Alehagen U, Aaseth J, Lindahl TL, Larsson A, Alexander J. Dietary supplementation with selenium and coenzyme Q10 prevents increase in plasma D-dimer while lowering cardiovascular mortality in an elderly Swedish population. Nutrients. 2021;13(4):1344.
To determine the effect of supplementation of selenium and CoQ10 on D-dimer and cardiovascular mortality in an elderly, Swedish population
Randomized, double-blind, placebo-controlled trial
Investigators screened 876 volunteers, out of which 443 were evaluated for study consideration. Of these, 213 participants met criteria and were enrolled in the study;106 participants received the active combined supplementation, and 107 received the control placebo. Participants ranged in age from 70 to 88 years. Investigators did not disclose the gender split in the published article. Participants were Swedish and Caucasian.
Inclusion criteria included:
- Age ≥70 years.
- Although this was not a specific inclusion criterion, all participants had low serum selenium levels (mean 67 µg/L, approximately equivalent to an intake of 35 µg per day).
- Participants were recruited only from a rural area in Sweden.
Exclusion criteria were:
- Unable to consistently (every 6 months) travel to Health Center for phlebotomy and assessment.
- Conditions known to affect D-dimer including atrial fibrillation, treatment with anticoagulants, malignancies, and enlarged left atrium (greater than 40 mm).
Additional factors of exclusion included recent myocardial infarction within the last month, a planned cardiovascular operation or procedure in the upcoming 4 weeks, concerns with cognition or consent, serious disease that would make 4-year survival unlikely, and alcohol/ drug abuse.
Study Parameters Assessed
Participants received either 100 mg of CoQ10 (ubiquinone) twice daily and 100 µg of selenium yeast twice daily or placebo for 48 months.
Primary Outcome Measures
D-dimer levels and cardiovascular mortality were the primary outcome measures of the study.
Investigators reported 2 important key findings. The first was that those participants who supplemented with CoQ10 and selenium yeast did not experience the same elevation in D-dimer as those in the placebo group (P=0.006). Second, those with baseline D-dimer levels above the median in the supplement group had significantly lower cardiovascular mortality (P=0.014).
This study asked a set of very specific questions, which makes extrapolation to other populations or typical practice relatively difficult. The population was elderly, aged more than 70 years. The study recruited from an area in Sweden with low selenium content of the soil, and participants, indeed, had low serum selenium levels. D-dimer did not increase during the study duration, so the study is primarily reporting a prevention of an anticipated rise in D-dimer. In terms of lowered cardiovascular risk, this endpoint was seen only in those with elevated D-dimer levels at the onset of the study. The duration of the study is long enough for some mortality information to be relevant, but the sample size is rather small, which may create uncertainty in the results. All participants being Caucasian makes it difficult to know if patients of other ethnicities would obtain the same benefit.
Replicating this in practice, exclusively on the basis of the published study, would suggest that coenzyme Q10 as ubiquinone 100 mg twice daily along with selenium as selenium yeast 100 µg twice daily for up to 4 years may be useful in elderly Caucasian patients with low serum selenium levels, at least slightly increased D-dimer levels, and none of the participant exclusion factors such as atrial fibrillation, use of anticoagulants, known malignancy, and enlarged left atria greater than 40 mm. Outside of these parameters, the usefulness of the intervention should be extrapolated with caution.
While that is a very specific practice takeaway in the context of the study, clinicians may glean a few other practice implications that are not directly related to the primary endpoints.
D-dimer is likely well-known for its role in the diagnosis of venous thromboembolism and exclusion of pulmonary embolism.1 However, D-dimer can also be used to evaluate the activity of peripheral artery disease since D-dimer represents the degradation of fibrin.2 Clinicians should also recognize that D-dimer increases after age 50.3 It may also be used as a marker of inflammation without thromboembolism.4 Another point of interest is that D-dimer may have prognostic value in Covid-19.5 D-dimer may be underutilized in evaluating patients with cardiovascular disease risk and atherosclerosis.5 It may also be one of the best markers for endothelial function.6 Since there is only a weak correlation between C-reactive protein (CRP) and D-dimer,7 clinicians should not exclusively rely on the former to determine systemic inflammation, especially that of cardiovascular origin. Bottom line is that clinicians should not forget about D-dimer or relegate it to embolic events only.
Bottom line is that clinicians should not forget about D-dimer or relegate it to embolic events only.
