Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1628 (Published 14 May 2019) Cite this as: BMJ 2019;365:l1628
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In the “Strengths and Limitations” section of this study the authors note that ‘most glucosamine products available on the market contain glucosamine sulphate’. A quick in-store review of the contents of such supplements will usually reveal, in the UK, that they also contain chondroitin sulphate. The “Conclusion” suggests further clinical trials are needed to test the hypothesis that glucosamine supplements might be related to lower risks of CVD events.
As a citizen scientist, may I respectfully suggest that focus also be placed on the sulphate aspect of glucosamine sulphate and chondroitin sulphate. It may be that that such supplements, to the extent that they are associated with CVD, satisfy a deficiency of sulphur, rather than, or as well as, glucosamine or chondroitin.
Of the many papers that have already been published on the topic, I cite the following, being well-aware of the possibility of personal bias.
Lack of dietary sulphur:
In their paper “Are we getting enough sulfur in our diet?” Nimni et al concluded “Out of this study came information that suggested that a significant proportion of the population that included disproportionally the aged, may not be receiving sufficient sulfur and that these dietary supplements, were very likely exhibiting their pharmacological actions by supplying inorganic sulfur.”
Nutrition & Metabolism 2007 4:24
https://www.ncbi.nlm.nih.gov/pubmed/17986345
Link between sulphur and atherosclerosis:
In 1960, GV Mann et al fed cholesterol to monkeys and induced atherosclerosis. Subsequently, sulphur containing nutrients were provided and atherosclerosis was prevented. They said ‘A form of vascular disease resembling human atherosclerosis has been produced in the New World primate Cebus fatuella … in order to produce these phenomena, the diets had to be rich in cholesterol, choline and neutral fat but relatively low in organic sulfur compounds. Without this deprivation of organic sulphur the response of the serum lipids to cholesterol feeding was small’.
https://www.researchgate.net/publication/9167001_Experimental_Atheroscle...
Treatment of heart disease with chondroitin sulphate:
Morrison et al reported apparently significant results from the use of chondroitin sulphate with one hundred and twenty patients with demonstrable ischemic heart disease or coronary heart disease, divided equally into a CSA-treatment group (with chondroitin sulphate A) and control group. After a 2.5 year observation period, 21 of the 60 patients in the control group had experienced acute cardiac episodes or myocardial ischemia, of which 4 were fatal. In the matched CSA-treated group there were 5 deaths.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1532-5415.1969.tb02328.x
Association with C-Reactive Protein:
Finally, the authors of this paper state (under “Biological plausibility”) that ‘regular use of glucosamine was associated with a statistically significant reduction in C reactive protein concentrations, which is a marker for systemic inflammation.’. In their paper “C-Reactive Protein test to screen for heart disease: Why do we need another test?”, Harvard Health Publishing discuss the use of hs-CRP testing to detect the 50% of people who have heart attacks but who did not have high LDL.
Harvard Health Publishing:
https://www.health.harvard.edu/heart-health/c-reactive-protein-test-to-s...
Another paper titled “High-Sensitivity C-Reactive Protein and Cardiovascular Disease” in the Journal of the American College of Cardiology discusses the current state of the art.
Journal of the American College of Cardiology, Vol 62,No 5, 2013:
https://www.ncbi.nlm.nih.gov/pubmed/23727085
Competing interests: No competing interests
This study supports the use of glucosamine for preventing and treating cardiovascular problems in nutritional therapy. Theoretically, in cases of glucosamine deficiency, whether due to diet or underative enzyme activity, dietary supplements can be expected to improve the structure of tissues containing glycoproteins, glycolipids, and glycosaminoglycans. These tissues include the tendons, ligaments, cartilage, synovial fluid, mucous membranes, structures in the eye, blood vessels, and heart valves.
Notably, glucosamine is present in the proteoglycan aggregates which are important for the elasticity of cartilage. Cartilage is found in the heart, aorta and arteries and so is crucial for cardiovascular function. Two questions:
1) Is there a relationship between joint problems and disorders of similar tissues such as the cardiovascular system?
2) Should glucosamine be classified as a nutrient or an anti-inflammatory agent?
Competing interests: No competing interests
Can glucosamine lower CVD risk by lowering insulin?
A possible mechanism for glucosamine's association with reduced CVD and mortality in this population may be that it mimics the glucokinase mutations that cause benign diabetic states.
Infused into rats, glucosamine causes severe impairment in glucose-induced insulin secretion. This glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine.[1]
Conventional wisdom has it that elevated glucose is the feature of diabetes that leads to cardiovascular risk, and there are good mechanistic reasons why this is true of very high glucose levels - however, persistent mildly elevated glucose levels in the pre-diabetic range, if they are due to a slightly impaired insulin response (i.e. insulin response to glucose elevations only occurs at a higher-than-usual serum glucose level) do not seem to be harmful in glucokinase mutations.
"Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001)."[2]
This set of correlations seems to support the view that CVD is promoted by the hyperinsulinaemia that accompanies type 2 diabetes, pre-diabetes, and the metabolic syndrome. Anecdotally, glucosamine can elevate LDL levels in some cases, but this has not been confirmed by RCTs - however, the effect is seem in mouse models of atherosclerosis.[3]
Therefore glucosamine potentially has two metabolic effects that should be consistent with increased CVD risk (increased glucose and increased LDL cholesterol), yet is associated with reduced CVD mortality (0.78, 95% CI: 0.70 to 0.87), because insulin is the dominant driver of this pathology and both the elevation in glucose and any elevation in LDL-C in the case of glucosamine are due to a reduced insulin response, and thus differ from glucose and LDL-C elevations in normal metabolic syndromes.
Of course a low-carbohydrate diet requires a reduced insulin response to maintain homeostatis, so the authors' claim that glucosamine is a low-carb diet mimic seems correct.
[1] Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism. 1998 May;47(5):573-7.
[2] Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980. http://www.ncbi.nlm.nih.gov/pubmed/24430320
[3] Lisa R. Tannock, Elizabeth A. Kirk, Victoria L. King, Renee LeBoeuf, Thomas N. Wight, Alan Chait, Glucosam ine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor–Deficient Mice, The Journal of Nutrition, Volume 136, Issue 11, November 2006, Pages 2856–2861, https://doi.org/10.1093/jn/136.11.2856
[4] Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia. 1991 Jun;34(6):416-22.
https://www.ncbi.nlm.nih.gov/pubmed/1884900
Competing interests: No competing interests