Glucosamine Chondroitin Intake and Mortality

In this podcast, Dana E. King, MD, discusses his team’s latest research that examined the association between glucosamine/chondroitin supplement use and mortality rates, as well as what the study results could mean for the future of this supplement use in US adults.

Additional Resource:

• King DE, Xiang J. Glucosamine/chondroitin and mortality in a US NHANES cohort. J Am Board Fam Med. 2020;33(6):842-847. doi:10.3122/jabfm.2020.06.200110 

Dana E. King, MD, is the department chair and a professor of family medicine at West Virginia University School of Medicine in Morgantown, West Virginia.

TRANSCRIPT:

Leigh Precopio:  Hello, everyone. Welcome to another installment of "Podcasts360," your go‑to resource for medical news and clinical updates. I'm your moderator, Leigh Precopio, with Consultant360 Specialty Network.

Despite approximately 77% of adults in the United States taking dietary supplements, the benefits of many of these supplements remains unclear. Until recently, the widely used and widely available glucosamine/chondroitin combination supplement was no different. The researchers have a recent study sought to determine the efficacy of this supplement and found encouraging results.

Joining us today to discuss these results is one of the study authors, Dr Dana E. King, who is the department chair and professor of family medicine at West Virginia University School of Medicine. Thank you for joining me today, Dr King. Let's dive into your study.

Your study focused on examining the relationship between glucosamine/chondroitin intake, and overall and cardiovascular mortality in US adults. What prompted this research question?

Dana E. King:  I was prompted to investigate glucosamine/chondroitin intake due to a hobby of mine, which is cycling. That's bicycling not motorcycling, peddling ourselves in the country road cyclists, West Virginia. I noticed that almost everyone, just in casual conversation, admitted that they were taking glucosamine chondroitin.

I thought that was fascinating that there was such unanimity about it since in the literature glucosamine/chondroitin has had some positive studies but a lot of neutral studies.

As I was examining the literature about it to decide if I was going to take it or not, I noticed an interesting study from several years ago that had noted an association between intake of glucosamine/chondroitin and mortality. I said "Mortality? It makes you live longer? That's interesting." It was in a single state, in the state of Washington. And so I thought that my research associate and I could investigate that further.

Leigh Precopio:  You and your team found that taking glucosamine supplements every day for a year or longer was associated with a 39% reduction in all‑cause mortality, and a 65% reduction in cardiovascular mortality. Did this result surprise you, or did you anticipate this?

Dana E. King:  I personally was very surprised by the result. Interestingly enough, while we were doing our study, another study came out about glucosamine/chondroitin and mortality in the British Medical Journal, looking at 466,000 people in something called the UK Biobank.

In Great Britain, of course, the people are under one national health system and they have electronic medical record for much of the country. They had the opportunity to examine whether people were taking this supplement and check into death rates by just looking at their database they have for health care in their country.

Interestingly enough, they found about a 15% decrease in the likelihood of death from taking glucosamine/chondroitin. Now, interestingly enough also, about 20% of people, which was also shocking, were taking the supplement. Their definition was the answer to a question, "Are you taking this? Yes or no?" It's interesting that it was that high.

In our study in the National Health and Nutrition Examination Survey, we wanted to know about more consistent use. We did not ask just if you were taking it. We asked if you were taking it for a year or longer. That was about 4% of people, a much lower proportion.

Among these people who were taking it very regularly for a year or longer, we don't know how many years they took it, but still, this was fairly consistent use. We found 39% reduction in mortality after controlling for age and a 65% reduction in cardiovascular mortality. It was astounding to me, actually.

Leigh Precopio:  The results revealed that participants taking glucosamine/chondroitin were more likely to be older, be White, have a high school or higher education, not smoke, and exercise more. Could you further discuss how certain demographics may have impacted the study findings?

Dana E. King:  Demographics would definitely impact the study. For one thing, those are all factors that are involved in death rates and mortality. Age, obviously the older you get, the more likely you would be to pass away. Also, I guess unfortunately for myself, women live longer, so males are more likely to die sooner. Race has an impact on death rates also.

Now, we did not know that people of a certain age or people of a certain race or education would take the supplement, would be more likely to be users. There were significant differences, not by sex, but by age. As people were older, they were a little more likely.

And then by race, there were differences. Non‑Hispanic Whites were more likely to take the supplement. Although there were quite a few people of non‑Hispanic Blacks, Hispanics, and others. That's the way that the National Health and Nutrition Examination Survey categorized them, not us.

