People who regularly take glucosamine supplements appear to have a moderately lower risk for cardiovascular disease (CVD) events, results from 22 centers participating in the UK Biobank suggest.
Glucosamine use was associated with a 15% lower risk for total CVD events and a 9% to 22% lower risk for stroke, coronary heart disease (CHD), and CVD death after adjustment for age, sex, body mass index, race, lifestyle factors, diet, medications, and other supplements.
“Even though the use of glucosamine is related to only 15% reduced risk, the effect size is similar to most of the protective dietary factors,” senior author Lu Qi, MD, PhD, from Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, told theheart.org | Medscape Cardiology.
“Another thing that really convinced me about the relationship was that glucosamine use showed a highly consistent association with the various events,” he said.
A few other cohort studies have raised this question including the Vitamins and Lifestyle (VITAL) cohort study, in which high glucosamine use (at least 4 days per week for at least 3 years) was associated with a 17% lower adjusted total mortality risk.
Animal studies suggest the associations may be driven by the anti-inflammatory properties of glucosamine or that the popular supplement may mimic a low carbohydrate diet by decreasing glycolysis and increasing amino acid catabolism, the authors write in their article published online May 14 in BMJ.
Qi and colleagues used data from 466,039 UK Biobank participants without baseline CVD who completed a questionnaire on regular supplement use, including glucosamine. In all, 19.3% reported glucosamine use at baseline.
After a median follow-up of 7 years, there were 10,204 incident CVD events, 3060 CVD deaths, 5745 CHD events, and 3263 strokes.
In multivariate analyses, the hazard ratios (HRs) associated with glucosamine use were:
0.85 for total CVD events (95% confidence interval [CI], 0.80 – 0.90; P < .001)
0.78 for CVD death (95% CI, 0.70 – 0.87; P < .001)
0.82 for CHD (95% CI, 0.76 – 0.88; P < .001)
0.91 for stroke (95% CI, 0.83 – 1.00; P = .04)
Glucosamine was associated with significantly lower risks for nonfatal and fatal CHD (HRs, 0.84 and 0.70; P for both < .001), but only a marginally lower risk for nonfatal stroke (HR, 0.91; P = .08), and had no association with fatal stroke risk (HR, 0.87; P = .30).
It is unclear why the association was weaker with stroke, but “coronary heart disease is a macrovascular disease, whereas stroke is microvascular,” Qi observed. “They affect different size blood vessels. So I think the etiology of stroke and coronary heart disease is totally different, even though there are some similarities.”
Of note, the association between glucosamine use and CHD was stronger in current smokers (37% lower risk) than in former (18%) or never smokers (12%; P = .004). This may reflect the anti-inflammatory effects of glucosamine, as smokers have more inflammation and a higher risk for CVD, he said.
There was no significant association between glucosamine use and stroke based on smoking status. The investigators also calculated genetic risk scores for CHD and stroke using previously reported single nucleotide polymorphisms and found no significant interactions between glucosamine use and either risk score on CHD or stroke risk.
“Really Provocative Data”
“This is interesting, really provocative data,” Laurence Sperling, MD, director of the Emory Heart Disease Prevention Center in Atlanta, Georgia, told theheart.org | Medscape Cardiology. “It’s hypothesis-generating but it’s a large cohort of long duration with a lot of events that at least adds some credence to this association.”
“But I would not recommend right now routine use of glucosamine for cardiovascular reduction until we have a critical mass of excellent cohort studies or the gold standard of a randomized controlled trial,” he said.
Although atherosclerosis is very clearly an inflammatory disease state, Sperling noted that the inflammatory pathways are complex and that there can be a downside when inflammation in suppressed biologically. Recent cardiovascular trials of anti-inflammatory drugs such as canakinumab (Ilaris, Novartis) in CANTOS and low-dose methotrexate in CIRT have produced mixed results.
Although some studies have suggested methotrexate may worsen glucose tolerance in persons at high risk for diabetes, subsequent clinical trials in healthy participants and patients with diabetes have shown this to be unfounded, Qi noted.
A cross-sectional Australian study, in which glucosamine use reached 22%, suggests that its finding of lower use in patients with cardiac conditions than in those with osteoporosis may be related to patients’ concerns or professional advice regarding the potential for drug interactions with prescription antiplatelets or anticoagulants.
Neither Sperling nor Qi were unaware of this potential interaction but Qi agreed that further investigation is needed before starting glucosamine for CVD reduction.
“For patients, I think at this stage we would not give any strong recommendation because the data is observation,” Qi said. “The most important thing is for not only epidemiologists, but people doing the basic science, to investigate why glucosamine affects cardiovascular disease. The second thing is test the casual relationship in clinical trials, which would not be very difficult.”
Although the authors note that glucosamine has been rated as the safest supplement for osteoarthritis, the study was limited by a lack of information in the UK Biobank on the side effects of glucosamine, the dosage and duration of glucosamine use, and the specific form of glucosamine in the supplements.
“If you have a patient with heart disease or cardiovascular risk, you should always be cautious about adding a supplement to the mix never knowing the impact of that until it’s very well studied,” Sperling said.
Patients also need to be forthright with their physicians if they are taking some type of supplement or herbal because “unless you specifically ask, you often don’t get those answers,” he said.
Qi was supported by grants from the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. Sperling reported no relevant financial relationships.
BMJ. Published online May 14, 2019. Full text