Plasma methylglyoxal levels are associated with amputations and mortality in severe limb ischemia patients with and without diabetes

<b>Introduction</b> <p>Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation endproducts (AGEs) and potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI.</p> <p><b>Methods</b> <b></b></p> <p>We measured plasma levels of MGO, free AGEs, and D-lactate, the detoxification endproduct of MGO, with ultra-performance liquid chromatography tandem mass spectrometry at baseline in 160 patients (64.8±13.3years, 67.5% male, 37.5% diabetes) with no-option SLI and recorded major adverse outcomes (n=86, containing death n=53 or amputations n=49 (First event counted)) over 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, eGFR, systolic blood pressure, cholesterol levels and BMI. Associations are reported per 1SD plasma marker. </p> <p><b>Results</b></p> <p>Higher plasma MGO levels were associated with more adverse outcomes (RR: 1.44; 95%CI: 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar, but weaker trend for mortality (1.28; 0.93-1.77). The MGO derived AGE N^ε-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). D-lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells. </p> <p><b>Conclusion</b></p> <p>Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.<br> </p>