Incretin Therapy and Heart Failure

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp large bowel, and glucose-dependent insulinotropic polypeptide (GIP), which is derived from the K cells of the proximal small intestine. GLP-1 and GIP are glucose-lowering agents that can interfere with postprandial hyperglycemia, which has been demonstrated as associated with cardiovascular complications. The biologically active forms of GLP-1 include GLP-1(7-37) and GLP-1(7-36)amide. These peptides arise from the selective cleavage of the proglucagon molecule. GLP-1(7-36)amide is abundant in the circulation after meals and stimulates insulin secretion by interacting with the GLP-1 receptors on pancreatic beta cells. DPP-4 degrades GLP-1(7-36)amide to inactive GLP-1(9-36)amide, and DPP-4 inhibitors bind to DPP-4 to prevent the breakdown of GLP-1 and GIP, 5 thereby increasing the half-life and bioavailability of active incretins, ultimately enhancing their physiological effects. GLP-1(7-36)amide has been widely studied for its role as an active incretin and is referred to as GLP-1, unless otherwise specified. GLP-1(9-36) amide is thought to be an inactive metabolite because of its 1,000-fold lower affinity for GLP-1R and action as a weak competitive antagonist without incretin activity at pharmacological doses. However, GLP-1(9-36)amide may have potent effects on the cardiovascular system, similar to GLP-1(7-36) amide. Although it remains controversial, GLP-1 may undergo multiple cycles of enzymatic degradation by DPP-4 and neprilysin. Therefore, the precise biological pathways of GLP-1 and related enzymes and the roles of metabolites in each step of the process in vivo need to be elucidated in the near future. Effects of Incretins on Cardiac FunctionCardiomyocytes in Vitro GLP-1 rapidly increases the 3'-5'-cyclic adenosine monophosphate (cAMP) levels in adult rat ventricular cardiac myocytes, consistent with its effect on pancreatic beta cells, in a manner ype 2 diabetes (T2DM) is one of the most important risk factors for the development of cardiovascular disease, as it promotes both systemic atherosclerosis and lifestyle-associated diseases. Incretin-based therapies, including treatment with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase (DPP)-4 inhibitors, have become widely used as a new class of antidiabetic drugs that exhibit different mechanisms of action from those of conventional antidiabetic agents. Incretin hormones depend on blood glucose to stimulate insulin. Because the use of DPP-4 inhibitors is associated with a lower incidence of hypoglycemia than is observed with conventional hypoglycemic drugs, they potentially improve the mortality rate of patients with T2DM by achieving strict glycemic control without causing fatal hypoglycemia. The GLP-1R has been detected in coronary endothelial cells, coronary smooth muscle cells, cardiomyocytes and human umbilical vein endothelial cells, as well as monocytes and macrophages. 1-4 Interestingly, GLP-1 acts on multiple organ...

Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis

“…3,17,20 We, thus, measured changes in cAMP concentrations in each mouse heart ( Figure 2B). We found a trend similar to that observed with circulating GLP-1 levels; specifically, the myocardial cAMP concentrations were reduced in TAC-CON, and this decline was prevented by ALO.…”

“…1 To date, ample preclinical evidence has demonstrated the pleiotropic effects of DPP4i and GLP-1 analogs on the cardiovascular protection, 2,3 including heart failure (HF). [4][5][6][7] Recent clinical evidence exploring the effect of DPP4i on cardiovascular safety in patients with type 2 diabetes mellitus reported that saxagliptin increased the incidence of hospitalization for HF via unknown mechanisms.…”

Type 2 Diabetes and Cardiovascular Complications: Is It Possible to Improve Prognosis by Glucose Lowering Therapy?

“…Одним из важных доводов в пользу переключения внимания на препараты этой группы является то, что они напрямую реализуют инсулинрегулирующую функцию и лишены некоторых системных эффектов, свойственных ингибиторам ДПП-4, гемодинамическая значимость которых остается неопределенной [42].…”

Heart failure in SAVOR‐TIMI 53: The hindsight of diabetic retinopathySAVOR‐TIMI 53研究中的心脏衰竭：糖尿病视网膜病变的后尘

“…Hypothesizing possible mechanisms that may have contributed to the increased likelihood of hospitalization for heart failure, some investigators have focused on a range of non‐incretin proteins that, like GLP‐1, are also degraded by DPP‐4 . However, although increased activity of certain DPP‐4 substrates, such as substance P and neuropeptide Y, may be detrimental, others may be beneficial so that the totality of effects remains speculative.…”

“…有一些研究者对DPP‐4抑制剂增加心脏衰竭住院风险的可能机制进行了假设，他们已经开始聚焦于对一系列非肠促胰素蛋白的研究，就像GLP‐1一样，它们也能够被DPP‐4所降解 12,13 。然而，虽然DPP‐4的某一个底物活性增加了，例如P物质与神经肽Y，它们可能是有害的，但是其他底物却可能是有益的，因此总体效应仍然有待推测。或者，这既不是一种GLP‐1效应也不是一种DPP‐4的非肠促胰岛素底物的作用结果，关键还是血糖本身的问题。在胰岛素抵抗的环境下葡萄糖转运体GLUT4活性下降的结果是 14 ，葡萄糖，心肌细胞应激的首选底物，在衰竭的糖尿病心脏中急需的转运更少了 15 。因此，作为血糖降低的结果，跨膜葡萄糖浓度梯度下降以后可能导致心肌细胞收缩以及舒张活跃期所需要的能量供应进一步地减少。然而，随着时间的过去，适应这些过程后，例如随着钠‐葡萄糖共转运体1（SGLT‐1）表达的增加，理论上这些变化将会减轻 16 。…”