OR WAIT null SECS
Vitamins have generally not fared well in recent years when it comes to high-profile randomized controlled trials (RCTs) or meta-analyses that statistically combine selected data from those studies. Why is that?
Let’s face it. Vitamins have generally not fared well in recent years when it comes to high-profile randomized controlled trials (RCTs) or meta-analyses that statistically combine selected data from those studies.
There have been some notable exceptions. For example, the AREDS trials found a specific combination of vitamins reduced the risk of age-related macular degeneration, and the Physicians’ Health Study II suggested a modest benefit that significantly reduced the risk of total cancer in the study population.
There have also been secondary outcomes in clinical trials that have produced positive findings worth exploring further, as is the case in the VITAL trial that suggested reduction in the rate of cancer deaths for the study population taking vitamin D.
But by and large, RCTs hypothesizing that vitamins will prevent chronic disease have been a swing and a miss-something disappointing to everyone from study funders to researchers and from the supplement industry to consumers.
Does this signal the end in the vitamin research wars, with a white flag raised by the supplement industry? Not by a long shot. Instead, it’s time to refresh the arsenal.
What’s Null Got to Do With It
Consumers are sticking with vitamins. With supplement use at an all-time high according to the 2019 Council for Responsible Nutrition (CRN; Washington, DC) Consumer Survey on Dietary Supplements, vitamins/minerals continue to be the most commonly consumed supplement category, with 76% of Americans taking them annually. The multivitamin (58% percent of Americans take them) and vitamins D, C, B, and E are all firmly planted in the list of most popular supplements in CRN’s survey.
When it comes to the science, preeminent nutrition researcher Jeffrey B. Blumberg, PhD, FASN, FACN, at the Friedman School of Nutrition Science and Policy, Tufts University (Boston, MA), has a lot to say on this topic.
To begin with, Blumberg offers, “No investigator I know wants to come out with a null outcome from their studies. Investigators would like to see something positive.”
It’s understandable that researchers want to swing for the fences, hoping to make their mark with that home-run clinical trial that can elevate their reputation and help secure future grants. But given the multifactorial nature of chronic diseases like cancer and heart disease, why would anyone expect that a simple vitamin pill or even a combination of vitamins would, on their own, prevent cancer?
“No one disagrees that nutrient-deficient diets are a risk factor for chronic disease, but they’re just one risk factor,” says Blumberg. “Let’s look at the normative state of Americans today-66% are overweight or obese. Therefore, I could be taking 10 supplements a day, but if I’m also obese with a BMI of 35 and smoke two packs of cigarettes daily, it should come as no surprise that those supplements won’t work to prevent chronic disease.”
“It’s asking way too much of a supplement,” he concludes.
Does the Past Predict the Future?
So why conduct these trials? Why spend the money and the time and risk the disappointment?
Blumberg explains that clinical trials build on prior research. He says, “In order to justify doing a clinical trial, you’re saying there is evidence that this intervention could work based on earlier research, from in vitro studies, animal models, observational studies, and maybe some small clinical trials.” In other words, there’s been some hint of benefit that would warrant the use of sponsor funding and all the time and effort involved from a research team to take the next step to the large RCT. “No one does an RCT without evidence that there could be a benefit,” he points out.
However, if the RCT doesn’t confirm that benefit, there shouldn’t be a rush to deny the prior benefits discovered. Says Blumberg, “That’s a pretty big condemnation of all research approaches except for one. Maybe there’s something limited about that ‘gold standard’ of an RCT in that it’s not truly able to measure the benefits that were found in all of the other studies that justified that RCT in the first place.”
Vitamins Are Not Drugs
Blumberg continues, “RCTs are a good model to test drugs because they can be done quickly, effectively, and efficiently because if your drug doesn’t work in one or two years, you’re not going to even market it.”
He sees a potential disconnect in the financial viability and long-term researcher commitment that could result in some success for vitamins and chronic disease. He asserts that it takes 20-30 years for cancers and heart disease to develop and that nutrients work best over a lifetime. “To my knowledge, there has never been a 20-year RCT on any dietary supplement. What investigator wants to put in 20 years or more before they get their final results?” he asks.
To compound the issue of studying vitamins and chronic disease prevention and considering how any positive results might be communicated to consumers, there is also the matter of a mandated government disclaimer for product labels using certain categories of claims not pre-approved by FDA. Blumberg gets the irony. If supplement product labels need to state the product is not intended to “diagnose, treat, cure, or prevent any disease,” Blumberg wants to know “why is all this research focused on disease?”
