Effect of Creatine and Guanidinoacetate Supplementation on Plasma Homocysteine in Metabolically Healthy Men and Women

Dear Editor,

Hyperhomocysteinemia is an independent risk indicator for several cardiometabolic diseases [1]. A number of nutritional factors, including protein malnutrition and consumption of certain food compounds, can lead to variations in homocysteine levels [2], stressing the role of diet in the homeostasis of this non-proteinogenic α-amino acid. Creatine synthesis appears to be a critical metabolic determinant of homocysteine turnover [3], and dietary provision of creatine and guanidinoacetate (creatine precursor) might markedly affect circulating homocysteine. Interestingly, the net effect of pro- and anti-hyperhomocysteinemic dietary ingredients is rarely investigated, albeit their widespread occurrence in human nutrition. The present pilot trial prospectively tested the effects of medium-term coadministration of creatine and guanidinoacetate on plasma homocysteine levels among men and women without prior cardiometabolic disease.

Eight apparently healthy and hyperhomocysteinemia-free young adults (age 24.3 ± 2.3 years, 4 women) volunteered to take part in this uncontrolled interventional trial. The participants received guanidinoacetate-creatine mixture (2,000 mg/day of guanidinoacetate and 2,000 mg/day of creatine) for 28 days; the guanidinoacetate dose was designed as a hyperhomocysteinemia-provoking dosage in healthy individuals [4], and the creatine dose was advanced for homocysteine reduction [5] and was equal to the amount recommended from dietary intake for the general population [6]. The primary outcome (total plasma homocysteine) and secondary outcomes (patient-reported side effects, plasma levels of clinical enzymes, total albumin, creatinine, and blood urea nitrogen) were assessed at baseline (pre-intervention) and 28-day follow-up. The study design was approved by the local IRB at the University of Novi Sad (#46-06-01/2020-1e2), with the study systematized following the Declaration of Helsinki. This study was an extension preliminary trial of the primary study [7], assessing whether guanidinoacetate-creatine mixture has additional metabolic activity or effects.

All participants completed the study, and compliance with the interventional regimen was 100%, as calculated by the number of unused sachets. Guanidinoacetate-creatine induced a mild increase in total plasma homocysteine (from 9.3 ± 1.7 μmol/L at baseline, to 11.6 ± 1.6 μmol/L at 28-day follow-up; p < 0.01). The mixture instigated no cases of hyperhomocysteinemia (e.g., total plasma homocysteine >15 μmol/L), with clinical enzymes and other safety biomarkers remaining within the normal ranges. The mean serum creatinine levels increased for 15.1% (95% confidence interval, from 3.7 to 26.5; p = 0.02), yet no participants experienced clinically significant creatinine elevation (>114.9 μmol/L for men and >97.2 μmol/L for women). The participants reported no side effects that precluded their participation in the study.

In this small-scale open-label preliminary trial, coadministration of creatine and guanidinoacetate elevated total plasma homocysteine for ∼25% over a treatment duration of 28 days. There was no evidence of intervention-driven hyperhomocysteinemia, suggesting a small-to medium-scale potential of the guanidinoacetate-creatine mixture to markedly upregulate homocysteine homeostasis. It appears that guanidinoacetate-inducing hyperhomocysteinemia is largely preventable by creatine coadministration in metabolically healthy men and women; this perhaps happens since exogenous creatine may temper endogenous creatine biosynthesis sufficiently to lower homocysteine production [5]. Whether these beneficial effects of supplemental creatine remain in metabolically compromised individuals and following more prolonged exposure to other dietary homocysteine-raising compounds (e.g., phosphatidylethanolamine, niacin, and xenobiotics) remains to be elucidated. Given that diet is a major risk factor for hyperhomocysteinemia [8], increased creatine intake may be a newly recognized dietary factor in the prevalence of hyperhomocysteinemia and its related diseases.