Association of Glucosamine Supplementation and Incidence of Heart Failure

It is estimated that 2.6% of the population worldwide is using glucosamine supplements, most commonly for osteoarthritis. Glucosamine, a popular over-the-counter supplement used for osteoarthritis, has been speculated to help with pain relief and to slow degenerative joint disease.1Yu H. Wu J. Chen H. et al.Glucosamine use is associated with a higher risk of cardiovascular diseases in patients with osteoarthritis: results from a large study in 685,778 subjects.Nutrients. 2022; 14: 3694Crossref Scopus (2) Google Scholar One in every 4 American adults have some form of osteoarthritis,2Murphy L.B. Helmick C.G. Schwartz T.A. et al.One in four people may develop symptomatic hip osteoarthritis in his or her lifetime.Osteoarthritis Cartilage. 2010; 18: 1372-1379Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar and half of them are aged 65 years or older, which is also the age group with the highest prevalence of cardiovascular disease (CVD).3Virani S.S. Alonso A. Benjamin E.J. et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics—2020 Update: a report from the American Heart Association.Circulation. 2020; 141: e139-e596Crossref PubMed Scopus (4870) Google Scholar Glucosamine inhibits the production of nitric oxide (NO)4Meininger C.J. Kelly K.A. Li H. Haynes T.E. Wu G. Glucosamine inhibits inducible nitric oxide synthesis.Biochem Biophys Res Commun. 2000; 279: 234-239Crossref PubMed Scopus (78) Google Scholar and increases fasting glycemia.1Yu H. Wu J. Chen H. et al.Glucosamine use is associated with a higher risk of cardiovascular diseases in patients with osteoarthritis: results from a large study in 685,778 subjects.Nutrients. 2022; 14: 3694Crossref Scopus (2) Google Scholar,5Dostrovsky N.R. Towheed T.E. Hudson R.W. Anastassiades T.P. The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature.Osteoarthritis Cartilage. 2011; 19: 375-380Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Biochemical studies in mice have found that excess NO production is implicated in the pathogenesis of arthritis.6Chiu H.W. Li L.H. Hsieh C.Y. et al.Glucosamine inhibits IL-1β expression by preserving mitochondrial integrity and disrupting assembly of the NLRP3 inflammasome.Sci Rep. 2019; 9: 5603Crossref Scopus (39) Google Scholar Nitric oxide is also important in endothelial function, and decreased NO is a fundamental step in the pathogenesis of atherosclerosis.7Naseem K.M. The role of nitric oxide in cardiovascular diseases.Mol Aspects Med. 2005; 26: 33-65Crossref PubMed Scopus (408) Google Scholar This led to the hypothesis that glucosamine consumption might reduce NO levels and potentially lead to endothelial dysfunction and CVD. Nevertheless, in vitro data have shown some anti-inflammatory properties of glucosamine,6Chiu H.W. Li L.H. Hsieh C.Y. et al.Glucosamine inhibits IL-1β expression by preserving mitochondrial integrity and disrupting assembly of the NLRP3 inflammasome.Sci Rep. 2019; 9: 5603Crossref Scopus (39) Google Scholar suggesting a potential preventive role in the atherosclerosis pathway. Furthermore, in small mice studies, glucosamine has been found to improve cardiac function during resuscitation after traumatically induced hemorrhage, reducing levels of inflammatory markers like tumor necrosis factor α and interleukin 6, among others, and improving cardiac function.8Zou L. Yang S. Champattanachai V. et al.Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-κB signaling.Am J Physiol Heart Circ Physiol. 2009; 296: H515-H523Crossref PubMed Scopus (122) Google Scholar A retrospective study conducted by Yu and colleagues1Yu H. Wu J. Chen H. et al.Glucosamine use is associated with a higher risk of cardiovascular diseases in patients with osteoarthritis: results from a large study in 685,778 subjects.Nutrients. 2022; 14: 3694Crossref Scopus (2) Google Scholar reported a 10% increased odds of CVD events in patients with newly diagnosed osteoarthritis during a median 6-year follow-up. Furthermore, the odds of CVD events increased to 68% for those who were more adherent to glucosamine. However, the study had multiple limitations, such as potential inaccuracy of actual glucosamine intake and interactions with potential confounders like body mass index, physical activity, smoking, and alcohol intake. A few large observational studies have evaluated cardiovascular effects of the use of glucosamine.1Yu H. Wu J. Chen H. et al.Glucosamine use is associated with a higher risk of cardiovascular diseases in patients with osteoarthritis: results from a large study in 685,778 subjects.Nutrients. 2022; 14: 3694Crossref Scopus (2) Google Scholar,9King D.E. Xiang J. Glucosamine/chondroitin and mortality in a US NHANES cohort.J Am Board Fam Med. 2020; 33: 842-847Crossref Scopus (25) Google Scholar,10Ma H. Li X. Sun D. et al.Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank.BMJ. 2019; 365: l1628Crossref Scopus (56) Google Scholar One such study used the National Health and Nutrition Examination Survey (NHANES), which included a sample of approximately 16,700 participants; 658 (4%) of them who consumed glucosamine/chondroitin for at least a year had a 27% lower overall mortality and a 58% lower cardiovascular mortality.9King D.E. Xiang J. Glucosamine/chondroitin and mortality in a US NHANES cohort.J Am Board Fam Med. 2020; 33: 842-847Crossref Scopus (25) Google Scholar Prospective data from the UK Biobank (sample of ∼470,000) also found a 15% lower rate of total cardiovascular events with regular use of glucosamine during a median follow-up of 7 years.10Ma H. Li X. Sun D. et al.Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank.BMJ. 2019; 365: l1628Crossref Scopus (56) Google Scholar The VITAL cohort study11White E. Patterson R.E. Kristal A.R. et al.VITamins And Lifestyle cohort study: study design and characteristics of supplement users.Am J Epidemiol. 2004; 159: 83-93Crossref PubMed Scopus (204) Google Scholar prospectively included patients of 50 to 76 years of age and found that the approximately 77,000 patients in the glucosamine group had a lower mortality risk.12Bell G.A. Kantor E.D. Lampe J.W. Shen D.D. White E. Use of glucosamine and chondroitin in relation to mortality.Eur J Epidemiol. 2012; 27: 593-603Crossref PubMed Scopus (64) Google Scholar Despite all of this, little is known about the potential associations between glucosamine intake and heart failure (HF) in humans. For this reason, Zheng and collaborators13Zheng J. Hukportie D.N. Zhang Y. et al.Association between glucosamine use and the risk of incident heart failure: the UK Biobank cohort study and mendelian randomization analysis.Mayo Clin Proc. 2023; 98: 1177-1191Google Scholar used epidemiologic and genetic data from the UK Biobank to investigate this topic. In this study, the investigators included 480,000 participants with data available for the supplement who had no history of HF at baseline and observed them for a median of 9 years. They calculated a weighted genetic risk score using 12 single-nucleotide polymorphisms linked to HF and performed Cox regression models to assess the inverse probability of treatment weighting. They also conducted a 2-sample mendelian randomization for validation and mediation. The investigators observed that the 19.1% of patients who were in the glucosamine group were more likely to be older, female, or White. Glucosamine-treated patients were also more likely to have healthier reported lifestyle, at least 1 metabolic risk factor, and arthralgia or osteoarthritis and to use aspirin, chondroitin, non-aspirin nonsteroidal anti-inflammatory drugs, β-blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker, thereby suggesting that these patients may have been slightly sicker and more medicated, especially with nonsteroidal anti-inflammatory drugs and chondroitin. The glucosamine group was 25% less likely to have HF after adjustment for age and sex. Furthermore, after accounting for multiple baseline characteristics, such as the ones mentioned before, glucosamine was associated with a 13% decrease in the risk of being diagnosed with HF. This difference attenuated to 8% after the regression-based multivariable mendelian randomization. Interestingly, in the mediation analysis, 22.7% of the effect of glucosamine on the incidence of HF was mediated by stroke and coronary artery disease, whereas more than two-thirds of its effect took place through more complex alternative disease pathways. It was also noticed that the lower risk of HF was more pronounced in men and in those with unfavorable lifestyle; classically, these 2 groups have been at higher risk of CVD, including HF with reduced ejection fraction. Although this research provides valuable information on the topic, the study had some important limitations, especially the lack of stratification of HF according to the left ventricular ejection fraction or cause. The observational nature of the design was also a major limitation because participants taking glucosamine, either by their own volition or by prescription from their local health care providers, may have had different profiles from those in the control group. Although these results are interesting and the investigators made great efforts undertaking a complex methodology to account for multiple potential confounders, large randomized clinical trials addressing the limitations of this study are warranted before definitive conclusions are drawn, especially for causal effects and pathways of glucosamine on HF incidence and clinical course. Future clinical trials should ideally provide details on myocardial structure and function on imaging and provider granular etiologic data. The authors report no competing interests. Association Between Glucosamine Use and the Risk of Incident Heart Failure: The UK Biobank Cohort Study and Mendelian Randomization AnalysisMayo Clinic ProceedingsVol. 98Issue 8PreviewTo evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease. Full-Text PDF