Revisão sobre o uso de inibidores de cotransportador sódio-glicose 2 e agonistas de peptídeo 1 em pessoas com diabetes mellitus tipo 2 e doença cardiovascular / Review on the use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists in people with type 2 diabetes mellitus and cardiovascular disease / Revisión sobre el uso de inhibidores del cotransportador de sodio-glucosa 2 y agonistas de péptido 1 similar al glucagón en personas con diabetes mellitus tipo 2 y enfermedad cardiovascular

Introdução: Introdução: Diabetes mellitus tipo 2 é um importante e crescente problema de saúde para todos os países. Objetivo: Este trabalho visa avaliar a qualidade da evidência disponível sobre os fármacos inibidores de sódio-glicose 2 e agonistas de glucagon 1 em pessoas com diabetes mellitus e doença cardiovascular aterosclerótica Métodos: Realizou-se revisão integrativa utilizando as bases de dados MEDLINE via PubMed, Embase via Cochrane Library, Cochrane Library, LILACS via BVS. A pergunta de pesquisa foi estruturada da seguinte forma: população ­ pessoas com diabetes mellitus tipo 2 e doença cardiovascular estabelecida; intervenção ­ tratamento usual exceto insulina + inibidores de sódio-glicose 2 ou tratamento usual exceto insulina + agonistas de glucagon 1; controle - tratamento usual exceto insulina + placebo; desfecho ­ mortalidade geral, mortalidade por causas cardiovasculares, morbidade, efeitos adversos. Resultados: Selecionaram-se dois estudos sobre empagliflozina. Esse medicamento associado ao tratamento usual foi superior ao placebo associado ao tratamento usual no desfecho primário (HR 0,86; IC95% 0,74­0,99; p=0,04), na redução de hospitalização por insuficiência cardíaca (HR 0,65; IC95% 0,50­0,85; p=0,002), da mortalidade cardiovascular (HR 0,62; IC95% 0,49­0,77) e da mortalidade geral (HR 0,68; IC95% 0,57­0,82; p<0,001). No subgrupo de pessoas com diabetes que não usavam insulina, houve benefício com empagliflozina em relação ao desfecho primário (HR 0,79; IC95% 0,64­0,97; DR 2,5; NNT 40) e a mortes de causa cardiovascular (HR 0,61; IC95% 0,44­0,85; DR 2; NNT 49). Houve heterogeneidade entre os subgrupos com benefício de empagliflozina no desfecho primário apenas para aqueles com idade ³65 anos (p=0,01) e hemoglobina glicada <8,5 (p=0,01). Em relação às mortes por causas cardiovasculares, houve diferença (p=0,05) com o uso de empagliflozina reduzindo o risco somente no subgrupo com índice de massa corporal <30. Não houve diferença significativa em relação ao placebo para acidente vascular encefálico fatal e não fatal, tampouco no desfecho composto de acidente vascular encefálico debilitante não fatal e acidente vascular encefálico fatal (HR 0,81; IC95% 0,43­1,50; p=0,50). Houve mais pessoas acometidas por acidente vascular encefálico no grupo intervenção em que a hemoglobina glicada inicial era ≥8,5%, favorecendo o placebo (p=0,01). Conclusões: Os dados encontrados favorecem o benefício de utilizar esse medicamento no Sistema Único de Saúde em pessoas com doenças cardiovasculares. Entretanto, houve heterogeneidade entre grupos populacionais, o que pode ajudar a delinear estratégias de uso para esses medicamentos. São necessários mais estudos para avaliar qual seria o motivo de não haver benefício em desfechos cerebrovasculares isoladamente.

