The Efficacy of Metformin and Exenatide in Polycystic Ovary Syndrome (PCOS) Patients / La eficacia de metformina y exenatida en pacientes con síndrome de ovario poliquístico (SOP)

Introducción: El Síndrome del Ovario Poliquístico (SOP) es un trastorno hormonal que afecta al 5-10% de las mujeres que se encuentran en edad reproductiva. este metanálisis tiene como objetivo evaluar la eficacia de la metformina y la exenatida, respectivamente, y comparar la eficacia de ambos fármacos utilizando el Índice de Masa Corporal (IMC), el colesterol de lipoproteínas de baja densidad (LDL-C), el colesterol de lipoproteínas de alta densidad (HDL-C) y los niveles de testosterona. Método: En este estudio se consultaron Scopus, Science Direct, Oxford Journal, Wiley Online Library y Medline a través del motor de búsqueda PubMed. El análisis estadístico de los estudios incluidos se realizó mediante el software RevMan 5.4. Resultados: Hubo 6 estudios incluidos en el análisis del estudio. Hubo una reducción significativa en el IMC de las pacientes con SOP con exenatida frente a metformina (diferencia de medias = 0,51; intervalo de confianza (IC) del 95 % = 0,07; 0,96; I 2 = 52 %; p = 0,02). También hubo una reducción significativa en el nivel de testosterona de los pacientes con SOP con exenatida frente a metformina (diferencia de medias = 0,15; intervalo de confianza (IC) del 95 % = 0,07; 0,22;I 2 = 0 %; p = 0,0002). No hubo efecto sobre la media de LDL-C y de HDL-C cuando se comparó entre metformina y exenatida. Este muestra que la exenatida es eficaz para reducir el IMC y los niveles de testosterona en pacientes con SOP. Conclusiones: Hubo una reducción significativa en el IMC y los niveles de testosterona de los pacientes con SOP cuando se usó exenatida en comparación con metformina. Sin embargo, no hubo efecto sobre la media de los niveles de LDL-C y HDL-C de las pacientes con SOP. (AU)

Introduction: Polycystic Ovary Syndrome (PCOS) is a hormonal disorder that affects 5-10% of women who are their reproductive age. This meta-analysis aims to evaluate the efficacy of metformin and exenatide, respectively, and to compare the efficacy of both drugs using Body Mass Index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and testosterone level. Method: Scopus, Science Direct, Oxford Journal, Wiley Online Library, and Medline (through the PubMed search engine) were used in this study. Statistical analysis of the included studies was done using the RevMan 5.4 software. Results: There were 6 studies included in the analysis of the study. There was a significant reduction in BMI of PCOS patients with exenatide versus metformin (mean difference = 0.51; 95% confidence interval (CI)= 0.07, 0.96, I 2= 52%; p=0.02). There was also a significant reduction in the testosterone level of PCOS patients with exenatide versus met-formin (mean difference = 0.15; 95% confidence interval (CI)= 0.07, 0.22, I 2= 0%; p=0.0002). There was no effect on the mean of LDL-C and of HDL-C when compared between metformin and exenatide This meta-analysis shows that exenatide is effective in reducing BMI and testosterone levels in PCOS patients. Conclusions: There were a significant reduction in BMI and testosterone levels of PCOS patients when exenatide was used as compared to metformin. However, there was no effect on the mean of the LDL-C and HDL-C levels of the PCOS patients. (AU)

Exenatida e exendina(9-39) oriundos do lagarto venenoso Heloderma suspectum e seus efeitos sobre a qualidade espermática de ratos obesos e diabéticos / Exenatide and exendin(9-39) from the poisonous lizard Heloderma suspectum and its effects on sperm quality in obese and diabetic rats