The Wrong Question
According to Blumberg, “A big part of the problem has been asking the wrong question. It sounds like a reasonable one: how do dietary supplements prevent non-communicable diseases; which nutrients prevent cancer, heart disease, osteoporosis, COPD, you name it,” he says. But with the critical limitations of using RCTs to test nutrients, it’s probably not the right question, and it’s likely not even what consumers are looking for a vitamin to do.
That doesn’t mean Blumberg suggests eliminating all RCTs for future nutrition research. From his perspective, it’s not appropriate to tell any researcher how or what research he or she should conduct. He does, however, have some forward-thinking research considerations for studying vitamins that link new technology with improving the quality of life-two areas he thinks will make a difference.
Resetting the Bar for Science
One of the areas to consider is how the changing scientific landscape will reset the stage of nutrition and vitamin research.
According to Thomas Li, business development manager for IFF Health (New York City), an ingredient supplier and the manufacturer of the Grow Nutrients line of vitamins and minerals, “Science is key for us because it aligns with our message of being premium and high quality; we want to prove our ingredients work. In this age of transparency, having new data is crucial to staying relevant.”
Still, he contends: “While it is true that many well-known ingredients with long histories of traditional use usually have a lot of science behind them, many product claims still rest on outdated science. With the emergence of new technologies and personalized nutrition, the bar for scientific research should be set higher.”
The growing influence of personalized nutrition could change the research in numerous ways. Blumberg is not only energized about what that science means for individuals; he’s energized about how that discipline can translate into clinical research.
Blumberg is so energized, in fact, that he co-authored a paper on personalized nutrition for the American Nutrition Association (ANA; Hinsdale, IL), for which he serves as the Board Chair, published in December 2019 in the Journal of the American College of Nutrition. The paper proposed a definition of personalized nutrition as a “field that leverages human individuality to drive nutrition strategies that prevent, manage, and treat disease and optimize health.”
“If our diets are poor (and they are),” says Blumberg, “will taking vitamins help improve structure or function? I think the evidence is there that it does.”
The Future of Research
In addition to research evolving in these ways, changing attitudes could also help improve the way we study these nutrients.
For instance, improving the daily quality of life may or may not lead to a risk reduction for chronic disease, but if improving how we feel improves our health right now, that may be the right outcome.
Says Blumberg, “It’s an outcome we can measure. These kinds of studies are doable because I don’t need to do a 10-year study to see if my immune responses, my cognitive performance, my muscle strength, or my vascular reactivity are improving. I don’t even need 25,000 people to do it right. I’m using the individual as his or her own control, as well as doing a group analysis. I can design a parallel design or a crossover RCT design looking at a physiological response or structure response.”
He points to an observational study which he co-authored that published online in October 2018 in Scientific Reports. In that study, the researchers analyzed data from a personalized nutrition company that provided results from 1032 individuals who had a personalized nutrition analysis and agreed to allow their anonymized data (baseline through follow-up tests after incorporating suggested nutrient interventions) to be analyzed. “What we learned about them en masse is that their numbers changed,” said Blumberg. “We saw vitamin D levels go up, and we saw LDL cholesterol levels and glucose levels go down.”
Using technologies that study the ‘omics sciences’ (nutritional genomics, proteomics, metabolomics, etc.) allow for measuring thousands of metabolites at a time and is “enormously powerful,” he says. “I can look at a nutrient with not just one outcome, but clusters of outcomes.”
He’s realistic that while the possibilities for all these new technologies are endless, the costs may currently be a deterrent. But he’s not personally deterred. “Fifteen years ago, it cost about $1000 to test one genome; now it’s about $100.”
More Sophistication in Science
Blumberg strongly believes that predictive analytics will also play a role. “Now we’re using machine learning and artificial intelligence. I can measure 1000 things in your body through the use of omics to make predictions, but that’s too expensive. Can I actually look at just 10 things and make predictions? Machines can take massive amounts of data from massive amounts of people and look for patterns. People are building these tools now and trying to understand how only a limited set of biomarkers are needed to tell you something about the state of your health and wellness to make an impactful prediction. This will work for vitamins and other nutrients.”
Blumberg says that RCTs will be better designed when we have better biomarkers and when there are also novel statistical analyses to analyze observational data in a manner more like a clinical trial.
