Effect of Linagliptin on Vascular Function: A Randomized, Placebo-controlled Study

Abstract

Context: The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans.

Objective: This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function.

Design and setting: This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base.

Patients and intervention: Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo.

Main outcome measures: Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified.

Results: Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo.

Conclusions: This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.

Trial registration: ClinicalTrials.gov NCT01969084.

Figures

Figure 1.

Scheme of the clinical trial. T2DM, type 2 diabetes mellitus. *, Withdrew due to unrelated serious adverse event.

Figure 2.

Changes in (A) IL-6, (B) IFNγ, (C) IL-12 (p70), and (D) MIP-1a following a 12-week treatment period with linagliptin compared with treatment with the placebo.