There were no differences in body mass index, so we did not use that as a control variable later. There were differences according to education. People with greater than high school education were more likely to be taking the supplement. Non‑smokers were more likely. People who exercise were more likely. It was about 60/40. 60% of people were exercising more than 150 minutes a week, whereas it was about 40/60 for people under 150 minutes a week of exercise. It was a little bit opposite proportion.

Because of that, we definitely had to take into account age, race, education. We did take into account smoking and exercise into account, and the findings into what we call a particular type of regression analysis, which is a Cox proportional hazards ratio analysis.

When we did that, we were still surprised to find that the initial findings were maintained. That people who were regular users of glucosamine/chondroitin were still less likely to have overall mortality and much less likely to have overall cardiovascular mortality.

Leigh Precopio:  How will these findings impact clinical practice and how physicians consider prescribing dietary supplements in the future?

Dana E. King:  Well, it's a little bit of a loaded question since the findings are so large in proportion, but I don't know that they'll have an outsize effect in physicians prescribing or recommending these supplements.

First of all, they are dietary supplements that are already used by millions of people. At 4% in the United States have approximately 300 million people use them. There's already greater than 12 million people using these supplements regularly. It's somewhat of an astounding number. Many more of them are using it casually or intermittently.

They are freely available at retail stores, drug stores, online merchants, etc. If and when free‑living patients hear about this, they may say, "I'm going to give that a try." Now, if they ask their physicians, I think they will get some advice about the fact that this is a long‑term cohort study, not a clinical trial. So the people that were taking the supplement, in this study, were self‑selected. There's going to be some biases. They were not randomized to take a particular supplement, a particular dose, and take it for 10 or 15 years.

Now, the strengths of the study are that we've started following people in 1999 and gathered people all the way up to 2010, and then checked the 2015 mortality index, merged those files, and we could see what happened to the people that we accumulated during that previous decade and whether or not they were still alive in 2015.

When you do an epidemiologic study like this, you want to take into account other factors that could have impacted either mortality or glucosamine intake. We felt like we did that.

Of course, you can take into account, always. There's always another factor and there's always two or three other things that you could have or should have taken into account. We felt like we took into account a reasonable number of confounding variables. No one can take into account all of them thus we've invented the concept of clinical trials where we randomize people so that the factors will be randomized to the two groups. When you're self‑selected, we're afraid that there's some other unknown factor that is not randomized. That's one of the weaknesses of epidemiology.

I always like to remind folks that before they write off epidemiologic studies, that smoking, and what we know about smoking was an epidemiologic finding.

There's never been a clinical trial. We never told half the people to smoke and half people not to smoke and then followed them for 25 years to see who got lung cancer. That has never happened, and it's not going to. We still strongly believe that smoking is not good for you. It's a significant factor in 90% of lung cancers, and so forth, as well as lung disease.

I personally think these were very strong findings. I think that that's for several reasons. We took into account other factors. It's a large study of over 16,000 people. They were followed for a long period of time. It's a national study with the national demographics of the United States, which is quite diverse. Interestingly, and simultaneously, while we were doing the study, the same direction of findings, and the same basic findings were found in Great Britain in a study of a half a million people. I don't think that the findings should be written off.

Nevertheless, epidemiologic studies usually raise as many questions as they solve. There seems to be an association. Is it causal? That cannot be proven in this way, and would have to be prospective or randomized trials, and a variety of other things such as looking at the mechanism.

In our paper, we presumed and looked at the literature and thought about what would be the mechanism of this? What could it be? You take an arthritis supplement, which has not really been very helpful, kind of marginally helpful for our cartilage and joints. And you say, "Oh, it makes you live longer." I mean, it's a little bit off base. We follow the science and we follow the observations. People said Benjamin Franklin was crazy when he said lightning was electricity, too. We follow our observations and keep asking questions.

I think there's something to it, personally. I think that in some short‑term prospective studies, that glucosamine/chondroitin has been associated with anti‑inflammatory effects, and lower inflammation biomarkers like C‑reactive protein, interleukins, and others.

We do have a plausible mechanism if glucosamine and chondroitin have a low‑grade anti‑inflammation effect from daily use. We know that that's a huge factor in cardiovascular disease and vascular health. It would make sense that we have seen the benefit in some cancers in the British study, and in cardiovascular mortality in our study, and then in an overall mortality.

It's also somewhat reassuring that it didn't lower cardiovascular mortality but caused something else to increase. The overall effect was zero. There's a net gain here, not necessarily causal yet, because it's not a clinical trial. It's very reassuring that that was maintained overall, that it doesn't increase something else that we didn't measure.

