Michelle van Oeteren¹, Petra Niessen¹, Jean Scheijen¹, Marjo van de Waarenburg¹, Tos Berendschot², Alfons Houben¹, Martijn Brouwers³, Casper Schalkwijk¹

1. Laboratory for Metabolism and Vascular Medicine, Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. 2. University Eye Clinic Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands 3. Division of Endocrinology and Metabolic Diseases, Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. michelle.vanoeteren@maastrichtuniversity.nl

Microvascular disease (MVD) remains a major burden in type 2 diabetes (T2D), even in individuals with adequate glycemic control. Methylglyoxal (MGO), a reactive byproduct of glycolysis, is increased in diabetes and has been implicated as a mediator of MVD. Pyridoxamine, a MGO scavenger, has previously been demonstrated to prevent the development of endothelial dysfunction in rodents and to reduce vascular inflammation in individuals with obesity. Here, we investigated whether pyridoxamine supplementation improves microvascular outcomes in individuals with T2D and MVD.

Forty adults with T2D and MVD, i.e. diabetic retinopathy, neuropathy, or nephropathy (eGFR <60ml/min/1.73m² or albumin-creatinine ratio >3mg/mmol), were assigned to receive either pyridoxamine (300 mg/day) or placebo for 8 weeks, followed by a 4-week washout and crossover to the alternate treatment. Compliance was evaluated by measuring pyridoxamine metabolites in plasma. We measured perfusion density of the superficial and deep retinal capillary plexus (SVP and DCP, respectively) and assessed vascular inflammation by plasma levels of soluble intercellular and vascular adhesion molecule-1 (sICAM-1 and sVCAM-1, respectively). Plasma MGO levels, HbA1c, and the C-peptidogenic index during an OGTT were evaluated as secondary outcomes. Treatment effects were analyzed with paired-samples t-test.

Thirty-eight participants completed the study protocol. Two individuals were excluded from the analyses due to non-compliance (final population n=36, mean age 69±7yrs, 86% male, average T2D duration 15±8yrs). Pyridoxamine significantly increased perfusion density in the SVP (+4.4%, 95%CI 0.4;7.5) and the DCP (+4.1%, 95%CI 1.2;6.8) compared to placebo. Furthermore, in comparison with placebo, pyridoxamine significantly reduced sICAM-1 levels (-21.1 ng/ml, 95%CI -44.1;-1.5) and numerically, but not significantly lowered sVCAM-1 levels (-18.5 ng/ml, 95%CI -42.0;3.8). No significant effects were observed for HbA1c, MGO levels, or the C-peptidogenic index.

Eight-week pyridoxamine supplementation significantly improved retinal vessel perfusion density and attenuated vascular inflammation in individuals with T2D and established MVD, independent of glucose homeostasis.