Vitamin D and Omega 3 Supplements Do Not Reduce Risk of Systemic Inflammation

Results from VITAL study find that neither supplement taken over the course of a year was associated with a decrease in biomarkers of inflammation

Vitamin D and marine omega-3 fatty acids — also known as fish oil — are purported to have many health benefits, including reducing systemic inflammation. Signals of systemic inflammation are tied to diseases of aging and obesity, including cardiovascular disease, heart failure, osteoporosis, diabetes mellitus, some cancers, and neurodegenerative diseases such as Alzheimer’s disease. While many consumers take supplements with the intention of lowering their inflammation and preventing disease, an analysis of the VITamin D and OmegA-3 TriaL (VITAL) by investigators at Brigham and Women’s Hospital indicates that neither vitamin D nor omega-3s were effective at reducing systemic inflammation. The team’s results are published in Clinical Chemistry.

“People commonly think that these supplements can prevent inflammatory diseases, but when a patient asks their doctor, ‘Should I take this supplement?’ doctors often don’t know what to advise because there haven’t been large scale clinical trials. VITAL provides a large dataset to address these questions,” said corresponding author Karen Costenbader, MD, MPH, director of the Lupus Program in the Division of Rheumatology, Inflammation and Immunity. “In this case, there isn’t a strong message that either supplement will reduce risk of systemic inflammation, at least not the biomarkers of disease.”

The VITAL study is a randomized, double-blind, placebo-controlled trial in which investigators tested the effects of supplements of vitamin D (2000 IU/day), omega 3s (1 gm/day) or both. For this analysis, Costenbader and colleagues tested levels of three known biomarkers of inflammation at the start of the trial and after one year of taking supplements or a placebo. They were interleukin-6 (IL-6), tumor necrosis factor-receptor 2, and high sensitivity C-reactive protein (hsCRP).

The team found that neither supplement reduced the biomarkers at one year. Surprisingly, among those taking the vitamin D supplement, instead of decreasing, IL-6 levels rose by 8.2 percent. The investigators also report that among participants who had lower fish intake at the start of the trial, hsCRP levels did decline for those taking the omega-3 supplement.

The authors note that they analyzed biomarkers for only a subgroup of the original trial’s population — approximately 1,500 of the over 25,000 participants — but they carefully selected a representative sample. In addition, VITAL only tested one formulation each of vitamin D and omega-3 supplements. A multitude of supplements are available.

“While the bottom line is that we didn’t see a reduction in markers of inflammation for those who took either supplement, we did see that people whose fish intake was low at baseline had a reduction in one of the biomarkers of inflammation,” said Costenbader. “It will be interesting and important to see the results of future VITAL analyses, especially those that look at risk of diseases rather than biomarkers.”

Funding for this work was provided by National Institute of Arthritis, Musculoskeletal and Skin Diseases R01 AR059086. VITAL was supported by grants U01 CA138962 and R01 CA138962, which included support from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. The ancillary studies are supported by the National Heart, Lung and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Mental Health; and others. Pharmavite LLC of Northridge, California (vitamin D) and Pronova BioPharma of Norway and BASF (Omacor n-3 FA) donated the study agents, matching placebos, and packaging in the form of calendar packs. Quest Diagnostics (San Juan Capistrano, CA) measured serum 25-hydroxyvitamin D and the n-3 phospholipid fatty acids at no cost to the study.

Paper cited: Costenbader, K et al. “The Effects of One Year of Vitamin D and Marine Omega-3 Fatty Acid Supplementation On Biomarkers of Systemic Inflammation in Older U.S. Adults” Clinical Chemistry DOI: 10.1373/clinchem.2019.306902.

Predicting Frailty, Disability and Death

Using a wristwatch-like device, researchers detected fluctuations in the daily motor activity of older adults that could predict increased risk of deteriorated quality of life or death years later

Movement is a part of daily life that most people rarely spend time contemplating, but changes in such movements can portend disease and decline. Watch-like devices known as actimetry sensors, which can be worn on the wrist or ankle, allow researchers to collect information about a subject’s motor activity. In a study led by investigators from Brigham and Women’s Hospital, researchers analyzed patterns of movement among elderly study participants and found that irregular, spontaneous fluctuations could predict a person’s risk of frailty, disability and death years later. Their results are published in Science Translational Medicine. 

