2022 NBJ Award: Science and Innovation

Most folks know Mars Inc. as a candy company. They may or may not know about its strong presence in pet nutrition and veterinary services. But it's safe to say the average American has no clue that Mars has a robust research division devoted to improving human nutrition and health. And if that's the case, they are probably unaware that Mars Edge facilitated one of the most groundbreaking human nutrition studies ever—one that, according to its just-published first findings, has demonstrated significant cardioprotective potential for cocoa flavanols.

The nutrition industry, on the other hand, is well aware. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS)—sponsored by Mars Edge, Pfizer Consumer Healthcare and the National Institutes of Health and conducted independently by world-renowned investigators—is a very big deal. A unique academia-private-public partnership, COSMOS is the first large-scale clinical trial to assess the long-term effects of cocoa flavanols and multivitamins on cardiovascular and cancer risks.

Mars Edge didn't conduct this study, but it helped make COSMOS possible—and this is hardly the company's first foray into cocoa flavanols science. Mars has been investigating the bioactive compounds for more than 20 years in partnership with leading research institutions, government bodies and other organizations. This work has resulted in more than 170 peer-reviewed papers and more than 40 human clinicals. Cumulatively, Mars Edge has done a ton to build the body of knowledge around flavanols and their potential health benefits.

Related:2022 NBJ Award: Efforts on behalf of industry

To celebrate its rich history of research, and to commend its role in advancing nutrition science through COSMOS, NBJ is proud to grant Mars Edge the 2021 Science and Innovation Award.

Exemplary science

The study, consisting of a randomized, double-blind, placebo-controlled trial of more than 21,000 healthy men and women over a five-year period—and assessing real-deal clinical outcomes—is gold-standard research, and a model for what's possible in the nutrition industry. 

"Nutrition science needs to develop strong, persuasive and, most importantly, unbiased data to substantiate benefits of key dietary constituents," says Jim Griffiths, Ph.D., senior vice president of international and scientific research at CRN, which participated in COSMOS. "Epidemiological data has suggested that both multivitamins and polyphenolic compounds in food have significant health-promoting advantages, but blinded clinical studies are the only way to corroborate [that] and progress public health recommendations."

COSMOS is a rock-solid example of such a study. But perhaps even more remarkable than its scientific rigor is that a nutrition-focused human trial has delivered positive results. As industry knows all too well, this often doesn't happen, and there are very few human studies of dietary supplements to begin with. And when there are positive results, they often get obscured by overarching negative headlines.

That isn't the case with COSMOS, however. According to the first two papers published in The American Journal of Clinical Nutrition in March, participants given Mars Edge's standardized cocoa flavanol supplement had 27% reduced risk of cardiovascular disease death compared to placebo, as well as 16% lower odds of combined heart attack, stroke and deaths.

But those results account for all participants, whether or not they actually took their study pills. When looking only at those who complied with the protocol, the findings are even more profound. For the primary endpoint, total count of all cardiovascular events, the cocoa flavanol group showed a 15% reduction in risk. For the secondary endpoint, deaths from cardiovascular disease, there was a 39% risk reduction. The researchers noted other improved cardiovascular markers as well.

More studies are needed to corroborate these findings, but the initial results represent "several promising signals" of cocoa flavanols' potential, says co-principal investigator JoAnn Manson, M.D., chief of preventive medicine at Brigham and Women's Hospital and professor of medicine at Harvard Medical School. Should the results be replicated in future studies, Manson says, they could influence clinical guidelines for cardiovascular disease prevention. Again, a very big deal.

"The groundbreaking COSMOS study will provide extensive conclusions that the entire nutrition sector can explore and use in their own product-development programs," Griffiths says. "Kudos to Mars Edge for boldly going where nutrition science needs to go."

Pioneering analytical research

The road to exploring the health benefits of cocoa was an unexpected one for the maker of M&Ms and Snickers. It all started because Mars scientists were trying to understand flavor, specifically which compounds in cocoa influenced taste.

