Effects of saxagliptin on adipose tissue inflammation and vascular function in overweight and obese people: a placebo‐controlled study

AIMS: To test the effect of the dipeptidyl peptidase-4 inhibitor saxagliptin on adipose tissue inflammation and microvascular function, and whole-body postprandial endothelial function. METHODS: A randomized, double-blind, placebo-controlled, parallel study was conducted between June 2013 and November 2016 in 44 overweight or obese people without diabetes (saxagliptin, n=28; placebo, n=16). Subcutaneous abdominal adipose tissue biopsies, a 4-h fat-enriched meal test and peripheral arterial tonometry for measurement of endothelial function were performed at baseline and after 6 weeks of treatment with saxagliptin (5 mg/day) or matching placebo. RESULTS: Forty participants were analysed (saxagliptin, n=26; placebo, n=14). Secretion of interleukin-8 from adipose tissue explants was reduced after saxagliptin (median fold-change from baseline: 0.8 saxagliptin vs 3.3 placebo; P=0.02). Adipose tissue expression of thioredoxin-inhibitory protein (TxNIP) was lower after saxagliptin (0.75 vs 1.0; P=0.02), while there were no significant differences in adipose tissue secretion of interleukin-1b, interleukin-6 or macrophage chemoattractant protein 1 (MCP-1), adipose tissue macrophage content, adipose tissue mRNA levels of mcp1, cd36, cd68, il6, il8, txnip and adpq, and activation of adipose tissue inflammatory pathways [extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF- κB)] or insulin-induced vasodilation of adipose tissue arterioles. Postprandial plasma glucose was slightly lower (by an estimated 0.3 mmol/l; P=0.01), while postprandial insulin, triglyceride levels and endothelial function were unchanged after saxagliptin. CONCLUSIONS: The effect of saxagliptin on adipose tissue inflammation was relatively modest, with many inflammatory markers unchanged. We also found no evidence that saxagliptin therapy improved adipose tissue arteriole vasodilation or postprandial endothelial function.