Incretinas, incretinomiméticos, inhibidores de DPP IV: (2ª parte) / Incretins, Incretinmimetics, Inhibitors (2nd part)

En los últimos años se reconoce un nuevo mecanismo involucrado en la fisiopatología de la Diabetes Mellitus tipo 2: el déficit de producción y/o acción de las incretinas. Las incretinas son enterohormonas que estimulan la secreción de insulina en respuesta a la ingesta de nutrientes. Glucagon like peptide-1 (GLP1) y Polipéptido insulinotrópico glucosa dependiente (GIP) son las principales incretinas descubiertas hasta hoy. Ambas presentan también efecto trófico sobre las células beta de los islotes pancreáticos. GLP-1 presenta otras acciones como son la inhibición de la secreción de glucagón, enlentecimiento del vaciamiento gástrico e inhibición del apetito. Ambas incretinas son rápidamente clivadas por la enzima dipeptidil peptidasa 4 (DPP-4). Nuevas drogas como los incretinomiméticos, análogos y los inhibidores de DPP-4 se presentan como una terapéutica prometedora para los pacientes con diabetes tipo 2. Conflicto de intereses: Dr. León Litwak - Miembro del Board Latinoamericano de Eli Lilly y Sanofi Aventis - Miembro del Board Nacional de los laboratorios Novo Nordisk, Novartis, GlaxoSmithKline, Sanofi Aventis, Boheringer Ingelheim, Bristol Myers, Astra Zeneca - Investigador principal de protocolos pertenecientes a Eli Lilly, Novo Nordisk, Novartis, GlaxoSmithKline, Takeda, PPDF, Pfizer, Merck Sharp and Dôhme, Amger, Roche, Minimed, Quintiles - Conferencista de los laboratorios mencionados.

Two main pathophysiological mechanisms are currently involved in Type 2 Diabetes (T2DM), insulin resistance and impairment of beta cell function. However, in recent years a new mechanism was reported: a significant decrease in incretins production and/or action. Incretins are gastrointestinal hormones whose main action is stimulating insulin secretion in response to nutrients. The best known incretins are glucagon like peptide-1 (GLP-1) and Gastric insulinotropic peptide (GIP). GLP-1 and GIP not only increase insulin secretion, but also decrease glucagon secretion, slow gastric emptying and reduce apetite, generating weight loss. Both incretins are rapidly clived by the enzyme dipeptidil peptidase 4 (DPP4). In order to emulate incretins action, several drugs were developed: GLP-1 receptor agonists, GLP-1 mimetics, and DPP4 inhibitors. All of them seem to became a very promising tool for the treatment of T2DM. Financial Interests: Dr. León Litwak - Member of the Latin American Board of Eli Lilly and Sanofi Aventis - Member of the National Board of the following laboratories: Novo Nordisk, Novartis, GlaxoSmithKlein Sanofi, Aventis, Boheringer Ingelheim, Bristol Myers, Astra Zeneca - Principal Investigator of Protocols from: Eli Lilly, Novo Nordisk, Novartis, GlaxoSmithKlein, Takeda, PPDF, Pfizer, Merck Sharp and Dôhme, Amgen, Roche, Minimed, Quintiles - Lecturer for the former laboratories.

Incretinas, Incretinomiméticos, Inhibidores de DPP IV: 1er parte / Incretins, Incretinmimetics, Inhibitors

En los últimos años se reconoce un nuevo mecanismo involucrado en la fisiopatología de la Diabetes Mellitus tipo 2: el déficit de producción y/o acción de las incretinas. Las incretinas son enterohormonas que estimulan la secreción de insulina en respuesta a la ingesta de nutrientes. Glucagon like péptido-1 (GLP1) y Polipéptido insulinotrópico glucosa dependiente (GIP) son las principales incretinas descubiertas hasta hoy. Ambas presentan también efecto trófico sobre las células beta de los islotes pancreáticos. GLP-1 presenta otras acciones como son la inhibición de la secreción de glucagón, enlentecimiento del vaciamiento gástrico e inhibición del apetito. Ambas incretinas son rápidamente clivadas por la enzima dipeptidil peptidasa 4 (DPP-4). Nuevas drogas como los incretinomiméticos, análogos y los inhibidores de DPP-4 se presentan como una terapéutica prometedora para los pacientes con diabetes tipo 2.

