The Effect of Saxagliptin on Adipose Tissue Inflammation in Overweight and Obese Nondiabetic Subjects

Inflammation plays a crucial role in early stages of both insulin resistance and atherosclerosis development. Preclinical evidence suggests an important role for DPP-4 in the regulation of adipose tissue (AT) inflammation. The present study tests the hypothesis that DPP-4 inhibition by saxagliptin reduces adipose tissue inflammation independent of changes in glucose metabolism. Forty-four overweight or obese individuals without diabetes were randomized to receive once daily saxagliptin (5 mg) or matching placebo (2:1 randomization) for 6 weeks. Adipose tissue biopsies, 4 hour fat-enriched meal challenge tests, and endothelial function measurement were performed at baseline and at the end of each treatment. Forty-two participants completed the study (27 saxagliptin/15 placebo). There were no group differences in the AT expression of inflammation-related genes (MCP-1, CD36, CD68, IL-6, IL-8, TxNIP and adiponectin) and protein pathway activation (ERK, JNK and NFκB). Secretion of IL-8 from adipose tissue explants was reduced after saxagliptin compared to placebo (median fold-baseline 0.8 saxagliptin vs. 2.3 placebo, p=0.01) and there was also a trend for reduced IL-6 release (0.7 vs. 1.5, p=0.06). After the high-fat meal, plasma glucose was slightly lower after saxagliptin (4 hour AUC, 0.96 vs. 1.0, p=0.04) while insulin and triglycerides were similar between the two groups. There were no treatment differences in endothelial function.

In conclusion, reduced AT secretion of IL-8 and IL-6 (trend) in obese nondiabetic subjects suggests saxagliptin may directly reduce AT inflammation. However, this effect was relatively modest, with many other indicators of tissue inflammation remaining unchanged. The reduction in AT inflammation did not appear sufficiently potent to influence postprandial metabolism or endothelial function.