"Through that, we've developed strong analytical capabilities," says Catherine Kwik-Uribe, Ph.D., vice president of scientific and regulatory affairs at Mars Edge. "Our first publication was on the analysis of these compounds."

The deeper the researchers probed into cocoa flavanols, the more they wanted to learn about their bioactivity and influence on human health. "There were all these stories about the red wine paradox with resveratrol and the benefits of green tea," Kwik-Uribe says. "The molecules [in those botanicals] are very similar to the chemistry of cocoa, so could cocoa flavanols have some of the same effects? Piece by piece the story came together."

Over the next several years, Mars Edge made several landmark discoveries, including identifying the key bioactive flavanol in cocoa, (-)-epicatechin, and confirming its acute vascular benefits.

Industry stakeholders applaud this early work. "Mars Edge has shown leadership by investing significantly in the development and validation of official methods of analysis for high-quality characterization of cocoa flavanol materials," says Holly E. Johnson, chief science officer at American Herbal Products Association. 

Discovering health benefits

Over time, Mars Edge's research ambitions grew and "studies got bigger and longer and expanded to new areas, including cognitive health," Kwik-Uribe says. The company also began forming partnerships with outside research entities.

"We realized that to really understand more about the health effects of cocoa flavanols, we needed to collaborate with people who knew more than we did," Kwik-Uribe says. "But we don't do contract research or just hand stuff over and walk away. We are scientists, and we collaborate with experts to better understand what role flavanols have in health."

These partnerships, Kwik-Uribe adds, are rooted in transparency and allowing investigations to unfold as they will. "It's fundamentally about having a belief in a scientific question, picking the best investigators, making sure it works for both parties and then letting the science lead its own path," she says. "Nobody is hiding behind the research. It's not about what's good for Mars; it's what's good for science."

Well, Mars Edge has certainly done a lot of good for science. For example, one study, part of the pan-European research project Flaviola, demonstrated the sustained vascular benefits of cocoa flavanols in 100 healthy adults over one month. Kwik-Uribe says these results, published in the British Journal of Nutrition in 2015, were the first sign that daily cocoa flavanols intake may reduce cardiovascular risk per the Framingham Risk Score.

In the cognitive health realm, another 2015 paper, published in Nature Neuroscience, showed that cocoa flavanol intake enhances memory function in healthy adults, linking that improvement to a specific part of the hippocampus. A longer, larger-scale study in Scientific Reports in 2021 delivered even more evidence for cocoa flavanols' memory benefits. "This provided the first indications that diet quality may be an important determinant of healthy cognitive aging, a novel finding not just important to flavanols," Kwik-Uribe says.

Reflecting on Mars Edge's scientific strides, Kwik-Uribe calls it "a journey of 20-plus years, piecing together analytical chemistry, biochemistry, cardiovascular health and cognitive health, coming up the road to where we are now."

COSMOS comes alive

COSMOS was not Mars Edge's idea. Manson, who conducts large-scale randomized trials of promising nutritional interventions at Brigham and Women's, had been following the cocoa flavanols literature for some time and became interested in studying them further.

"They'd looked very promising for many years, both in observational studies and small randomized trials," she says. "We were increasingly seeing small-scale, mechanistic trials on high-dose cocoa flavanols and blood pressure lowering, flow-mediated dilation, inflammatory markers and glucose tolerance."

Having just finished recruitment for the now-well-known vitamin D and omega-3 Trial (VITAL), Manson hoped to launch a parallel study to test the effects of flavanols on multiple cardiovascular endpoints in older men and women. To do so, she'd need a standardized cocoa flavanol supplement.

Noting Mars Edge's involvement in past research, Manson called up the company in 2013 to propose a collaboration. Kwik-Uribe says it wasn't an immediate "yes" for Mars Edge. But once they learned more about the project, hammered out their role and established guardrails, they eagerly signed on.

