase in cardiovascular risk. Currently, there is evidence that associated metformin (biguanide), empagliflozin (sodium-glucose cotransporter 2 inhibitor), and liraglutide (a glucagon-like peptide analogue), with less cardiovascular deaths and cardiovascular events in patients with established cardiovascular disease. Conclusion: Patients with known cardiovascular disease may have an additional benefit in selecting glucose-lowering drugs with a better cardiovascular safety profile.

Custo-utilidade da empagliflozina em pacientes diabéticos do tipo 2 com alto risco cardiovascular na perspectiva do Sistema Único de Saúde / Cost-utility of empagliflozin in type 2 diabetic patients with high cardiovascular risk in the Brazilian Public Healthcare System perspective

Objetivo: Realizar uma análise de custo-utilidade de empagliflozina em pacientes com diabetes mellitus tipo 2 (DM2) e alto risco cardiovascular. Métodos: O modelo empregado foi uma simulação de eventos discretos, com dados baseados na incidência de eventos cardiovasculares do ensaio clínico EMPA-REG OUTCOME. A população-alvo foi de sujeitos com DM2 e alto risco cardiovascular (histórico de cardiopatia isquêmica, acidente vascular cerebral ou doença vascular periférica). O horizonte temporal foi o de tempo de vida; a taxa de desconto, de 5% ao ano; e a perspectiva, a do Sistema Único de Saúde (SUS). Os dados de utilidade foram obtidos de estudos brasileiros e internacionais. Os custos refletiram valores desembolsados pelo SUS. Foram conduzidas análises de sensibilidade determinísticas nos principais parâmetros e probabilística para avaliar a robustez global dos resultados. Resultados: No caso-base, a empagliflozina gerou 0,66 ano de vida ajustados para qualidade (QALY) a mais, com custo de R$ 19.176 maior, gerando relação de custo-efetividade incremental (RCEI) de R$ 28.960/QALY. As análises de sensibilidade univariadas mostraram oscilações da RCEI entre R$ 23.644 e R$ 38.850/QALY, sendo este valor mais alto de RCEI resultante da variação do valor de utilidade de pacientes com diabetes. Na análise probabilística, os percentis 2,5% e 97,5% foram de R$ 22.336 a R$ 39.571/QALY. Conclusão: O estudo mostrou uma RCEI de R$ 28.960/QALY, estando abaixo do valor de uma vez o produto interno bruto (PIB) per capita (R$ 30.407 em 2016), sendo, portanto, uma tecnologia custo-efetiva, considerando esse limiar. Na análise probabilística, o intervalo de credibilidade mostrou que a RCEI pode oscilar entre 0,73 e 1,30 PIB per capita, sendo, portanto, uma estimativa robusta.

Objective: To perform a cost-utility analysis of empagliflozin in type 2 diabetes (T2D) patients with high cardiovascular risk. Methods: The model was a discrete events simulation, with data based on the incidence of cardiovascular events in the EMPA-REG OUTCOME clinical trial. The target population was composed by patients with T2D and high cardiovascular risk (history of ischemic heart disease, stroke or peripheral vascular disease). We used a lifetime horizon, 5% discount rate and the Brazilian Public Healthcare System (SUS) perspective. Utility data were based both on Brazilian and international data. Costs employed reflected reimbursement SUS values. We conducted deterministic sensitivity analysis in main model parameters and a probabilistic sensitivity analysis to globally evaluate robustness of the results. Results: In the base case, empagliflozin generated incremental 0.66 QALY and R$ 19,176, resulting in an incremental cost-effectiveness ratio (ICER) of R$ 28,960/QALY. Univariate sensitivity analysis showed variations in the ICER between R$ 23,644 and R$ 38,850/QALY, with the diabetes status utility the variable with most influence in the ICER. In the probabilistic sensitivity analysis, 2.5% and 97.5% percentiles were R$ 22,336 and R$ 39,571/QALY. Conclusion: The study showed an ICER of R$ 28,960/QALY, which is below the value of one GDP per capita in Brazil (R$ 30,407 in 2016), which would therefore be deemed cost-effective under this threshold. In probabilistic sensitivity analysis, credible interval ranged between 0.73 and 1.30 per capita GDP, therefore showing robust results.

How useful in the daily practice of nephrologists are the new antidiabetics with cadiovascular protection? / ¿Qué tan útiles en la práctica diaria para los nefrólogos son los nuevos antidiabéticos con protección cardiovascular?

Abstract In recent years, several new antidiabetic drugs have been developed, among which only two have demonstrated superiority in cardiovascular protection. They are liraglutide and empagliflozine, which belong, respectively, to GLP-1 RA and SGLT-2Í. These medications have also shown benefits in kidney protection. However, in a recent survey of the author among nephrologists in a large colombian city, it has been detected that most do not use these drugs. The greater resistance to the limitation in its use is due to the advanced stages of chronic kidney disease where they are contraindicated, but also to the anawareness of their potential benefits. In this regard, the nephrologists accepted they should learn more about these antidiabetic medicines, because the type of patient that is frequently attended in their consultation will undoubtly benefit, and considering they are obligated to handle the diabetic patient directly.

