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Publié dans PharmacoFACT (english version).

#F018 Adverse effects of systematic vitamin supplementation

What is the subject ?

The risks associated with vitamin supplements, particularly in products from the agri-food industry.

Why are we addressing this subject ?

On 19 February 2024, an article published in Nature Medicine highlighted the deleterious role of metabolites of niacin (vitamin B3) in endothelial inflammation, increasing cardiovascular risk 1. This study may provide an explanation for the disappointing results of recent supplementation trials, and the paradox that niacin-induced lowering of LDL-cholesterol levels does not achieve the expected reduction in cardiovascular disease risks 2,3.

The opinion of the SFPT (French Society of Pharmacology and Therapeutics)

Systematic vitamin supplementation outside a situation of vitamin deficiency seems unnecessary and potentially dangerous.
Apart from formal indications for supplementation (malabsorption pathologies, toxic deficiencies, at-risk subjects, osteoporosis, etc.), vitamin supplementation is unnecessary. We must insist on the importance of a varied, balanced diet based on fresh produce.

For more information

An article entitled "A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk” reminds us that there is still a residual cardiovascular risk in patients who follow recommended treatment regimens perfectly. Prevention of cardiovascular risk can be summed up schematically by controlling a number of well-identified risk factors. These include smoking status, hypertension, overweight, certain dyslipidemias, diabetes and chronic renal failure. To this day, statins remain the cornerstone of treatment for patients at cardiovascular risk, thanks to their undeniable cholesterol-lowering effect, combined with probable additional protective effects 4. The therapeutic arsenal at our disposal has now been enriched by the arrival of incretinomimetics and gliflozines, which are currently recommended as 1st-line therapy in target populations 5. These therapeutic classes have a clear effect on reducing cardiovascular mortality, particularly in diabetic or obese patients 6,7. Despite control of modifiable risk factors, and the achievement of very low circulating LDL-c levels with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, residual mortality persists 8,9. Even at low levels and independently of lipid control, systemic inflammation appears to be a persistent factor. Moreover, downward modulation of inflammation appears to have a beneficial effect on mortality 10.

Vitamins and their metabolites are compounds essential to the body's proper functioning, either by acting as co-factors in chemical reactions, or by directly regulating the genome. Classically, 14 main vitamins are described: A; B1; B2; B3; B5; B6; B8; B9; B12; C; D; E; K; and choline 11. For each of these vitamins, three dietary reference values are defined : the average requirement (AR), the population reference intake (PRI) and the adequate intake (AI). The AR is determined in experimental studies by evaluating individual intake data against a predefined nutritional adequacy criterion. The PRI is the theoretical intake covering the needs of 97.5% of the population according to experimental data, and the AI corresponds to the average intake of a population with satisfactory nutritional status. This index is often derived from observational data, when AR cannot be estimated from experimental data.

When vitamin intake is unsatisfactory, either due to a primary intake deficiency or to increased metabolism of the latter, pathological situations may appear. As an example, vitamin A deficiency leads to immune dysfunction, skin disorders due to cell differentiation defects, and visual disorders dominated by dry eyes 12. Vitamin C deprivation is classically associated with scurvy 13, vitamin D deficiency with fracture or infectious risk 14, and vitamin K deficiency with bleeding or bone fragility 15.

Nevertheless, while each vitamin class is associated with a deficiency pathology, an excessive intake can also be associated with significant toxicity. In the case of vitamin D, hypercalcemia has been reported 16, while in the case of vitamin C, an excess risk of renal lithiasis in men and excess mortality in critical care patients have been described 17,18. We can also cite the neurotoxicity of vitamin B6 overdose 19. Like deficiency, vitamin excess induces a loss of homeostasis, leading to the emergence of pathological situations. A report on 13 March 2015 by the French national food authority (Anses : Agence nationale de sécurité sanitaire, alimentation, environnement, travail) revealed that the prevalence of dietary supplement consumption was estimated at 22.4%. In this population, the vitamin intake induced by supplements statistically significantly exceeded the intake of the rest of the population. However, due to the often enriched diet and possible reporting bias in this study, it is difficult to conclude on the actual differential impact of these exogenous intakes.

Vitamin supplementation in the general diet is defined as dietary fortification. It is supposed to protect populations most at risk of deficiency, but its systematization and over-consumption of processed products can lead to an excess of intakes. The Nature Medicine article mentions a very high niacin intake in the American population, with a median of 37 mg (IQR: 27-50mg) 20 well above the AR of around 14 to 18 mg 21.

In this article, the authors initially followed 1162 patients undergoing cardiac evaluation in whom they performed a metabolomic analysis to identify residual markers of cardiovascular risk unrelated to conventional factors. This research led to the identification of two isomers, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY). These two molecules are terminal metabolites of the niacin cycle. Secondly, two validation cohorts in Europe and the USA also positively correlated circulating levels of 2PY and 4PY with the occurrence of cardiovascular adverse events, and significantly so, independently of renal function for 4PY. In the US cohort, genomic variant analysis identified the ACMSD (aminocarboxymuconate semialdehyde decarboxylase) gene as linked to high circulating levels of 2PY and 4PY when repressed, notably in the presence of the rs10496731 allele. An animal model in mice confirmed this finding, observing high circulating levels of 2PY and 4PY after inhibition of ACMSD expression products.

