Controlled-ileal-release nicotinic acid (CIR-NA) for a targeted gut microbiome interventionfor remission of prediabetes

肠道微生物群的变化与肥胖和2型糖尿病（T2DM）等西方常见疾病有关。因此，肠道微生物组代表了创新代谢疗法的新目标。然而，与SGLT2抑制剂和GLP1类似物等新型糖尿病药物相比，微生物组的治疗效果应该相当温和，因此不太可能作为糖尿病药物使用。相比之下，微生物组可能对代谢紊乱相当轻微的糖尿病前期患者特别感兴趣，并且经典药物在德国未获批准。此外，糖尿病预防计划（DPP）的随访分析表明，糖尿病前期受试者发生糖尿病微血管并发症的风险已经增加。此外，前驱糖尿病非常常见（2035年全球估计有5亿人），并且转化为明显的2型糖尿病非常常见（年转化率为5-10%），这表明这种疾病前期是创新微生物组治疗的理想靶点。在过去的动物实验和人体研究中，我们的团队开发了一种使用微胶囊烟酸的微生物组干预方法，这种方法既可以诱导微生物组的变化，也可以改善全身胰岛素敏感性。因此，微胶囊化过程抑制了上消化道的全身吸收（以避免潮红等副作用），并将烟酸输送到大多数微生物群集中的回肠末端/结肠（=控制回肠释放）。在过去，我们在人类受试者中进行了为期6周的概念验证研究，显示了治疗对肠道微生物组和肝脏和骨骼肌的全身胰岛素敏感性的有益影响。这项概念验证研究反映了拟议干预试验的合理性。拟议的干预试验的目的是在520名受试者中检查控制回肠释放烟酸（cirr - na）治疗是否能够诱导前驱糖尿病的缓解（=主要终点）。为此，三个不同的干预组（100mg， 200mg和500mg cirr - na）将在德国三个不同的中心进行为期6个月的时间内与安慰剂组（每个组130名糖尿病前期受试者）进行比较。

Changes in the gut microbiome are associated with common western-world diseases like obesity and type 2 diabetes mellitus (T2DM). The gut microbiome therefore represents a novel target for innovative metabolic therapies. However, compared to novel Diabetes medications like SGLT2 Inhibitors and GLP1 analogues, therapeutic effects of the microbiome are supposed to be rather mild making usage as a diabetic drug unlikely. In contrast, microbiome might be of special interest for prediabetic patients in which the metabolic disturbances are rather mild and for which classical pharmacological agents are not approved in Germany. Furthermore, the Diabetes Prevention Program (DPP) follow-up analysis has shown that the risk for the development of diabetic microvascular complications is already increased in subjects with prediabetes. In addition, prediabetes is very common (in 2035 estimated ½ Billion worldwide), and transformation into manifest type 2 diabetes is very common (annual conversion rate 5-10%), suggesting this pre-disease to be an ideal target for an innovative microbiome-based therapy.In the past using animal experiments and human studies our group has developed a microbiome intervention using microencapsulated niacin, which is able to induce both, changes in the microbiome as well as improvement of systemic insulin sensitivity. The microencapsulation procedure thereby inhibits systemic resorption in the upper GI tract (to avoid side effects like flushing) and delivers the niacin into the terminal ileum/colon, where most of the microbiota are localized (=controlled ileac release). In the past we performed a proof-of-concept study in human subjects in a period of 6 weeks showing beneficial effects of the treatment on gut microbiome and systemic insulin sensitivity of liver and skeletal muscle. This proof-of-concept study reflects the rational for the proposed intervention trial.The aim of the proposed intervention trial is to examine in 520 human subjects if treatment with controlled-ileac release nicotinic acid (CIR-NA) is able to induce a remission of prediabetes (=primary end-point). For that, 3 different intervention groups (100 mg, 200 mg and 500 mg CIR-NA) will be compared to a placebo group (130 prediabetic subjects each) in a time period of 6 month at 3 different centers in Germany.