“Human movements possess complex fluctuations that are not simply determined by scheduled events. In this study, we found that more random activity fluctuations were associated with increased risk for frailty, disability and mortality in older adults,” said corresponding author Peng Li, PhD, an associate physiologist in the Brigham’s Medical Biodynamics Program, Division of Sleep and Circadian Disorders. “Importantly, these alterations occurred many years before any incident when people still had no overt symptoms, providing a possible opportunity of early prediction and prevention.”

To conduct their study, Li and colleagues analyzed motor activity data from 1,275 older participants and looked at the participants’ outcomes up to 13 years later. Motor activity data were collected daily using an activity monitor that participants wore on their wrist.

The team found that elderly people with more random fluctuations in daily motor activity had increased risk of death, disability and frailty. Specifically, the team reports that risk of frailty increased by 31 percent, the risk of disability increased by 15 to 25 percent, and the risk of death increased by 26 percent for one standard deviation increase in the randomness from the mean.

The authors note that to establish the current technique as a diagnostic tool, results will need to be replicated in a larger dataset. Participants in the current study were relatively old and it remains to be determined if the same method can predict outcomes in middle-aged and younger adults.

As compared to traditional clinical assessments, actimetry sensors are unobtrusive, cost-efficient, and feasible for long-term health monitoring. In addition, traditional activity measures such as physical activity levels and daily activity rhythms can be affected by the daily schedules and environmental conditions (such as interactions with caregivers). The proposed fractal measures are less affected by these external influences.

“Our proposed motor activity measures may provide a potential tool for remote medicine and facilitate mobile health care, which is clearly important considering the challenge of population aging on health care systems all over the world,” said Li.

Funding for this work was provided by the National Institutes of Health (grant numbers RF1AG059867, RF1AG064312, R01AG048108, and R01AG048108-04S1, R01AG017917, R01NS078009, R56AG59732, R01AG47976, R01AG056352, P01AG009975) and the International Postdoctoral Exchange Fellowship (grant number 20150042) from the China Postdoctoral Council.

Paper cited: Li, Peng et al. “More random motor activity fluctuations predict incident frailty, disability, and mortality” Science Translational Medicine DOI: 10.1126/scitranslmed.aax1977

Investigators Build a Better Targeted Drug Therapy Using the Power of Computation

Team designs LEGO-like linkers that can stably click a drug payload to an antibody that can bind to tumor tissue with specificity

Antibody drug conjugates (ADCs) — cancer drugs that are designed to target and destroy cancerous tissue while leaving healthy cells intact — represent a long sought-after advancement in cancer therapy. ADCs work by attaching a cancer drug to an antibody that is unique to a specific type of tissue, allowing ADCs to deliver treatment directly to the site of a tumor rather than throughout the body. To date, five ADCs have received Federal Drug Administration approval for treating cancer and 56 drug companies are developing ADCs. However, ADCs currently have substantial limitations. They can have unpredictable effects and may be unstable, losing their payloads and producing toxicity. Investigators from Brigham and Women’s Hospital set out to design more stable and predictable ADCs by using computer simulations to predict and plan out how the drug payload and antibody can stay linked to each other. The team tested out their predictions in human and mouse plasma and in a model of human lung adenocarcinoma. Their findings are published in Nature Biomedical Engineering.

“The goal of this technology is to empower currently used antibodies in cancer treatment, making them more effective against cancer,” said corresponding author Shiladitya Sengupta, PhD, an associate professor of medicine in the Division of Engineering in Medicine at the Brigham. “We designed a LEGO-like linker that just clicks a drug payload to any antibody we want. That means we can deliver a drug specifically to any tissue that expresses the target of the antibody.”