The effects of exenatide (EXE) and exendin(9-39) (EXE9), peptides isolated from poisonous lizard H. suspectum on obesity and diabetes mellitus on male fertility are still poorly understood. The aim of this study was to evaluate the effects of EXE and EXE9 on parameters that contribute to sperm quality in hypothalamic injury-induced obesity (MSG) and hypercaloric diet (DIO) as well as streptozotocin-induced diabetes mellitus (STZ). Obese and diabetic rats received 10μg EXE / kg or 100μg EXE9 / kg sc daily or remained untreated for 20 days. Healthy rats at same age for each experimental models were used for comparison, only MSG model used healthy rats treated with exenatide. Biometric and glucoregulatory parameters treated with EXE (STZ) and EXE9 (STZ, DIO, MSG) were evaluated. Blood, testes and tail of the epididymis were collected. Sex hormones, leptin and insulin were evaluated by ELISA. Sperm were obtained from the epididymal tail by washing with HTF culture medium. The percentage of abnormal sperm morphology was analyzed under a phase contrast microscope. Functional analyzes of sperm were performed only STZ and MSG models. Sperm kinetics was evaluated by Computer Aided Analysis. The EXE-treated STZ group (STZ-E) improved the biometric parameters, glycemic control as well as the morphology, functionality and kinetics of mature sperm and EXE9 (STZ-E9) has an EXE effect on essential parameters for maintaining sperm quality. DIO showed impaired sperm quality, but there were occasional changes in the parameters that affect sperm quality. DIO-E improved sperm quality, suggesting that the antiobesogenic, antidislipidemic, and antidiabetogenic action of EXE restored the accuracy of the pathway of mature sperm, whereas treatment with EXE9 did not dramatically affect sperm kinetics, but was unable to restore path accuracy. EXE, through glucoregulatory improvement in MSG, has beneficial effects on hormone levels as well as sperm morphology, functionality and kinetics. Negative changes caused by EXE9 in glycorregulatory parameters, exacerbated increase in mass of periepididimal adipose tissue deposition, decreased testosterone and FSH plasma levels, with consequences on kinetics negatively affect sperm quality. EXE has been shown to be an excellent therapeutic agent to be used for beneficial effects on sperm quality in obese and diabetic patients. Results of treatment with EXE9 similar to those obtained with EXE in some evaluated parameters suggest two hypotheses (1) the use of an alternative to classical receptor; or (2) a dose-dependent situation if the dose of EXE9 administered is not sufficient for its action as an antagonist in a given organ and / or tissue. Therefore clinical research is needed to deepen the knowledge as well as the use of exenatide in a new incretinomimetic function as therapy.

Os efeitos da exenatida (EXE) e da exendina(9-39) (EXE9), peptídeos isolados do lagarto venenoso H. suspectum sobre a obesidade e diabetes melito na fertilidade masculina ainda são pouco compreendidos. O objetivo deste estudo foi avaliar os efeitos da EXE e da EXE9 sobre parâmetros que contribuem para a qualidade espermática na obesidade induzida por injúria hipotalâmica (MSG) e dieta hipercalórica (DIO) bem como no diabetes melito induzido por estreptozotocina (STZ). Ratos obesos e diabéticos receberam 10μg EXE/kg ou 100μg EXE9/kg sc diariamente ou permaneceram sem tratamento por 20 dias. Ratos saudáveis de mesma idade para cada modelo experimental foram utilizados para comparação, somente para o modelo MSG houve ratos saudáveis tratados com exenatida. Foram avaliados parâmetros biométricos e glicorregulatórios tratados com EXE (STZ) e EXE9 (STZ, DIO, MSG). Sangue, testículos e cauda do epidídimo foram coletados. Hormônios sexuais, leptina e insulina foram avaliados por ELISA. Os espermatozoides foram obtidos da cauda epididimal por lavagem com meio de cultura HTF. A porcentagem de morfologia anormal dos espermatozoides foi analisada sob um microscópio de contraste de fase. Foram realizadas análises funcionais dos espermatozoides somente para os modelos STZ e MSG. A cinética espermática foi avaliada pela Análise Assistida por Computador. O grupo STZ tratado com EXE (STZ-E) melhorou os parâmetros biométricos, controle glicêmico bem como a morfologia, funcionalidade e cinética de espermatozoides maduros e EXE9 (STZ-E9) possui efeito contrário a EXE em parâmetros essenciais para manutenção da qualidade espermática. DIO apresentou comprometimento da qualidade espermática, porém foram alterações pontuais nos parâmetros que afetam a qualidade espermática. DIO-E melhorou a qualidade espermática, sugerindo que a ação antiobesogênicao, antidislipidêmico e antidiabetogênico de EXE restaurou a acurácia da trajetória do espermatozoide maduro, já o tratamento com EXE9 não afetou drasticamente a cinética espermática, mas foi incapaz de restaurar a acurácia da trajetória. EXE, através da melhora glicorregulatória em MSG, tem efeitos benéficos nos níveis hormonais, bem como na morfologia, funcionalidade e cinética dos espermatozoides. As alterações negativas causadas por EXE9 nos parâmetros glicorregulatórios, aumento exacerbado da massa do depósito de tecido adiposo periepididimal, diminuição dos níveis plasmáticos de testosterona e FSH, com consequências sobre a cinética repercutem negativamente sobre a qualidade dos espermatozoides. A EXE mostrou-se um excelente agente terapêutico para ser utilizado em busca de efeitos benéficos sobre a qualidade espermática em obesos e diabéticos. Os resultados do tratamento com EXE9 similares aos obtidos com EXE em alguns parâmetros avaliados sugerem duas hipóteses (1) a utilização de um receptor alternativo ao clássico; ou (2) uma situação dose-dependente no caso da dose de EXE9 administrada não ser o suficiente para sua ação como antagonista em determinado órgão e/ou tecido. Portanto são necessário pesquisas clínicas para aprofundar o conhecimento bem como a utilização da exenatida em uma nova função incretinomimética como terapia.

