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

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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.