Introduction: Introduction: Type 2 diabetes mellitus is an important and growing health problem worldwide. Objective: This study aims to evaluate the quality of the evidence available on sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists in people with diabetes mellitus and atherosclerotic cardiovascular disease. Methods: This integrative review was performed using the following databases: MEDLINE via PubMed, Embase via Cochrane Library, Cochrane Library, LILACS via VHL. The research question was structured as follows: population ­ people with type 2 diabetes mellitus and established cardiovascular disease; intervention ­ usual treatment, except insulin + sodium-glucose cotransporter 2 inhibitors or usual treatment, except insulin + and glucagon-like peptide 1 agonists; control ­ usual treatment, except insulin + placebo; outcome ­ overall mortality, mortality from cardiovascular causes, morbidity, adverse effects. Results: Two studies on empagliflozin were selected. This drug associated with the usual treatment was superior to placebo associated with the usual treatment in the primary outcome (hazard ratio ­ HR 0.86; 95% confidence interval ­ 95%CI 0.74­0.99; p=0.04), in reducing heart failure hospitalization (HR 0.65; 95%CI 0.50­0.85; p=0.002), in cardiovascular mortality (HR 0.62; 95%CI 0.49­0.77), and in overall mortality (HR 0.68; 95%CI 0.57­0.82; p<0.001). The subgroup of people with diabetes who were not on insulin benefited from using empagliflozin concerning the primary outcome (HR 0.79; 95%CI 0.64­0.97; risk difference ­ RD 2.5; number needed to treat ­ NNT 40) and cardiovascular mortality (HR 0.61; 95%CI 0.44­0.85; RD 2; NNT 49). The analysis of the subgroups showed heterogeneity. Participants aged 65 years or older (p=0.01) and those with glycated hemoglobin lower than 8.5 benefited from empagliflozin in the primary outcome. A difference (p=0.05) related to cardiovascular mortality was found, with the use of empagliflozin reducing the risk only in the subgroup with body mass index <30. No significant difference was identified with respect to placebo for fatal and nonfatal stroke nor for the composite outcome of nonfatal disabling stroke and fatal stroke (HR 0.81; 95%CI 0.43­1.50; p=0.50). More people had strokes in the intervention group in which the initial glycated hemoglobin was ≥8.5%, favoring placebo (p=0.01). Conclusions: The data found suggest the benefit of the Brazilian public health system using this drug in people with cardiovascular diseases. However, the population groups were heterogeneous, which may help outline strategies for using these medications. Further studies are necessary to assess why isolated cerebrovascular outcomes showed no benefit.

Introducción: Diabetes mellitus tipo 2 es un importante y creciente problema de salud para todos los países. Objetivo: Este trabajo busca evaluar la calidad de la evidencia disponible sobre los fármacos Inhibidores del Cotransportador de Sodio-Glucosa 2 y agonistas de Péptido 1 similar al glucagón en personas con diabetes mellitus y enfermedad cardiovascular aterosclerótica. Métodos: Se realizó revisión integrativa utilizando las bases de datos MEDLINE vía PubMed, Embase vía Cochrane Library, Cochrane Library, LILACS vía BVS. La pregunta de investigación fue estructurada de la siguiente manera: población ­ personas con diabetes mellitus tipo 2 y enfermedad cardiovascular establecida; intervención ­ tratamiento usual excepto insulina + inhibidores de sodium-glucose cotransporter-2 o tratamiento usual excepto insulina + agonistas de Péptido 1 similar al glucagón; control ­ tratamiento habitual excepto insulina + placebo; desenlace ­ mortalidad general, mortalidad por causas cardiovasculares, morbilidad, efectos adversos. Resultados: Se seleccionaron dos estudios sobre empagliflozina. Este medicamento asociado al tratamiento habitual fue superior al placebo asociado al tratamiento usual en el resultado primario (HR 0.86; IC95% 0.74­0.99; p=0,04), en la reducción de hospitalización por insuficiencia cardíaca (HR 0.65; IC95% 0.50­0.85; p=0.002), de la mortalidad cardiovascular (HR 0,62; IC95% 0,49­0,77) y de la mortalidad general (HR 0,68; IC95% 0,57­0,82; p=0,001). En el subgrupo de personas con diabetes que no usaban insulina, hubo beneficio con empagliflozina con relación al desenlace primario (HR 0.79; IC95% 0.64­0.97; DR 2.5; NNT 40) y a muertes de causa cardiovascular (HR 0.61; IC95% 0.44­0.85; DR 2; NNT 49). No hubo diferencia significativa con relación al placebo para accidentes cerebrovasculares fatal y no fatal, tampoco en el resultado compuesto de accidente cerebrovascular debilitante no fatal y fatal (HR 0.81; IC95% 0.43­1.50; p=0.50). Hubo más personas acometidas por accidente cerebrovascular en el grupo intervención en que la hemoglobina glicada inicial era un 8,5%, favoreciendo el placebo (p=0.01). Conclusión: Los datos encontrados favorecen el beneficio de utilizar ese medicamento en el Sistema Único de Salud en personas con enfermedad cardiovascular. Entretanto ha habido heterogeneidad entre los grupos de población, lo que puede ayudar a delinear qué estrategias de uso para estos medicamentos. Son necesarios más estudios para evaluar cuál sería el motivo de no haber beneficio en resultados cerebrovasculares aisladamente.

