Summary DO-HEALTH first findings published in JAMA 2020
In the year 2030, one in three people in Europe will be over 65 years of age who all wish to be able to enjoy life actively into old age. The most important requirement for this is maintaining physical and mental health.
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The DO-HEALTH study led by the University of Zurich Professor of Aging Medicine Heike A Bischoff-Ferrari, in collaboration with a European & US network of researchers, examines the effect of three public health interventions among healthy adults aged 70+. These include an additional higher dose of vitamin D, omega-3 fatty acids (ω-3s), and a simple home strength-training exercise program. The first evaluation of primary outcomes shows no superior improvement in terms of bone fractures, leg and memory function by the interventions overall. However, the study suggests a reduction in all infections by ω-3s, with significant reductions in acute upper respiratory infections and urinary tract infections by ω-3s among all participants and a significant reduction of any infections among men. Also, vitamin D contributed to a significant reduction in any infections among younger participants age 70 to 74 and a reduction in systolic blood pressure among men.
A big thank you to all participants
Trial Design DO-HEALTH
Study design: DO-HEALTH was a 3-year double-blind, placebo-controlled, 2x2x2 factorial design randomized clinical trial. The trial included 2157 community-dwelling adults age 70 years and older, with good mobility and cognitive function and without major health events in the 5 years prior to enrolment. The trial included seven centers in 5 European countries (Switzerland, Germany, Austria, France, Portugal).
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Interventions: Participants were randomized in 8 treatment groups to receive 2000 IU/d vitamin D3, and/or 1 g/d of omega-3 fatty acids (ω-3s), and/or a strength-training exercise program. All study participants were allowed to take the current recommendation of 800 IU vitamin D per day next to the study medication.
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Main Outcomes and Measures: The six primary outcomes were: Change in systolic and diastolic blood pressure, the Short Physical Performance Battery (lower extremity function), the Montreal Cognitive Assessment (cognitive function), and incidence of non-vertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary endpoints, a p-value <0.01 was required for statistical significance.
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Overall Results: Among 2157 randomized participants (mean age 74.9 years; 61.7% women), 1900 (88%) completed the study. The median follow-up was 2.99 years. At year 3, participants randomized to vitamin D had higher mean serum concentrations of 25(OH)D than those not randomized to vitamin D (37.6 versus 24.4 ng/mL, respectively). Those randomized to ω-3s had higher concentrations of DHA and EPA compared to those not randomized to ω-3s (135.6 µg/mL vs. 76.3 for DHA and 64.7 µg/mL vs. 33.8 for EPA) at 3 years.
Over 3 years, all participants improved significantly with regard to systolic and diastolic blood pressure, lower extremity and cognitive function, and had a 3.5-fold lower than expected fracture rate. However, these benefits did not differ by any of the interventions individually or in combination. For all infections, however, ω-3 achieved a benefit that reached a p-value of 0.02, and for acute respiratory and urinary tract infections a p-value <0.01. For the two primary endpoints infection rate and systolic blood pressure, a significant benefit of vitamin D and ω-3 could be demonstrated in subgroups of the study population.
Vitamin D
For infections, there was a 16% reduction in the rate of infections among younger participants (age 70-74) in response to vitamin D ([99% CI 71%-99%], P=0.007).
For systolic blood pressure, there was a benefit of vitamin D among men with a mean reduction of -2.5 mmHg [99% CI -4.5, -0.4], P=0.002).
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Omega-3 (ω-3s)
For infections, ω-3s reduced the rate of any infections by 11% compared to placebo, however, missing the significance threshold of p < 0.01 (0.89, (99% CI 0.78-1.01; P=0.02) for any infection. Further, ω-3s significantly reduced the rate of upper respiratory infections by 10% (99% CI 81%-99%], P=0.005) and urinary tract infections by 62% (99% CI 23%-62%, P<0.0001) Also, men benefited significantly from ω-3s with a 22% reduction in the rate of any infection ([99% CI 61%-99%], P=0.008), and there was an 18% reduction in the rate of any infections in participants with higher baseline polyunsaturated fatty acid levels (DHA+EPA ≥100 ug/ml; [99% CI 68%-99%], P=0.007).
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For the strength-training exercise program,
there were no overall or subgroup benefits with regard to any of the six primary endpoints.
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Limitations: The unexpectedly low fracture rate and high physical activity of the study population led to a ceiling effect in the leg function test with the SPPB test and may have reduced our ability to detect small effects of the 3 interventions. In fact, 83% of DO-HEALTH participants were already moderately to heavily physically active at the start of the study, which may also have reduced the potential for benefits from the simple home exercise program. Also, only 40.7% of the participants were vitamin D deficient with 25 (OH) D values <20 ng / ml at the start of the study and all study participants were allowed to take the current recommendation of 800 IU vitamin D per day in addition to the study medication. Likewise, more participants than expected had values in the upper target range for the measurements of the SPPB leg function test and cognitive function at the start of the study, which could have reduced the chance of detecting small benefits of the interventions on these outcomes.
Strengths: The detailed follow-up with yearly visits and phone calls every 3 months in all participants, high adherence for all interventions, minimal mortality and loss to follow-up will support further evidence from the ancillary studies of DO-HEALTH, including the cost-effectiveness of the interventions, fall risk, incident cancer, frailty and more.
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Side effects: All interventions were well-tolerated without a greater risk of side effects compared to control.
Clinical perspective: The results of DO-HEALTH refer to active and relatively healthy people aged 70 and over. In this target population, DO-HEALTH supports:
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- supplementation with 1 g ω-3 / day for the prevention of acute respiratory and urinary tract infections.
- supplementation with an additional 2000 IU vitamin D per day for the prevention of any infections between the ages of 70 and 74, and blood pressure control in men aged 70 and older.
- DO-HEALTH does not support the supplementation with 1 g ω-3 / day or an additional supplementation with 2000 IU vitamin D / or the simple home training program with regard to the prevention of fractures, the prevention of cognitive decline as measured by the MoCA test and prevention of functional decline as measured with the SPPB test.
Our result regarding the effects of ω-3 and vitamin D on infections deserves further investigation, possibly also in the context of COVID-19.
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Given the high frequency and mortality related to infections among older adults1, these findings may have public health relevance.
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Impact on current recommendations
Our findings apply to the additional intake of 2000 IU vitamin D on top of the current recommendation of 800 IU vitamin D per day, and refer to the target population of active and relatively healthy adults age 70 and older.
Our findings do not invalidate current recommendations of 800 IU vitamin D among more vulnerable older adults at risk of osteoporosis and vitamin D deficiency for bone health and the prevention of vitamin D deficiency. Also, our findings do not invalidate the multiple health benefits of exercise programs on health.
What are further study results of DO-HEALTH?
Ancillary studies of DO-HEALTH are examining the interventions with regard to their cost-effectiveness, incident falls, incident cancer, incident cardio-vascular disease and changes in blood lipids, incident frailty, change in bone mineral density and incident vertebral fractures, change in mental health & depression, and other outcomes2. The results of the ancillary studies are expected in 2021 and will complete this evaluation of the potential role of the supplements and the home exercise program with regard to prevention and healthy aging.
¹ Mouton CP, Bazaldua OV, Pierce B, Espino DV. Common infections in older adults. Health Care Food Nutr Focus. 2001;18(3):1, 3-7.
² Bischoff-Ferrari HA, Molino CdGRC, Rival S, et al. DO-HEALTH: Vitamin D3 – Omega3 – Home exercise – Healthy aging and longevity trial – Design of a multinational clinical trial on healthy aging among European seniors. Contemporary Clinical Trials. 2020:106124.