Sengupta and colleagues used computational docking molecular simulations to create prototype that could link an antibody and drug payload. They mapped the binding sites to determine how ligand-drug pairs would bind to different antibodies. They synthesized the various components and showed that when they were incubated together, they could self-assemble into ADCs, like magnets that find one another. Inspired by this observation, the team named this approach MAGNET ADCs, which stands for multivalent and affinity-guided antibody empowerment technology.

The team reports that MAGNET ADCs could be generated rapidly and did not require modifying antibodies. The MAGNET ADCs showed long-term stability in plasma, lasting 14 days and showing low toxicity. The team tested MAGNET ADCs in a model for human lung cancer, but the authors note that this technology could be adapted to a variety of therapeutic or diagnostic uses.

“We envisage that the MAGNET-ADC approach can be extended to a wide range of therapeutic molecules as well as to diagnostics, with potential uses beyond the treatment of cancer,” the authors write.

Sengupta is a co-founder and board member of Akamara Therapeutics and owns equity in the company. Three co-authors are employees of Akamara Therapeutics and also own equity. Co-authors are listed as inventors on a patent on this technology.

Paper cited: Gupta, N et al. “Computationally designed antibody–drug conjugates self-assembled via affinity ligands” Nature Biomedical Engineering DOI: 10.1038/s41551-019-0470-8

Study Looks at Distribution of New Cases of Diabetes, Density of Specialists

Endocrinologists limited in certain states; cardiologists well positioned to engage with care teams

In the last five years, the landscape of type 2 diabetes treatment has changed dramatically. Two new classes of drugs — SGLT2 inhibitors and GLP-1 receptor agonists — have been shown to prevent some of the most serious diabetes complications, including heart and kidney conditions, in patients. While primary care physicians treat the majority of patients with type 2 diabetes, many patients also seek out internal medicine specialists, including nephrologists, endocrinologists and cardiologists for care. To better understand the distribution of specialists in the U.S. who may be able to help care for the rising number of patients with diabetes, researchers from Brigham and Women’s Hospital analyzed national data on the prevalence of diabetes and the number of internal medicine specialists in each U.S. state. They found that cardiologists were the highest represented specialists and conclude that they are well positioned to be integral members of a patient’s care team. Their findings are published in JAMA Cardiology.

“While patients with diabetes traditionally seek care from endocrinologists and/or primary care physicians, these national data suggest that a broader network of clinicians, including cardiologists and nephrologists, may provide additional avenues for care delivery,” said corresponding author Muthiah Vaduganathan, MD, MPH, a cardiologist at the Brigham. “This is especially important as the cardiovascular and renal risks associated with diabetes are becoming increasingly recognized, and as new strategies become available to modify disease course.”

Vaduganathan and colleagues used 2016 data from the U.S. Centers for Disease Control and Prevention U.S. Diabetes Surveillance System to find the number of new diabetes cases in each state. They also gathered data on the number of practicing endocrinologists, cardiologists,

and nephrologists in each U.S. state using 2016 Centers for Medicare and Medicaid Services physician and other supplier public files.

In 2016, 1.9 million U.S. adults were newly diagnosed with diabetes. Colorado had the lowest density of cases (6.2 percent) and Puerto Rico had the highest (13.7 percent). The density of specialists varied widely, but overall, cardiologists were the highest represented specialists and there was a lower ratio of patients with diabetes to cardiologists than to nephrologists or endocrinologists.

“For any patient seeing a specialist, it’s important to ask how your diabetes may put you at risk and if there’s anything that can be done to reduce risk,” said lead author Ravi B. Patel, MD, a former internal medicine resident at the Brigham. Patel is now a clinical fellow in cardiovascular medicine at Northwestern University. “Diabetes is a systemic disease and should be treated as such, with many specialists as part of a team providing optimal care.”

Patel is supported by National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL069771.Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator

Training award from Harvard Catalyst (National Institutes of Health [NIH]/National Center for Advancing Translational Sciences award UL 1TR002541); serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, and Boehringer Ingelheim; and participates on clinical end point committees for studies sponsored by Novartis and the NIH.

Paper cited: Patel, R et al. “Implications of Specialist Density for Diabetes Care in the United States” JAMA Cardiology DOI:10.1001/jamacardio.2019.3796



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