Modulation of circulating osteocalcin-expressing monocytes by glucagon like peptide-1 receptor agonists in type 2...

The phenotypic drift of circulating monocytes toward osteoblast-like cells expressing osteocalcin (OCN) has been linked to vascular calcification in individuals with type 2 diabetes (T2D). The synergistic action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and metformin may reduce the cardiovascular risk by modulating OCN-expressing monocytes, representing a novel mechanism of cardiovascular protection.

To investigate the impact of GLP-1 RA add-on metformin therapy on the percentage of circulating CD14⁺OCN⁺ monocytes.

This longitudinal study enrolled patients with T2D receiving metformin monotherapy who either initiated GLP-1 RA therapy (Group A, n = 7) or did not (Group B, n = 28). Clinical parameters and circulating CD14+OCN+ cell levels were assessed at baseline (V0), after 1 week (V1) and after 12 weeks (V2). In vitro experiments were conducted using peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 10), treated with metformin or exendin-4 for 24 h.

In group A, the percentage of CD14+OCN+ significantly decreased from baseline (4.5 [2.5-7.6]) to V2 (2.2 [1.73-4.9]% p = 0.019). This reduction was already significant at V1 (p = 0.039). No significant change over time was observed in Group B (p = 0.31). In vitro treatment of PBMCs with metformin significantly reduced the percentage of CD14⁺OCN⁺ cell (- 34.9%, p < 0.0001), whereas exendin-4 yielded a non-significant downward trend (- 8.5%, p = 0.1).

GLP-1 RA add-on therapy to metformin reduces OCN expression in circulating monocytes in patients with T2D. In vitro data suggest that this effect might not result from a direct effect on mononuclear cells, but rather from indirect systemic mechanisms that warrant further investigation. These findings identify OCN-expressing monocytes as a potential novel therapeutic target for GLP-1 RA to reduce cardiovascular risk in T2D.