O consumo de produto à base de yacon (Smallanthus sonchifolius) aumenta glucagon-like peptide-1 e diminui o peso corporal de ratas Wistar ovariectomizadas / Yacon-based product consumption (Smallanthus sonchifolius) increases glucagon-like peptide-1 and reduces the body weight of ovariectomized Wistar rats

A raiz do yacon (Smallanthus sonchifolius), em função da rica concentração de fruto-oligossacarídeos, é classificada como prebiótico e tornou-se promissora da obesidade pelo aumento da saciedade. O objetivo deste estudo foi avaliar a inclusão de um produto à base de yacon (PBY) em ratas ovariectomizadas (OVX) no consumo alimentar, na modulação de medidas antropométricas e do imunomarcador da saciedade glucagon-like peptide-1 (GLP-1) em ratas Wistar ovariectomizadas (OVX). Analisou-se o consumo alimentar pela pesagem diária de sobra de dieta, a porcentagem de gordura corporal foi determinada pelo índice de Lee e também foram avaliados o peso, o índice de massa corporal (IMC) e circunferência abdominal. Fragmentos do ceco foram utilizados para imunomarcação de GLP-1, de ratas OVX, após serem alimentadas por 24 semanas com dieta padrão adicionadas ou não de 6% de FOS/inulina/PBY. Observou-se diminuição da circunferência abdominal (p=0,2173) em 3,5%, também houve decréscimo de IMC (p=0,3822) em 6,25% e de percentual de gordura corporal (p=0,3528) em 2,14% em animais que receberam PBY durante 24 semanas (G4) comparado aos animais do grupo controle. No grupo G4 o GLP-1 aumentou (p<.0001), os animais aumentaram o consumo (p=0,0064) e, paradoxalmente, tiveram menor ganho de peso (p<.0001), o que pode estar associado ao fato de que as fibras diminuem a eficiência de absorção de lipídeos ao longo do intestino delgado, o que pode diminuir a assimilação calórica de nutrientes. Esse fenômeno demonstra que o PBY possui potencial na modulação da obesidade, portanto, melhoria da qualidade de vida de mulheres na menopausa.(AU)

The yacon root (Smallanthus sonchifolius), due to the rich concentration of fructo-oligosaccharides, is classified as prebiotic and has become promising for obesity due to increased satiety. The aim of this study was to evaluate the inclusion of a yacon-based product (PBY) in ovariectomized rats (OVX) in food consumption, in the modulation of anthropometric measurements and in the satiety immunosorbent glucagon-like peptide-1 (GLP-1) in rats Wistar ovariectomized (OVX). Food consumption was analyzed by daily weighing of leftover diet, the percentage of body fat was determined by the Lee index, and weight, body mass index (BMI) and waist circumference were also evaluated. Cecum fragments were used for immunostaining GLP-1, from OVX rats, after being fed for 24 weeks with a standard diet with or without 6% FOS / inulin / PBY. There was a decrease in abdominal circumference (p = 0.2173) in 3.5%, there was also a decrease in BMI (p = 0.3822) in 6.25% and a percentage of body fat (p = 0.3528) 2.14% in animals that received PBY for 24 weeks (G4) compared to animals in the control group. In the G4 group GLP-1 increased (p <.0001), the animals increased their consumption (p = 0.0064) and paradoxically, they gained less weight gain (p <.0001), which may be associated with the fact that fibers decrease the efficiency of absorption of lipids along the small intestine, which can decrease the caloric assimilation of nutrients. This phenomenon demonstrates that PBY has the potential to modulate obesity, thus improving the quality of life of women in menopause. (AU)

Nuevos hipoglucemiantes en el cuidado de las personas con diabetes tipo 2: por fin hay un avance / New hypoglycemic agents in the care of people with diabetes: finally, there is a breakthrough

En este artículo, la autora jerarquiza la relevancia de la eficacia documentada de los agonistas del péptido similar alglucagón-1 y los inhibidores del cotransportador sodio-glucosa tipo 2, que ha conducido a recientes modificaciones en el paradigma del cuidado en los pacientes con diabetes tipo 2. (AU)