"Mars was interested because their mechanistic studies had been very promising," Manson says. "They hadn't yet looked at clinical events like heart attack, stroke or cardiovascular disease death in a large, randomized trial, so the logical next step was a large-scale trial with clinical endpoints. In some ways, the rest is history."

Collaboratively, Manson, co-principal investigator Howard Sesso and Mars Edge designed the trial, adding the multivitamin component because multis had looked promising for cancer risk reduction in an earlier trial. They conducted nationwide recruitment, pulling some participants from ongoing cohorts such as VITAL and the Women's Health Initiative. "Ultimately, we randomized 21,442 participants from every state," Manson says.

Throughout this entire process, Manson says her team and Mars Edge have maintained an excellent working relationship. "We have a very strong firewall with all industry partners, and Mars has been very respectful of that, allowing us to maintain complete independence," she explains. "Because Mars also has scientists and a very strong research orientation, the company has been very interested in supporting additional studies to help us understand the COSMOS study findings."

For example, Mars Edge sponsored the collection of blood samples from some 9,000 participants, allowing for analysis of biomarkers such as glucose levels and telomere length. The company also supported in-clinic visits for about 600 participants to conduct a range of detailed tests. Manson says these efforts made it possible to examine the effects of cocoa flavanols on a variety of biological pathways.

The next galaxy

While COSMOS has generated two pivotal publications, Kwik-Uribe insists they are only the beginning. "There will be a lot more to unpack over the next decade," she says. "In the next few months we expect papers looking more in-depth at secondary endpoints such as blood pressure and glucose. Also, COSMOS includes a multiyear cognitive study, and we expect that research to be out soon." Additionally, Manson hopes to continue follow-up of the cohort to see if the results strengthen or weaken over time.

But for Mars Edge, the science certainly won't end with this trial. "COSMOS is not the culmination of our work—we are not done," Kwik-Uribe says. "It's an important milestone that likely opens up another chapter of exciting research by Mars and others."

This next chapter, she notes, can extend well beyond the cocoa plant. "Now we're in a position where cocoa flavanols have been shown to reduce the risk of cardiovascular disease and support health as we age. Full stop," Kwik-Uribe says. "I hope this means that for many decades to come, Mars and others, whether in the carotenoid, omegas or lutein field, are talking about the bioactive components in food and their role in health. We've been talking about vitamins and minerals for a long time, but the evidence increasingly points to food being more than the sum of its vitamin and mineral parts."

Ultimately, she hopes this conversation advances to the consumer domain. "Consumers are fundamentally interested in doing good things for their health, whether it's knowing which foods to eat or which supplements to take," Kwik-Uribe says. "But [experts] are hesitant to make recommendations around bioactive components." As more evidence illuminates areas in which certain compounds have an effect, such as for heart health, as well as areas in which they don't, she hopes clearer consumer guidance can emerge.

For industry, COSMOS is a shining example of how private-public partnerships can propel science for the benefit of all. "Industry can and does bring value to the table from a scientific perspective," Kwik-Uribe says. "Usually, companies have the most in-depth knowledge about the material, consumers or other aspects that are valuable to research. But it is important to be open and transparent and establish your guardrails upfront."

It's also essential to accept that legit research and analysis present risk. "We do studies because there is a fundamental scientific question and we want to test a hypothesis," Kwik-Uribe says. "Once studies are running, they are out of your control, and it's not guaranteed which way the science will go. But you have to let the science be the science and publish your findings. Be willing to accept that each paper, whether it supports the hypothesis or not, adds value to science."]

The fact that Mars Edge accepts this responsibility in the name of science is highly commendable. "Sometimes companies are reticent to invest in large-scale clinical studies looking at long-term effects of consistent dietary supplement use in healthy humans," says AHPA's Johnson. "Mars Edge has shown leadership in recognizing the value and impact of conducting this type of large study in healthy humans."