Resumen En los últimos años se han desarrollado nuevos fármacos antidiabéticos, entre los que sólo dos han demostrado superioridad en protección cardiovascular. Son liraglutida y empagliflozina, que pertenecen, respectivamente, a los grupos GLP-1 RA y SGLT-2Í. Estos medicamentos también han demostrado beneficios en nefroprotección. Sin embargo, en una reciente encuesta del autor entre nefrólogos, en una gran ciudad colombiana, se ha detectado que la mayoría no utilizan estos fármacos. La mayor resistencia a su uso se debe a consideraciones sobre su restricción en etapas avanzadas de la enfermedad renal crónica, pero también al desconocimiento de sus beneficios potenciales. Al respecto, los nefrólogos aceptaron que deberían aprender más acerca de estos medicamentos antidiabéticos, porque el tipo de paciente que frecuentemente asiste a su consulta sin duda se beneficiaría, y más teniendo en cuenta que por el gran número de diabéticos los nefrólogos están obligados a manejar directamente al paciente con esta patología.

Efectos renales y nefroprotección inducidos por el inhibidor del SGLT2 Empagliflozina en pacientes con diabetes mellitus: revisión de la literatura / Renal effects and nephroprotection induced by SGLT2 inhibitor Empagliflozin in patients with Diabetes Mellitus: a literature review

La insuficiencia renal es una comorbilidad frecuente en pacientes con diabetes mellitus (DM) e incrementa en ellos el riesgo cardiovascular; la hiperglucemia crónica en pacientes con DM induce una gran cantidad de alteraciones directas e indirectas en la estructura y la función renal, y constituye el principal factor para el desarrollo de la nefropatía diabética y la enfermedad renal terminal. En la presente revisión, se exponen los resultados de los estudios en los que se ha demostrado la alta tolerabilidad de empagliflozina en pacientes diabéticos con insuficiencia renal concomitante en estadios I a III. Empagliflozina, mediante la inhibición de SGLT2, ofrece una terapia novedosa con efectos benéficos no sólo sobre el control glucémico, sino también beneficios cardiovasculares y renales, los cuales han sido demostrados en el estudio EMPA-REG OUTCOME y continúan en evaluación en otros estudios

Chronic kidney disease is a frequent comorbidity in patients with diabetes mellitus (DM) and it increases their cardiovascular risk; chronic hyperglycemia in patients with DM leads to direct and indirect disorders in kidney's structure and function, and it is the principal risk factor for the development of diabetic nephropathy and end-stage renal disease. In the current review, results of studies are exposed in which high tolerability of empagliflozin is exposed in diabetic patients with kidney disease. Empagliflozin by inhibiting SGLT2 provides a novel therapy with benefic effects, not only in glycemic control, but it also has cardiovascular and renal benefits, which they have been demonstrated in the EMPA-REG OUTCOME trial, and continue in evaluation in other studies

El papel del riñón en la homeostasis de la glucosa y drogas de acción renal en el tratamiento de la diabetes mellitus tipo 2 / Kidney role in the glucose's homeostasis and drugs of renal action in the treatment of type 2 diabetes mellitus

Los riñones contribuyen a la homeostasis de la glucosa a través de varios mecanismos, incluyendo la gluconeogénesis, utilización y reabsorción de la glucosa a partir del filtrado glomerular. Bajo condiciones fisiológicas normales, la glucosa filtrada es casi totalmente reabsorbida en el epitelio de las células tubulares; en consecuencia, no aparece glucosa en la orina. El transporte de glucosa dentro de las células epiteliales del túbulo se cumple gracias a cotransportadores activos glucosa-sodio (SGLT), una familia de proteínas dependientes de adenosin trifosfato (ATP) involucradas en el transporte de glucosa contra un gradiente de concentración con carga simultánea de sodio, igualmente en contra gradiente. La mayoría de la glucosa filtrada es reabsorbida por medio del SGLT2, un transportador de baja afinidad pero elevada capacidad localizado, predominantemente, en el segmento S1 del tubo contorneado proximal. Por largo tiempo la inhibición del SGLT2 ha sido considerada como un abordaje terapéutico potencial de la hiperglucemia en la diabetes mellitus tipo 2 (DM2), ya que al prevenir la reabsorción de glucosa por los túbulos renales promueven su excreción renal y descienden los valores de la glucemia. Los datos en humanos indican que los inhibidores de SGLT2 representan una estrategia novedosa y efectiva para controlar las cifras de glucemia en los pacientes con DM2. El recién publicado estudio EMPA-REG OUTCOME diseñado para examinar los desenlaces cardiovasculares con empagliflozina en sujetos con DM2 y enfermedad ardiovascular coexistente mostró beneficios tempranos, los cuales se mantuvieron durante el período de observación(AU)

The kidneys contribute to glucose homeostasis through several mechanisms, including gluconeogenesis, glucose use, and glucose reabsorption from the glomerular filtrate. Under normal physiological conditions, this filtered glucose is almost completely reabsorbed by renal tubular epithelial cells; thus, there is no glucose in urine. The transport of glucose into renal tubular epithelial cells is mediated by active cotransporters, the SGLT, a family of ATP-dependent proteins involved in the transport of glucose against a concentration gradient with simultaneous transport of Na+ down a concentration gradient. Most of the filtered glucose is reabsorbed through SGLT2, a low-affinity high-capacity transporter located predominantly in the S1 segment of the renal proximal tubule. Inhibition of SGLT2 has long been regarded as a potential treatment approach for hyperglycemia during T2DM, as they prevent glucose reabsorption from renal tubules, thereby promoting urinary glucose excretion and decreasing plasma glucose levels. Current data in humans indicate that SGLT2 inhibitors represent an effective and novel strategy to control the plasma glucose concentration in patients with T2DM. The recently published EMPA-REG OUTCOME trial, which assessed cardiovascular outcomes with empagliflozin therapy in persons with type 2 diabetes mellitus and coexisting cardiovascular disease showed that the benefits were noted early and continued throughout the study(AU)