In this article, the author highlights the relevance of the documented efficacy of glucagon-like peptide-1 agonists and type 2 sodium-glucose cotransporter inhibitors, which has led to recent changes in the paradigm of care in patients with type 2diabetes. (AU)

Does evolutionary biology help the understanding of metabolic surgery? a focused review / A biologia evolutiva ajuda na compreensão da cirurgia metabólica? uma revisão com foco

ABSTRACT Introduction: The wide net of physiological issues involved in metabolic surgery is extremely complex. Nonetheless, compared anatomy and phisiology can provide good clues of how digestive tracts are shaped for more or less caloric food, for more or less fiber, for abundance and for scarcity. Objective: To review data from Compared Anatomy and Physiology, and in the Evolutionary Sciences that could help in the better comprehension of the metabolic surgery. Method: A focused review of the literature selecting information from these three fields of knowledge in databases: Cochrane Library, Medline and SciELO, articles and book chapters in English and Portuguese, between 1955 and 2019, using the headings "GIP, GLP-1, PYY, type 2 diabetes, vertebrates digestive system, hominid evolution, obesity, bariatric surgery ". Results: The digestive tract of superior animals shows highly specialized organs to digest and absorb specific diets. In spite of the wide variations of digestive systems, some general rules are observed. The proximal part of the digestive tract, facing the scarcity of sugars, is basically dedicated to generate sugar from different substrates (gluconeogenesis). Basic proximal gut tasks are to proportionally input free sugars, insulin, other fuels and to generate anabolic elements to the blood, some of them obesogenic. To limit the ingestion by satiety, by gastric emptying diminution and to limit the excessive elevation of major fuels (sugar and fat) in the blood are mostly the metabolict asks of the distal gut. A rapid and profound change in human diet composition added large amounts of high glycemic index foods. They seem to have caused an enhancement in the endocrine and metabolic activities of the proximal gut and a reduction in these activities of the distal gut. The most efficient models of metabolic surgery indeed make adjustments in this proximal/distal balance in the gut metabolic activities. Conclusion: Metabolic surgery works basically by making adjustments to the proximal and distal gut metabolic activities that resemble the action of natural selection in the development the digestive systems of superior animals.

RESUMO Introdução: A rede de questões fisiológicas envolvidas na cirurgia metabólica é muito complexa. No entanto, a anatomia e fisiologia comparadas podem fornecer boas pistas sobre como o trato digestivo é moldado para alimentos mais ou menos calóricos, para mais ou menos fibras, para abundância e escassez. Objetivo: Selecionar e analisar dados de Ciências Evolucionárias e Anatomia e Fisiologia Comparadas que ajudam na compreensão da cirurgia metabólica. Método: Revisão focada da literatura, selecionando informações desses três campos de conhecimento em bancos de dados da Cochrane Library, Medline e SciELO, artigos e capítulos de livros em inglês e português, entre 1950 e 2019, usando como descritores "GIP, GLP-1, PYY, type 2 diabetes, vertebrates digestive system, hominid evolution, obesity, bariatric surgery". Resultado: O trato digestivo de animais superiores mostra órgãos altamente especializados para digerir e absorver dietas específicas..A parte proximal, diante da escassez de açúcares, é basicamente dedicada à geração de açúcar a partir de diferentes substratos (gliconeogênese). As tarefas básicas do intestino proximal consistem em fornecer proporcionalmente açúcares livres, insulina e outros combustíveis e gerar elementos anabólicos no sangue, alguns deles obesogênicos. Limitar a ingestão pela saciedade, por diminuir o esvaziamento gástrico e limitar a elevação excessiva dos principais combustíveis (açúcar e gordura) no sangue são principalmente as tarefas metabólicas do intestino distal. Mudança rápida e profunda na composição da dieta humana causa elevação nas atividades endócrinas e metabólicas do intestino proximal e redução no intestino distal. Os modelos mais eficientes de cirurgia metabólica fazem ajustes nesse equilíbrio proximal-distal das atividades metabólicas intestinais. Conclusão: A cirurgia metabólica funciona basicamente fazendo ajustes nas atividades metabólicas do intestino proximal e distal que se assemelham à ação da seleção natural no desenvolvimento dos sistemas digestivos de animais superiores.