Two main patophysiological mechanisms are currently involved in Type 2 Diabetes (T2DM), insulin resistance and impairment of beta cell function. However in the last years a new mechanism was reported: a significant decrease in incretins production and or action. Incretins are gut hormones whose main action is stimulating insulin secretion in response to nutrients. The more known incretins are glucagon like peptide-1 (GLP-1) and Gastric insulinothropic peptide (GIP). GLP-1 and GIP not only increase insulin secretion, nor decrease glucagon secretion, slow gastric emptying and reduce apetite generating weight lose. Both incretins are rapidly clived by the enzyme dipeptidil peptidase 4 (DPP4). In order to emulate incretins action, several drugs where developed: agonists of GLP-1 receptors, GLP-1 mimetics, and inhibitors of the DPP4. All of them seems to became a very promise tool for the treatment of T2DM.

Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2 / Exenatide trials for the treatment of type 2 diabetes

La diabetes mellitus tipo 2 es una enfermedad metabólica crónica, frecuente y progresiva, responsable del 90% de los casos de diabetes a nivel mundial. Aproximadamente el 60% de los individuos que padecen este desorden no alcanzan niveles óptimos de hemoglobina glicosilada, a pesar de la disponibilidad de numerosas alternativas terapéuticas. Los dos objetivos más importantes a cumplir en el manejo actual de la diabetes tipo 2 son la capacidad de los agentes antidiabéticos de exhibir eficacia prolongada y la capacidad de preservar la función de las células beta pancreáticas. El efecto incretina se encuentra reducido en pacientes con diabetes tipo 2. Exenatida pertenece a un nuevo grupo de drogas antidiabéticas que mejoran el control de la glucemia en estos pacientes a través de mecanismos fisiológicos glucorregulatorios que mejoran el efecto incretina. Los ensayos clínicos fase III con exenatida demostraron una reducción media de aproximadamente el 1% en los valores de hemoglobina glicosilada. Los datos a largo plazo de estudios de extensión no controlados indican una mejoría sostenida en los niveles de hemoglobina glicosilada y una reducción progresiva del peso luego de 3 años de tratamiento con esta droga. La droga es generalmente bien tolerada y los efectos adversos más frecuentes son los gastrointestinales, con una intensidad leve a moderada. El objetivo de esta revisión es analizar la evidencia publicada hasta la fecha sobre la eficacia y tolerabilidad del tratamiento con exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes / Incretinomiméticos e inibidores da dipeptidil peptidase-4: terapias inovadoras para o tratamento do diabetes tipo 2

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

É previsto que a prevalência de diabetes e a intolerância à glicose aumente dramaticamente ao longo das próximas duas décadas. As terapias clínicas para diabetes melito tipo 2 (DM2) têm tradicionalmente incluído modificação do estilo de vida, agentes antidiabéticos orais e, por último, o início da insulina. Neste artigo, revisamos os resultados dos estudos clínicos de duas terapias inovadoras no tratamento do DM2 baseadas nos efeitos glicorregulatórios dos hormônios incretina. Os incretinomiméticos são medicamentos peptídeos que mimetizam várias das ações do peptídeo semelhante ao glucagon-1 (GLP-1) e têm demonstrado reduzir níveis de hemoglobina glicada (A1C) em pacientes com DM2. Adicionalmente, incretinomiméticos reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon, e são associados com redução de peso. Os inibidores da dipeptidil peptidase-4 (DPP-4) aumentam os níveis de GLP-1 endógeno pela inibição da degradação enzimática do GLP-1. Estudos clínicos em pacientes com DM2 têm demonstrado que inibidores da DPP-4 reduzem A1C elevada, reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon e são neutros quanto ao peso. Coletivamente, estas novas medicações, administradas em combinação com outros agentes antidiabéticos, como metformina, sulfoniluréias e/ou tiazolidinedionas (TZDs), podem ajudar a recuperar a homeostase glicêmica de pacientes com DM2 não-controlados.