Physicians would do well to say, "Yeah, give it a try." The final reason is that there's no or almost minimal side effects. Occasionally, people will say, "Well, gee, it bothers my stomach," or, "The capsules are kind of large, and I have trouble swallowing them." There have been no long‑term effects. A government study of four years looking at glucosamine/chondroitin in relation to its arthritis and joint effects did not find any significant differences between glucosamine/chondroitin and placebo, and really no adverse effects.

It's something that many people and many patients will say, "Well, I might give it a try. I might just try it and if I tolerate it, and it seems to be OK, you know, who knows?" And we'll, kind of watch the literature. It's going to be awhile before we have "the final answer."

Leigh Precopio:  What knowledge gap still exists concerning glucosamine/chondroitin supplement use, both in general and in relation to mortality rates?

Dana E. King:  There's still knowledge gaps. As I mentioned, epidemiologic studies of this type raise more questions then they answer sometimes. It's a very intriguing finding. It does not answer the question of the mechanism. We've gotten a lot of questions about, "What was the dose?" There are at least 50 different combinations, and combinations of capsules of glucosamine/chondroitin on the market, and there are probably more I don't know about that could have been used by patients in this study.

The glucosamine/chondroitin supplements often have other supplements in them. Something called MSM, methylsulfonylmethane. They sometimes have turmeric in it. They sometimes have proprietary other substance supplements that the manufacturers come up with cute names for, like optimal whatever. There's sometimes other supplements in there. Was it these other supplements that did it or was it the glucosamine/chondroitin? Now I think the glucosamine/chondroitin is the consistent component. Nevertheless, there could be some other component that either helps or blunts the effect. We certainly don't know about that. We certainly don't know about the dose.

Now the manufacturers, and I do not know how they determine this, since they don't have to go through the FDA to get approval, because it's a supplement and not a prescribed medication. They have come up with a recommendation for 1,500 milligrams a day of glucosamine and 1,200 milligrams of chondroitin.

They are sometimes in 300‑milligram capsules, 400‑milligram capsules, 500‑milligram capsules for the glucosamine component. We don't know if that's good or bad. We don't know if it says you have to take five capsules a day, do people take all five. We did not put in the paper because we didn't feel comfortable with the analysis, frankly because it was so complex, and there were so many different types of supplements. Because I've been asked about it, we did an analysis after the paper to see if we could come as close as we could to an average dose that people took during the study.

Now remember, they were just said, "I've been taking this much, you know, for a year or more." That doesn't mean they took it consistently, for the 15 years between 1999, 2000 and 2015. Nevertheless, people were taking approximately half of the recommended dose. 600‑some or 700 milligrams of glucosamine, and then slightly less chondroitin.

We have a knowledge gap about how much it is you really need, or how much does it take to get the mortality benefit? Remember, in the UK Biobank study, they asked people, "Are you taking it?" "Oh, yes." The people, they just merely said yes.

Are they taking one a day, instead of five a day, or one a day instead of the recommended three a day, depending on the strength? Was that enough? Was taking it Monday, Wednesday, Friday enough? We don't know. That's a huge knowledge gap.

Finally, of course we haven't done the trial to end all trials, a 10‑year follow‑up study, which is admittedly going to be not only expensive but unlikely to do a 10‑year follow‑up mortality study for glucosamine, and give half the people glucosamine/chondroitin of 1500 milligrams and 1200 milligrams of chondroitin, and then placebo of that.

It's difficult to get people to do things for a month or three months or a year‑long study. It's huge. To achieve doing that for 10 years would be a monumental task. I'm worried and afraid that the knowledge gaps will remain.

This may be the great glucosamine mystery, but it's still interesting result to think that a pill a day could help you live longer, and has the same strength as exercise.

I made a joke, I said, "It's five o'clock one day, and you were running late and you wanted to get home for dinner," and say, "Should I go by the gym today or should I just pop on another glucosamine and head home?"

That was a joke because there's hundreds - no, thousands of studies and they are perspective that have shown that exercise is good for you. 150 minutes a week is good for you. Exercise is good at all ages. It was a statistical anomaly that the impact was the same as glucosamine in our study, but made for an interesting comparison and let people know about the strength of the association that we found.

I just to appreciate the opportunity to share with the public or in this case my colleagues about this study. I'm sure they'll understand the limitations of this study. I hope that we've stayed within the findings and our description of the results.

Leigh Precopio:  Great. Thank you again for answering all my questions today.