Retrovectors packaged in CHO cells to generate GLP-1-Fc stable expression CHO cell lines

Background: Chinese hamster ovary (CHO) cells are the most dependable mammalian cells for the production of recombinant proteins. Replication-incompetent retroviral vector (retrovector) is an efficient tool to generate stable cell lines. Multiple copies of integrated genes by retrovector transduction results in improved recombinant protein yield. HEK-293 and their genetic derivatives are principal cells for retrovector production. Retrovectors packaged in HEK-293 cells pose a risk of infectious agent transmission, such as viruses and mycoplasmas, from serum and packaging cells. Results: In this report, retrovectors were packaged in CHO cells cultured in chemically defined (CD) media. The retrovectors were then used to transduce CHO cells. This method can block potential transmission of infectious agents from serum and packaging cells. With this method, we generated glucagon-like protein-1 Fc fusion protein (GLP-1-Fc) stable expression CHO cell lines. Productivity of GLP-1-Fc can reach 3.15 g/L. The GLP-1-Fc protein produced by this method has comparable bioactivity to that of dulaglutide (Trulicity). These stable cell lines retain 95­100% of productivity after 40 days of continuous culture (~48­56 generations). Conclusions: Suspension CHO cells are clean, safe, and reliable cells for retrovector packaging. Retrovectors packaged from this system could be used to generate CHO stable cell lines for recombinant protein expression.

Terapia complementaria a la insulina en el tratamiento de niños y adolescentes con diabetes mellitus tipo 1- (DM1) / Therapies complementaries to insulin in the treatment of children and adolescents with type 1 diabetes mellitus (T1DM)

La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.

Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.

La controvertida participación del GLP-1 en los mecanismos fisiológicos desencadenados tras cirugía bariátrica / The controversial participation of GLP-1 in the physiological mechanisms unchained after bariatric surgery

RESUMEN: Numerosas hipótesis se invocan para explicar el efecto beneficioso sobre el metabolismo glucídico tras la cirugía bariátrica. Algunos autores abogan por la secreción y liberación de distintas sustancias con funciones endocrinas (enterohormonas). Una de las sustancias más señaladas como efector, con efectos contrastados pero datos controvertidos, es el GLP-1. Nuestro estudio se realizó en ratas Wistar macho sanas, para evitar la ausencia de factores de confusión como son la DMT2 y la obesidad. Para conocer el mapa de adaptación a la secreción de GLP-1 tras la cirugía, se designaron 5 grupos: dos grupos control (de ayuno y de estrés quirúrgico); y tres grupos quirúrgicos (gastrectomía vertical, resección del 50 % del intestino medio y el Bypass gástrico con montaje en Y de Roux). Después de tres meses se estudiaron mediante técnicas inmunohistoquímicas el patrón de síntesis de GLP-1 en las distintas porciones del intestino delgado. También se estudió la expresión de los receptores de membrana en las células de los islotes pancreáticos. Se observó la existencia de un significativo aumento del número de células secretoras en íleon, duodeno y yeyuno en los grupos quirúrgicos de técnicas mixtas (RYGB) y malabsortivas (RI50). Igualmente se observó una elevación de los receptores pancreáticos en las mismas técnicas frente a los controles. Nuestros datos indican que la secreción intestinal de GLP-1 y su sensibilidad a nivel pancreáticas están aumentada, como efecto adaptativo a la agresión mecánica del tubo y a la alteración del flujo de nutrientes tras la cirugía.

SUMMARY: Numerous hypotheses are invoked to explain the beneficial effect on glucose metabolism after bariatric surgery. Some authors advocate for the secretion and release of various substances with endocrine functions (enterohormones). One of the substances most marked as effector, with contrasting effects but controversial data, is Glucagon-like peptide-1 GLP-1. Our study was performed in healthy male Wistar rats, to avoid the absence of confounding factors such as DMT2 and obesity. In order to know the map of adaptation to GLP-1 secretion after surgery, five groups were designated: Two control groups (fasting and surgical stress); and three surgical groups (vertical sleeve gastrectomy, 50 % midgut resection and Roux-en-Y gastric bypass). After three months, the GLP-1 synthesis pattern was studied by immunohistochemical techniques in the different portions of the small digestive tract. The expression of membrane receptors in pancreatic islet cells was also studied. There was a significant increase in the number of secretory cells in ileum, duodenum and jejunum in mixed surgical (RYGB) and malabsorptive (RI50) groups. An elevation of pancreatic receptors was also observed in the same techniques against controls. Our data indicated that intestinal secretion of GLP1 and its sensitivity to the pancreatic level were increased, both to an adaptive effect to the mechanical aggression of the digestive tube and to the alteration of nutrient flow after surgery.

