SLR - February 2021 - Aleksey Kozlov

Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes

Reference: Hanssen NMJ, Teraa M, Scheijen JLJM, Van de Waarenburg M, Gremmels H, Stehouwer CDA, Verhaar MC, Schalkwijk CG. Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes. Diabetes Care 2021 Jan; 44(1): 157-163

Level of Evidence: Level III

Scientific Literature Review 

Reviewed By: Aleksey Kozlov, DPM
Residency Program: Highlands/Presbyterian St. Luke's Medical Center – Denver, CO

Podiatric Relevance: Podiatric surgeons play an essential role in the multi-disciplinary approach to caring for patients with peripheral arterial disease. Understanding the pathophysiology and associated diagnostic markers can help improve outcomes for patients with advanced stage vascular disease. This article investigates whether plasma levels of Methylglyoxal (MGO) and its associated metabolic derivatives corelate with amputation and mortality rates in diabetic and non-diabetic cohorts with severe limb ischemia (SLI). Establishing potential biomarkers related to a disease process allows physicians to have more informative interactions with patients and lays the groundwork for potential targeted therapies in the future. 

Methods: Data on 160 patients with no-option SLI were retrospectively assessed from the JUVENTAS trial. Inclusion criteria consisted of having severe infrapopliteal atherosclerosis (Fontaine grade IIB–IV) and ineligibility for surgical intervention. Plasma levels of MGO, free advanced glycation end products (AGEs) and MGO’s natural detoxification product D-lactate were measured with ultraperformance liquid chromatography–tandem mass spectrometry at baseline. Secondary baseline lab values including CRP, IL-6, and circulating WBCs/ thrombocytes were utilized for correlation analysis. Adverse outcomes data (amputation and/or death) was recorded for the cohort and analyzed in light of baseline plasma marker levels. Data was processed via linear and Cox regression and was adjusted for variables including sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. 

Results: Higher plasma MGO levels were associated with more adverse outcomes in both diabetic and non-diabetic patients (relative risk 1.44), more amputations (relative risk 1.55) and greater mortality (relative risk 1.28). Increased levels of MGO were found to be associated with higher average CRP and IL-6 levels, higher neutrophil, monocyte, and thrombocyte counts, and lower circulating BM progenitor cells. N-(carboxyethyl) lysine (an MGO-derived AGE) was also associated with more adverse outcomes (relative risk 1.46) and amputations (relative risk 1.71). D-Lactate was not found to be associated with adverse incident outcomes. 

Conclusions: The authors concluded that plasma MGO levels are associated with adverse outcomes in patients with SLI. Elevated levels of MGO corelate with a variety of physiological manifestations including dysregulation of inflammatory pathways, prolonged hyperglycemia, and increased oxidative stress. The identification of biomarkers associated with poor outcomes is essential in further characterization of disease models and is a key first step to the development of treatment modalities. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI cohorts. This study can be strengthened by increasing population size and through utilization of a prospective study design.

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