Efeitos da obesidade induzida por dieta hipercalórica e de seu tratamento com exenatida sobre a neurotransmissão colinérgica muscarínica em hipocampo de ratos / Effects of obesity induced by hypercaloric diet and its treatment with exenatide on the muscarinic cholinergic neurotransmitter in rat hippocampus

Introduction: Molecular cloning studies have revealed the existence of five distinct muscarinic acethylcholine receptor (mAChRs) subtypes (M1 to M5), which interact, via a G protein-regulated process, with multiple effector systems. The M1, M3 and M5 subtypes couple primarily to PLC-mediated phosphoinositide hydrolysis, while the M2 and M4 subtypes couple primarily to adenylyl cyclase inhibition. In the Hippocampus, the modulation of excitatory transmission by mAChRs seems particularly relevant to learning and memory processing in the hippocampal formation, where the diversity and differential localization of the receptors are likely to account for the complex cholinergic modulation in this structure. Experimental studies has been shown that obesity-associated with hypercaloric diet impair learning and memory in rodents, suggesting a strong association between obesity and cognitive dysfunction. However, the mechanisms of how the obesity induced by hypercaloric diet affect memory are not understood fully. Objective: The aim of this study was to investigate the possible effects of obesity induced by hypercaloric diet and its treatment with exenatide, an antidiabetogenic and potential antiobesogenic drug derived from the venom of the Gila monster Heloderma suspectum, on the affinity, density, subtypes and intracellular signaling pathways linked to activation of mAChRs in rat hippocampus. Methodology: Male Wistar rats were divided into three groups: control (CT), obese induced by hypercaloric diet (DIO) and DIO treated with exenatide (DIO+E). The experimental procedures were approved by the Research Ethics Committee of the Butantan Institute (# 22381003/17). In the hippocampus obtained from CT, DIO and DIO+E were performed: I- [ 3H]QNB binding to determine the affinity (KD) and density (Bmax) of mAChRs; II- Expression of each mAChR subtype (M1 to M5) by immunoprecipitation assays and III- Determination of [3H]inositol phosphates accumulation. Results: Specific binding analysis showed that the affinity did not differ among CT, DIO and DIO+E. In contrast, the density of mAChRs obtained in DIO animals was lower than that obtained from CT rats. Moreover, the density of mAChRs from DIO+E was similar when compared with CT rats. Immunoprecipitation assays induced a decrease in the expression of M1 and M3 subtypes of DIO animals when compared with CT. Treatment with exenatide (DIO+E) recovered the expression of the two subtypes similar to CT. On the other hand, the M2, M4 and M5 subtypes did not differ among CT, DIO and DIO+E. Carbacol caused a concentration-dependent increase in the accumulation of [3 H]inositol phosphates in the 3 experimental groups. However, the magnitude of the maximal response to carbachol was lower in the DIO group compared to CT and DIO+E animals, which did not differ from each other. Conclusion: Our results indicate that obesity induced by hypercaloric diet strongly influences the expression and intracellular signaling coupled to M1-M3 subtypes. The exenatide reversed these effects, suggesting an important role on hippocampal muscarinic cholinergic system. This action of obesity might be a key step mediating cellular events important for learning and memory.