A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans

Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.

The Role of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Reducing Cardiovascular Events in Patients with Type 2 Diabetes

The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.

2019 Clinical Practice Guidelines for Type 2 Diabetes Mellitus in Korea

The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the 6th Clinical Practice Guidelines in 2019. Targets of glycemic, blood pressure, and lipid control in type 2 diabetes mellitus (T2DM) were updated. The obese and overweight population is increasing steadily in Korea, and half of the Koreans with diabetes are obese. Evidence-based recommendations for weight-loss therapy for obesity management as treatment for hyperglycemia in T2DM were provided. In addition, evidence from large clinical studies assessing cardiovascular outcomes following the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with T2DM were incorporated into the recommendations.

Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials

BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Factors Related to Blood Intact Incretin Levels in Patients with Type 2 Diabetes Mellitus

BACKGROUND: We performed this study to identify factors related to intact incretin levels in patients with type 2 diabetes mellitus (T2DM). METHODS: We cross-sectionally analyzed 336 patients with T2DM. Intact glucagon-like peptide 1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 minutes after ingestion of a standard mixed meal. The differences between 30 and 0 minute iGLP-1 and iGIP levels were indicated as ΔiGLP-1 and ΔiGIP. RESULTS: In simple correlation analyses, fasting iGLP-1 was positively correlated with glucose, C-peptide, creatinine, and triglyceride levels, and negatively correlated with estimated glomerular filtration rate. ΔiGLP-1 was positively correlated only with ΔC-peptide levels. Fasting iGIP showed positive correlations with glycosylated hemoglobin (HbA1c) and fasting glucose levels, and negative correlations with ΔC-peptide levels. ΔiGIP was negatively correlated with diabetes duration and HbA1c levels, and positively correlated with Δglucose and ΔC-peptide levels. In multivariate analyses adjusting for age, sex, and covariates, fasting iGLP-1 levels were significantly related to fasting glucose levels, ΔiGLP-1 levels were positively related to ΔC-peptide levels, fasting iGIP levels were related to fasting C-peptide levels, and ΔiGIP levels were positively related to ΔC-peptide and Δglucose levels. CONCLUSION: Taken together, intact incretin levels are primarily related to C-peptide and glucose levels. This result suggests that glycemia and insulin secretion are the main factors associated with intact incretin levels in T2DM patients.

Effects of Thiazolidinedione and New Antidiabetic Agents on Stroke / 대한뇌졸중학회지

Patients with hyperglycemia are at a high risk of cardio- and cerebrovascular diseases. Diabetes patients also have poor outcomes after cerebrovascular disease development. Several classes of drugs are used for diabetes management in clinical practice. Thiazolidinedione (TZD) was introduced in the late 1990s, and new antidiabetic agents have been introduced since 2000. After issues with rosiglitazone in 2007, the U.S. Food and Drug Administration strongly recommended that trials investigating cardiovascular risk associated with new antidiabetic medications should be conducted before drug approval in the United States, to prove the safety of these new drugs and to determine their superiority to previous medications. Currently, results are available from two studies with TZD focusing on cardiovascular diseases, including stroke, and from 12 cardiovascular outcome trials focusing on major adverse cardiovascular events associated with new antidiabetic agents (four with dipeptidyl peptidase-4 inhibitors, three with sodium-glucose cotransporter-2 inhibitors, and five with glucagon-like peptide-1 analogues). These studies showed different results for primary cardiovascular outcomes and stroke prevention. It is important to determine whether prescription of TZD or new antidiabetic medications compared to conventional treatment, such as sulfonylurea or insulin, is better for stroke management. Furthermore, it is unclear whether drugs in the same class show greater safety and efficacy than other drugs for stroke management.

