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How incretin-based therapies address the spectrum of physiologic disturbance in type 2 diabetes

机译：基于肠降血糖素的疗法如何解决2型糖尿病的生理障碍

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Blood glucose-lowering agents that exert their therapeutic effect through the incretin hormone system are emerging as effective and well-tolerated therapies for type 2 diabetes. Due to their glucose-dependent mode of action these agents are associated with minimal hypoglycemic risk, and do not cause weight gain, thus avoiding limitations associated with many existing treatments that may threaten treatment adherence. Of the two classes of incretin therapies currently available, the GLP-1 receptor agonists have shown the ability to decrease HbA1c to a greater extent than DPP-4 inhibitors, and GLP-1 agonists may also reduce cardiovascular risk through modification of certain known risk factors, including via weight loss. This article explains the rationale behind using incretin-based therapies, summarizes key data from clinical trials of the GLP-1 agonists exenatide and liraglutide, and licensed DPP-4 inhibitors including sitagliptin and saxagliptin, and provides practical guidance on the use of these agents in clinical practice. Introduction Diabetes mellitus is currently a foremost public health concern, with the most recent data indicating that 23.6 million people in the United States (7.8% of the population) have a diagnosis of diabetes (1). Despite continuous advances in treatment, approximately 44% of patients in 2003–2004 were still failing to reach the hemoglobin A1c (HbA1c) target of <7% currently recommended by the American Diabetes Association (2,3).Despite the wide range of treatment options available, a solution to the inevitable decline in beta cell function that underpins the progression of type 2 diabetes remains elusive, and treatment intensification, including the addition of insulin, becomes necessary in many patients (4). While insulin is essential in patients with insufficient beta cell reserve, its use is associated with increased risk of hypoglycemia and weight gain, both of which can reduce treatment adherence (5,6). Despite the fact that weight gain itself is a recognized risk factor for type 2 diabetes, emphasis on weight management is often trumped by the need to prioritize glycemic control. Importantly however, weight loss of just 5–10% can reduce HbA1c by 0.5% (7). Since weight loss can improve glycemic control, reduce cardiovascular risk and reduce the use of medications (8), it remains an essential goal of treatment. The ideal diabetes treatment would therefore provide effective, sustained glycemic control with negligible risk of hypoglycemia, while improving cardiovascular risk and avoiding weight gain. The crowning glory would be the ability to modify the disease trajectory by forestalling the decline in beta cell mass. With these concerns in mind, incretin-based therapies offer a practical strategy for glucose control, with many associated metabolic benefits, for patients with sufficient beta cell reserve. The physiology of the incretin systemInsulin secretion is greater following oral glucose intake than after an intravenous glucose bolus (the incretin effect) (Figure 1; 9,10), an effect mediated by incretin hormones that may be responsible for up to 70% of the insulin response to a meal (9).
机译：通过肠降血糖素激素系统发挥治疗作用的降血糖药正在成为2型糖尿病的有效且耐受性良好的疗法。由于它们的葡萄糖依赖性作用方式，这些药物与最小的降血糖风险相关，并且不会引起体重增加，从而避免了与许多可能威胁治疗依从性的现有治疗方法相关的局限性。在目前可用的两类肠降血糖素疗法中，与DPP-4抑制剂相比，GLP-1受体激动剂具有降低HbA1c的能力，并且GLP-1激动剂还可通过改变某些已知的危险因素来降低心血管疾病的风险。 ，包括减肥。本文解释了使用基于降钙素的疗法的基本原理，总结了GLP-1激动剂艾塞那肽和利拉鲁肽以及许可的DPP-4抑制剂（包括西他列汀和沙格列汀）的临床试验中的关键数据，并提供了在这些药物中使用这些药物的实用指导临床实践。简介当前，糖尿病是最重要的公共卫生问题，最新数据表明，美国有2360万人（占人口的7.8％）患有糖尿病（1）。尽管治疗取得了持续的进步，但2003-2004年约有44％的患者仍未能达到美国糖尿病协会目前推荐的<7％的血红蛋白A1c（HbA1c）目标（2,3）。尽管治疗范围广泛有多种选择可供选择，解决导致2型糖尿病进展的β细胞功能不可避免下降的解决方案仍然遥遥无期，在许多患者中必须加强治疗，包括添加胰岛素（4）。虽然胰岛素对于β细胞储备不足的患者必不可少，但使用胰岛素会降低低血糖和体重增加的风险，这两者都会降低治疗依从性（5,6）。尽管体重增加本身是2型糖尿病的公认危险因素，但重视血糖控制常常被优先考虑血糖控制的需求所压倒。但是重要的是，仅体重减轻5-10％即可将HbA1c降低0.5％（7）。由于减肥可以改善血糖控制，降低心血管风险并减少药物的使用（8），因此它仍然是治疗的基本目标。因此，理想的糖尿病治疗将提供有效，持续的血糖控制，低血糖风险可忽略不计，同时改善心血管疾病风险并避免体重增加。最重要的荣耀将是通过阻止β细胞质量下降来改变疾病轨迹的能力。考虑到这些问题，基于肠降血糖素的疗法为具有充足β细胞储备的患者提供了一种控制血糖的实用策略，具有许多相关的代谢益处。肠降血糖素系统的生理学口服葡萄糖摄入后，胰岛素分泌比静脉推注葡萄糖后更大（胰岛素降血糖素作用）（图1; 9，10），这是由肠降血糖素激素介导的，可能占70％的胰岛素分泌。餐后胰岛素反应（9）。

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