The authors then carried out a metabolomic and proteomic evaluation associated with the presence of the rs10496731 variant, and identified vascular cell adhesion molecule-1 (VCAM-1), whose circulating levels were found to be correlated with an increase in cardiovascular events [aHR (95%CI) =2.38 (1.14-4.95), p=0.02] but also correlated with circulating levels of 2PY and 4PY.

In the light of these results, functional tests were carried out, both in vitro and in vivo. Cultures of human endothelial cells were incubated with the metabolites 2PY and 4PY and production of both VCAM-1 mRNA and mature VCAM-1protein were observed. In mice, the metabolites were injected intraperitoneally and an increase in VCAM-1 expression was also observed, leading to an increase in leukocyte adhesion to the endothelial lining visualized by intravital microscopy. In both cases, the increase in VCAM-1 levels was reported only when 4PY was injected or incubated, suggesting that this metabolite is the only biologically active isomer.

This investigative work highlights the complexity of biological homeostasis, but also the existence of cardiovascular risk factors different from those traditionally considered. Finally, it also puts into perspective the dualistic vision of dietary fortification. Nearly 2 billion people in the world still suffer from food insecurity 22. The fight against deficiency diseases on a global scale remains necessary, even if the model based on food fortification is debated. However, in developed countries, the promotion of dietary health should probably focus on diversification of intake and consumption of fresh produce. We must prevent the illusion that vitamin supplements are all-purpose remedies against various ailments.

References :

  1. Ferrell M, Wang Z, Anderson JT, et al. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat Med. 2024;30(2):424-434. doi:10.1038/s41591-023-02793-8
  2. The HPS2-THRIVE Collaborative Group. Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients. N Engl J Med. 2014;371(3):203-212. doi:10.1056/NEJMoa1300955
  3. The AIM-HIGH Investigators. Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med. 2011;365(24):2255-2267. doi:10.1056/NEJMoa1107579
  4. Sirtori CR. The pharmacology of statins. Pharmacological Research. 2014;88:3-11. doi:10.1016/j.phrs.2014.03.002
  5. Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. European Heart Journal. 2023;44(39):4043-4140. doi:10.1093/eurheartj/ehad192
  6. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The Lancet Diabetes & Endocrinology. 2021;9(10):653-662. doi:10.1016/S2213-8587(21)00203-5
  7. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
  8. Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and Cholesterol Risk in the FOURIER Trial. Circulation. 2018;138(2):131-140. doi:10.1161/CIRCULATIONAHA.118.034032
  9. Pradhan AD, Aday AW, Rose LM, Ridker PM. Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy. Circulation. 2018;138(2):141-149. doi:10.1161/CIRCULATIONAHA.118.034645
  10. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914
  11. Références nutritionnelles en vitamines et minéraux.https://www.anses.fr/fr/content/les-références-nutritionnelles-en-vitamines-et-minéraux. Published April 24, 2021.
  12. Polcz ME, Barbul A. The Role of Vitamin A in Wound Healing. Nut in Clin Prac. 2019;34(5):695-700. doi:10.1002/ncp.10376
  13. Dresen E, Lee Z, Hill A, Notz Q, Patel JJ, Stoppe C. History of scurvy and use of vitamin C in critical illness: A narrative review. Nut in Clin Prac. 2023;38(1):46-54. doi:10.1002/ncp.10914
  14. Amrein K, Scherkl M, Hoffmann M, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr. 2020;74(11):1498-1513. doi:10.1038/s41430-020-0558-y
  15. Akbulut AC, Pavlic A, Petsophonsakul P, et al. Vitamin K2 Needs an RDI Separate from Vitamin K1. Nutrients. 2020;12(6):1852. doi:10.3390/nu12061852
  16. Walker MD, Shane E. Hypercalcemia: A Review. JAMA. 2022;328(16):1624. doi:10.1001/jama.2022.18331
  17. Ferraro PM, Curhan GC, Gambaro G, Taylor EN. Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones. American Journal of Kidney Diseases. 2016;67(3):400-407. doi:10.1053/j.ajkd.2015.09.005
  18. Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022;386(25):2387-2398. doi:10.1056/NEJMoa2200644
  19. Hadtstein F, Vrolijk M. Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity. Advances in Nutrition. 2021;12(5):1911-1929. doi:10.1093/advances/nmab033
  20. Bryan S, Afful J, Carroll M, et al. NHSR 158. National Health and Nutrition Examination Survey 2017–March 2020 Pre-Pandemic Data Files. National Center for Health Statistics (U.S.); 2021. doi:10.15620/cdc:106273
  21. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements (Eds Otten, J. J., Hellwig, J. P. & Meyers, L. D) (The National Academies Press, 2006).
  22. Objectif 2 : Éliminer la faim, assurer la sécurité alimentaire, améliorer la nutrition et promouvoir l’agriculture durable.https://www.un.org/sustainabledevelopment/fr/hunger/#:~:text=Dans%20le%20monde%2C%202%20milliards,ans%20étaient%20atteints%20d%27émaciation.
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