Premeal Consumption of a Protein-Enriched, Dietary Fiber-Fortified Bar Decreases Total Energy Intake in Healthy Individuals

BACKGROUND: A premeal load of protein can increase satiety and reduce energy intake. Dietary fiber also conveys metabolic benefits by modulating energy intake. We made a protein-enriched, dietary fiber-fortified bar (PFB) and aimed to investigate its effects on food intake and gut hormone secretion in healthy individuals.METHODS: Twenty subjects with normal glucose tolerance were enrolled. On three separate visits, the subjects received, in a randomized order, one of the following: a PFB containing 73 kcal with 10.7 g of protein and 12.7 g of dietary fiber; a usual bar (UB) containing the same calories as the PFB but only 0.9 g of protein and no dietary fiber; or water (control). After 15 minutes, the subjects had ad libitum intake of a test meal. Food consumption, appetite, and plasma gut hormone levels were measured.RESULTS: Total energy intake, including the bar and the test meal, was significantly reduced with the PFB preload compared to the water (904.4±534.9 kcal vs. 1,075.0±508.0 kcal, P=0.016). With the UB preload, only the intake of the test meal was reduced (P=0.044) but not the total energy intake (P=0.471) than the water. Fullness was also significantly increased after the PFB. In addition, postprandial glucose levels decreased and glucagon-like peptide-1 levels increased with the PFB compared with both the UB and water.CONCLUSION: In healthy individuals, a premeal supplementation of PFB reduced total energy intake and decreased postprandial glucose excursion. This finding necessitates long-term studies regarding clinical use in obesity.

Downregulation of IL-18 Expression in the Gut by Metformin-induced Gut Microbiota Modulation

IL-18 is a crucial pro-inflammatory cytokine that mediates chronic intestinal inflammation. Metformin, an anti-diabetic drug, was reported to have ameliorative effects on inflammatory bowel disease. Recently, the mechanism of action of metformin was explained as a modulation of gut microbiota. In this study, fecal microbiota transplantation (FMT) using fecal material from metformin-treated mice was found to upregulate the expression of GLP-1 and pattern-recognition receptors TLR1 and TLR4 for the improvement in hyperglycemia caused by a high-fat diet. Further, FMT downregulated the expression of the inflammatory cytokine IL-18. Within the genera Akkermansia, Bacteroides, and Butyricimonas, which were promoted by metformin therapy, Butyricimonas was found to be consistently abundant following FMT. Our findings suggest that modulation of gut microbiota is a key factor for the anti-inflammatory effects of metformin which is used for the treatment of hyperglycemia.

Oral Hypoglycemic Agents for Patients with Type 2 Diabetes Mellitus / 임상당뇨병

For patients with newly diagnosed type 2 diabetes mellitus (T2DM), lifestyle modifications including medical nutrition therapy, weight control, physical activity, smoking cessation, and avoidance of alcohol abuse should be initiated. Metformin must be considered as the first-line oral glucose-lowering therapy, but other drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones, glucagon-like peptide 1 receptor agonists, sulfonylureas, glinides, α-glucosidase inhibitors, and insulin can be considered based on patient circumstances. If the initial HbA1c level of a patient is ≥ 7.5% or the HbA1c target is not achieved within three months of initiating monotherapy, dual combination therapy can be considered. If the HbA1c target is not achieved within 3 months of initiating dual therapy, a third agent with a complementary mechanism of action can be added for triple combination therapy. In addition, evidence from large clinical studies assessing cardiovascular outcomes following the use of SGLT-2 inhibitors in T2DM patients with cardiovascular risk factors have been incorporated into the updated recommendations.

Injectable Therapy for Diabetes Mellitus: Glucagon-Like Peptide-1 Receptor Agonist / 임상당뇨병

According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes guideline for treatment of diabetes, glucagon-like peptide-1 receptor agonist (GLP-1 RA) is recommended in diabetic patients with established atherosclerotic cardiovascular disease. This recommendation is based on the results of recent cardiovascular outcome trials of this kind of medications. GLP-1 RAs have a glucose lowering effect with weight loss and a lower incidence of hypoglycemia, and can improve cardiovascular outcomes such as three-point major cardiovascular events composed of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke. Also, several GLP-1 RAs have beneficial effects on renal outcomes, mainly due to improvement in macroalbuminuria. In addition, high-dose liraglutide (3 mg/day subcutaneous injection) showed efficacy for reducing body weight. Therefore GLP-1 RA may be effective in patients with established cardiovascular disease, chronic kidney disease, and/or metabolic syndrome.