“Our sophistication in looking at molecular and biochemical outcomes is getting much better in doing assessments and making predictions, but at the same time people doing the biostatistics are developing more sophisticated algorithms and approaches than we used to have before,” he says.
Even as there is hope for future research, there is another dilemma the supplement industry faces: how best to get the research funded.
Nutrition research is not well-funded by the government, and academic institutions aren’t generally ponying up funds. Nor does there appear to be many (or any) Mike Bloomberg-esque scientists able to pull out personal checkbooks to fund their own studies. This is where industry can and should step in.
IFF Health prides itself “on the clinical science for our branded ingredients to prove and support the claims made in marketing. We have a robust clinical pipeline to keep enhancing this. Not only do we want to make sure our science is updated to be relevant with what the industry is demanding, but also to find new unique features to pass on to our customers. We conduct our own research, but also partner with customers on clinical studies as well as a value added to our services.”
Li advises “IFF Health is always looking to support our customers in joint studies utilizing their finished products with our ingredients,” as he sees “a big gap in the lack of finished products being used in science.”
Darned If You Do, Darned If You Don’t
Herein lies the quandary: While companies that support nutrition research should be commended, considering the general lack of funding, that research or funding is often discounted by the medical journals and not always welcomed by the consumer press because it comes from the industry.
Taylor C. Wallace, PhD, CFS, FACN, at George Mason University, and editor-in-chief at the Journal of Dietary Supplements, worked in the supplements industry for a short time and now runs “Think Healthy Group,” a food and science nutrition consulting firm with expertise in developing and executing research to support product claims, policy decision-making, and educational campaigns. Wallace insists that transparency disclosures should be “standard practices” and are used by “most researchers who are honest, credible, and transparent.” He says that “accusing” a scientist of “industry funding or industry bias” implies that the scientist “somehow deviated from standard procedure or either manipulated or fully fabricated data.”
Wallace says he “doesn’t know any credentialed scientist in the field that would even vaguely consider manipulating or fabricating data to suit an industry sponsor,” adding “that act would be career-ending, extremely unethical, and embarrassing.”
Blumberg, who was the director of the Antioxidants Research Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, has been an academic researcher for 44 years, beginning at Boston’s Northeastern University and joining the Tufts University faculty in 1981. He’s received research grants from the food and dietary supplements industries, served on industry scientific boards, and accepted honorariums to speak at industry conferences. He is also highly regarded in the scientific research community. Yet, he’s felt the discrimination that comes with working with industry and says he’s “not special in that regard.”
“You are tainted if you take money from a company or from a commodity board, even if it’s a non-branded thing-somehow it’s thought you can’t be objective,” says Blumberg. “How can I do the research if I don’t get the money to do it?”
He gets the catch-22 of it all-for himself and for the supplement industry. “You want to blame the supplement companies for not having evidence that their products work, but if they fund the studies to get the evidence, then you can’t believe the evidence because the company funded it.”
“No one questions that drug companies shouldn’t be funding their own clinical trials. It’s a conundrum that food and vitamin companies are demonized for supporting research that would provide evidence for their products. I don’t know how we ever get over the hump except to change attitudes,” Blumberg says.
Can We Change Attitudes?
Only time will tell. Wallace thinks it’s time for nutrition scientists to break away from using protocols, tools, and research methods that were designed for studies of drugs, noting that drugs and nutrients (or other bioactive constituents in food) are not the same.
Blumberg advises: “What we’re really talking about is promotion of health. There’s a difference between not-sick and sick, and a difference between not-sick and well.”
He explains that while someone may not be sick with a chronic disease, that doesn’t mean they’re well. What he’s interested in-and what he believes consumers are interested in-is the acute effect of vitamins in terms of physiology and structure or function.
“I might not have cancer or heart disease or dementia, but let’s say my immune system is sluggish, my energy levels are low, I don’t sleep well, I’m just not alert as I could be-these are things that are impacted by nutrient intake. These are measurable outcomes, and we know that nutrients have impacts on these outcomes,” says Blumberg.
If we can learn to think about vitamins this way, the world would find a whole new value for vitamins and supplements.
Judy Blatman Communications LLC specializes in strategic counsel, media training, writing, and talent solutions. In her spare time, Blatman volunteers as a puppy socializer for the nonprofit Hero Dogs.