Introdução: Estudos de clonagem molecular revelaram a existência de cinco diferentes subtipos de receptores muscarínicos de acetilcolina (mAChRs) (M1-M5) que interagem com múltiplos sistemas efetores através de um processo regulado pela proteína G. Os subtipos M1, M3 e M5 acoplam-se principalmente à hidrólise do fosfoinositídeos mediada pela fosfolipase C. Por outro lado, os subtipos M2 e M4 acoplam-se principalmente à inibição da adenililciclase. No hipocampo, a modulação da transmissão excitatória pelos mAChRs é relevante para o aprendizado e o processamento da memória aonde a diversidade e a localização diferencial dos mAChRs são responsáveis pela complexa modulação colinérgica nessa estrutura. Estudos experimentais demonstraram que a obesidade induzida por dieta hipercalórica prejudica o aprendizado e a memória em roedores, sugerindo uma associação entre obesidade e disfunção cognitiva. No entanto, os mecanismos pelos quais a obesidade afeta os processos cognitivos não são totalmente compreendidos. Objetivo: O objetivo deste estudo foi investigar os possíveis efeitos da obesidade induzida por dieta hipercalórica e seu tratamento com exenatida, uma droga anti- diabetogênica e anti-obesogênica, derivada do veneno do Monstro-de-Gila (Heloderma suspectum), sobre a afinidade, densidade, subtipos e sinalização intracelular acoplada à ativação de mAChRs no hipocampo de ratos. Metodologia: Ratos machos Wistar foram divididos em três grupos: controle (CT), obeso induzido por dieta hipercalórica (DIO) e DIO tratado com exenatida (DIO+E). Os procedimentos experimentais foram aprovados pelo Comitê de Ética em Pesquisa do Instituto Butantan (no 22381003/17). No hipocampo obtido de animais CT, DIO e DIO+E foram realizados: I- Ensaios de saturação da ligação do [3H]QNB para determinar os parâmetros farmacológicos KD (afinidade) e Bmax (densidade); II- A expressão de cada subtipo de receptor muscarínico (M1 a M5) por ensaios de imunoprecipitação com anticorpo que reconhece cada um dos subtipos de mAChRs e III- Determinação do conteúdo intracelular de [3H]fosfatos de inositol. Resultados: A análise da ligação específica mostrou que a afinidade não diferiu entre os grupos CT, DIO e DIO-E. Contrariamente, a densidade de mAChRs obtida nos animais DIO foi menor que a observada em ratos CT. A densidade dos animais DIO+E foi similar ao CT. Animais DIO induziram uma diminuição na expressão dos subtipos M1 e M3 quando comparada com o CT. O tratamento com exenatida (DIO+E) recuperou a expressão dos dois subtipos similar ao CT. Por outro lado, os subtipos M2, M4 e M5 não diferiram entre os grupos CT, DIO e DIO+E. O carbacol causou um aumento, dependente da concentração, sobre o acumulo de [3H]fosfatos de inositol nos 3 grupos experimentais. Entretanto, a magnitude da resposta máxima ao carbacol foi menor no grupo DIO comparativamente aos animais CT e DIO+E que não diferiram entre si. Conclusão: Nossos resultados indicam que a obesidade induzida por dieta hipercalórica, influência de maneira contundente, por meio da diminuição da expressão e sinalização intracelular acoplada aos subtipos M1 e M3. A exenatida reverteu esses efeitos, sugerindo ter um papel importante na neurotransmissão colinérgica muscarínica hipocampal. O presente estudo é também o primeiro passo para outras abordagens como a avaliação da importância funcional dessa modulação sobre os mAChRs no hipocampo.

[Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes]. / Efectos extrapancreáticos de los agonistas del receptor de GLP-1: una ventana hacia nuevos objetivos del tratamiento farmacológico de la diabetes mellitus tipo 2.

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

[Effects of GLP-1 receptor agonists on carbohydrate metabolism control]. / Efectos de los agonistas del receptor de GLP-1 sobre el control del metabolismo hidrocarbonado.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

[Twice-daily and weekly exenatide: clinical profile of two pioneer formulations in incretin therapy]. / Exenatida diaria y semanal: perfil clínico de dos formulaciones pioneras en la modulación incretínica.

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

[Effects of GLP-1 receptor agonists on carbohydrate metabolism control]. / Efectos de los agonistas del receptor de GLP-1 sobre el control del metabolismo hidrocarbonado.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

[Twice-daily and weekly exenatide: Clinical profile of two pioneer formulations in incretin therapy]. / Exenatida diaria y semanal: perfil clínico de dos formulaciones pioneras en la modulación incretínica.

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

[Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes]. / Efectos extrapancreáticos de los agonistas del receptor de GLP-1: una ventana hacia nuevos objetivos del tratamiento farmacológico de la diabetes mellitus tipo 2.

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

[Type 2 diabetes mellitus and obesity: should we treat the obesity or the diabetes?]. / Diabetes mellitus tipo 2 y obesidad: ¿tratar la obesidad o la diabetes?

In this article, we review the results that can be expected after significant weight loss in patients with type 2 diabetes mellitus. We provide consensus-based documentation supported by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation on the importance of physical exercise, metabolic-bariatric surgery, and drug therapy. Lastly, we report the results of studies published in the last few years on glucagon-like peptide-1 analogs and the new family of oral drugs known as gliflozins, specifically studies published on dapagliflozin.

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.