Clinicians may speculate why the investigators selected this combination of coenzyme Q10 and selenium. First, there are previous studies available. This same research group published on CoQ10 and selenium on other markers of inflammation including sP-selectin, CRP, osteopontin, osteoprotegerin, and soluble tumor necrosis factor receptors 1 and 2.8,9 Save CRP, these are not common, relevant markers for most clinicians. Von Willebrand factor and plasminogen activator inhibitor-1 were also endpoints of studies using the CoQ10 and selenium combination.10 Another study looked at the combination in those who suffered myocardial infarction.11
Previous human studies are certainly a good jumping-off point for future studies, but is there biochemical relevance? Interestingly, there is very good rationale for this combination biochemically speaking. Many clinicians are familiar with the 2 most common commercially available versions of CoQ10 being ubiquinone and ubiquinol, with the latter often referred to as the active or reduced form. Ubiquinone converts to ubiquinol within cells. In the cytosol of cells, there exists a selenoenzyme known as thioreductase1, which supports this conversion. It should be noted that this study used selenium yeast as the supplemented form rather than other common forms of selenium, such as selenomethionine or selenium selenite. It is unclear if forms of selenium other than selenium yeast would be as useful in this population. In other populations, it has been speculated that the form of selenium is quite important.12 The different forms of selenium do have variable physiologic effects as demonstrated by an in vivo study designed to assess this variation.13
In individuals with sufficient selenium levels, it is not clear if supplementation is necessary or useful. Optimal cellular function is thought to require 75 µg of selenium per day;14 however, intakes of 100 to 150 µg per day may be required for optimal expression of selenoproteins.15 This amount may be adjusted upward in the case of increased oxidative stress or inflammatory conditions.16 Serum selenium concentrations considered adequate would be greater than 100 µg/L. Northern European countries, such as Sweden where this study was conducted, are thought to have low soil levels of selenium, which may contribute to low dietary intakes and low serum levels and an association with higher cardiovascular mortality.17
In the absence of the very specific population of this study, clinicians may find a wider relevance of D-dimer as a marker of inflammation and endothelial function, better understanding of CoQ10 forms as well as choice of selenium forms, and consideration of serum concentrations of selenium for optimal function.
The dosing of CoQ10 and selenium yeast seems quite safe and not excessive from a clinical perspective. And while positive benefits cannot necessarily be conferred to extrapolated populations, it seems reasonable to assess or supplement with selenium when insufficiency is possible or likely, especially for those aged more than 50 years or those who have mildly elevated D-dimer. Dosing 200 mg of CoQ10 per day also seems often prudent due to its uses in most tissues of the body.
- D-dimer. Merck Manual Professional Version. Accessed September 27, 2021. https://www.merckmanuals.com/professional/multimedia/lab-tests/v42968348
- Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113:2878-2887.
- Urban K, Kirley K, Stevermer JJ. PURLs: It’s time to use an age-based approach to D-dimer. J Fam Pract. 2014;63:155-158.
- Bruinstroop E, Van De Ree M, Huisman M. The use of D-dimer in specific clinical conditions: a narrative review. Eur J Intern Med. 2009;20:441-446.
- Bai Y, Zheng YY, Tang JN, et al. D-dimer to fibrinogen ratio as a novel prognostic marker in patients after undergoing percutaneous coronary intervention: a retrospective cohort study. Clin Appl Thromb Hemost. 2020;26:1076029620948586.
- Zhang J, Tecson KM, McCullough PA. Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy. Rev Cardiovasc Med. 2020;21:315-319.
- Folsom AR, Delaney JAC, Lutsey PL, et al. For the multiethnic study of atherosclerosis investigators associations of factor VIIIc, D-dimer, and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality. Am J Hematol. 2009;84:349-353.
- Alehagen U, Alexander J, Aaseth J, Larsson A. Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK. J Inflamm. 2019;16:5.
- Alehagen U, Lindahl TL, Aaseth J, Svensson E, Johansson P. Levels of sP-selectin and hs-CRP decrease with dietary intervention with selenium and coenzyme Q10 combined: a secondary analysis of a randomized clinical trial. PLoS ONE. 2015;10:e0137680.
- Alehagen U, Alexander J, Aaseth J, Larsson A, Lindahl TL. Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and coenzyme Q10 to an elderly population with a low selenium status. Eur J Nutr. 2020;59:3581-3590.
- Kuklinski B, Weissenbacher E, Fähnrich A. Coenzyme Q10 and antioxidants in acute myocardial infarction. Mol Asp Med. 1994;15:s143-s147.
- Richie JP Jr, Das A, Calcagnotto AM, et al. Comparative effects of 2 different forms of selenium on oxidative stress biomarkers in healthy men: a randomized clinical trial. Cancer Prev Res (Phila). 2014;7(8):796-804.
- Xu XJ, Zhang DG, Zhao T, Xu YH, Luo Z. Dietary selenium sources differentially regulate selenium concentration, mRNA and protein expression of representative selenoproteins in various tissues of yellow catfish Pelteobagrus fulvidraco. Br J Nutr. 2021;1-13. doi:10.1017/S000711452100194X.
- Xia Y, Hill K, Li P, et al. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects. Am J Clin Nutr. 2010;92:525-531.
- Brodin O, Hackler J, Misra S, et al. Selenoprotein P as biomarker of selenium status in clinical trials with therapeutic dosages of selenite. Nutrients. 2020;12:1067.
- Manzanares W, Biestro A, Galusso F, et al. Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill? Intensive Care Med. 2009;35:882-889.
- Alehagen U, Johansson P, Björnstedt M, Rosén A, Post C, Aaseth J. Relatively high mortality risk in elderly Swedish subjects with low selenium status. Eur J Clin Nutr. 2015;70:91-96.