Saxenda® Frenzy: Opinions of an Endocrine and Metabolism Specialist / 임상당뇨병

Globally, the problem of obesity is increasing, and the prevalence of obesity in Korea is also rising rapidly. Obesity is a risk factor for cardiometabolic diseases including type 2 diabetes mellitus, hypertension, cardiovascular disease, and some types of cancer. Therefore, prevention of various metabolic diseases or symptom relief through effective treatment of obesity is a very important problem. According to the obesity guidelines of the Obesity Society of Korea in 2018, obesity medication is recommended for patients with a body mass index (BMI) of 30 kg/m² or more or a BMI of 27 kg/m² or more, and one or more obesity accompanying diseases (type 2 diabetes, hypertension, dyslipidemia). In this case, it is recommended that the basic treatment for obesity (diet, exercise, and behavior therapy) should be performed in parallel with Saxenda® treatment. The glucagon-like peptide 1 analogue, Saxenda®, has been validated as a long-term effective and safe treatment for obesity, and is expected to be a promising drug for the treatment of obesity and the prevention of pre-diabetes in the future. However, in Korea, where non-standard obesity treatments are widely practiced, it is necessary to improve the health of obese patients by being treated with Saxenda® along with diet, exercise and behavior therapy.

Management of Hyperglycemia in Type 2 Diabetes: A Summary of New Consensus Report from the American Diabetes Association and the European Association for the Study of Diabetes in 2018 / 임상당뇨병

In 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a consensus recommendation on management of hyperglycemia. This consensus report emphasized the need for patient-centered management considering multimorbidity and individual patient preferences and barriers. Patients with type 2 diabetes with established atherosclerotic cardiovascular disease who fail to control blood glucose with the initial glucose-lowering medication are recommended a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist. For patients with chronic kidney disease and heart failure, SGLT2 inhibitors are recommended. In patients who need an injectable medication, GLP-1 receptor agonists are the preferred choice over insulin. In this section, we summarize “Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).”

Rol del enterocito en la dislipidemia de la diabetes mellitus tipo 2 / Role of the enterocyte in type 2 diabetes mellitus associated dyslipidemia

En la diabetes mellitus tipo 2 el aumento en la producción de quilomicrón en el estado post-prandial se asocia a mayor riesgo cardiovascular. La evidencia actual posiciona al enterocito como actor principal en la dislipemia de la diabetes mellitus tipo 2 debido a que aumenta la producción de apolipoproteína B-48 en respuesta a una elevación de ácidos grasos libres y glucosa. El metabolismo del quilomicrón se encuentra regulado por múltiples factores independientes además de la ingesta de grasa alimentaria. Entre estos factores se destacan las hormonas intestinales, como el péptido similar al glucagón tipo 1 que disminuye la producción de apolipoproteína B-48 y el péptido similar al glucagón tipo 2 que la aumenta. Por otro lado, la insulina inhibe de forma aguda la producción de quilomicrón en el sujeto sano mientras que en la diabetes mellitus tipo 2, este efecto está ausente. La comprensión de los factores reguladores emergentes de la secreción de quilomicrón permite vislumbrar nuevos mecanismos de control en su metabolismo y aportar estrategias terapéuticas focalizadas en la hiperlipidemia posprandial en la diabetes mellitus tipo 2 con la reducción del riesgo cardiovascular.

In type 2 diabetes mellitus there is an overproduction of chylomicron in the postprandial state that is associated with increased cardiovascular risk. Current evidence points out a leading role of enterocyte in dyslipidemia of type 2 diabetes mellitus, since it increases the production of apolipoprotein B-48 in response to a raise in plasma free fatty acids and glucose. The chylomicron metabolism is regulated by many factors apart from ingested fat, including hormonal and metabolic elements. More recently, studies about the role of gut hormones, have demonstrated that glucagon-like peptide-1 decreases the production of apolipoprotein B-48 and glucagon-like peptide-2 enhances it. Insulin acutely inhibits intestinal chylomicron production in healthy humans, whereas this acute inhibitory effect on apolipoprotein B-48 production is blunted in type 2 diabetes mellitus. Understanding these emerging regulators of intestinal chylomicron secretion may offer new mechanisms of control for its metabolism and provide novel therapeutic strategies focalized in type 2 diabetes mellitus postprandial hyperlipidemia with the reduction of cardiovascular disease risk.