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Effects of vitamin D, omega-3 and a simple strength exercise programme in cardiovascular disease prevention: The DO-HEALTH randomized controlled trial.
Gaengler, S, Sadlon, A, De Godoi Rezende Costa Molino, C, Willett, WC, Manson, JE, Vellas, B, Steinhagen-Thiessen, E, Von Eckardstein, A, Ruschitzka, F, Rizzoli, R, et al
The journal of nutrition, health & aging. 2024;(2):100037
Abstract
BACKGROUND The effects of non-pharmaceutical interventions in the prevention of cardiovascular diseases (CVD) in older adults remains unclear. Therefore, the aim was to investigate the effect of 2000 IU/day of vitamin D3, omega-3 fatty acids (1 g/day), and a simple home strength exercise program (SHEP) (3×/week) on lipid and CVD biomarkers plasma changes over 3 years, incident hypertension and major cardiovascular events (MACE). METHODS The risk of MACE (coronary heart event or intervention, heart failure, stroke) was an exploratory endpoint of DO-HEALTH, incident hypertension and change in biomarkers were secondary endpoints. DO-HEALTH is a completed multicentre, randomised, placebo-controlled, 2 × 2 × 2 factorial design trial enrolling 2157 Europeans aged ≥70 years. RESULTS Participants' median age was 74 [72, 77] years, 61.7% were women, 82.5% were at least moderately physically active, and 40.7% had 25(OH)D < 20 ng/mL at baseline. Compared to their controls, omega-3 increased HDL-cholesterol (difference in change over 3 years: 0.08 mmol/L, 95% CI 0.05-0.10), decreased triglycerides (-0.08 mmol/L, (95%CI -0.12 to -0.03), but increased total- (0.15 mmol/L, 95%CI 0.09; 0.2), LDL- (0.11 mmol/L, 0.06; 0.16), and non-HDL-cholesterol (0.07 mmol/L, 95%CI 0.02; 0.12). However, neither omega-3 (adjustedHR 1.00, 95%CI 0.64-1.56), nor vitamin D3 (aHR 1.37, 95%CI 0.88-2.14), nor SHEP (aHR 1.18, 95%CI 0.76-1.84) reduced risk of MACE or incident hypertension compared to control. CONCLUSION Among generally healthy, active, and largely vitamin D replete, older adults, treatment with omega-3, vitamin D3, and/or SHEP had no benefit on MACE prevention. Only omega-3 supplementation changed lipid biomarkers, but with mixed effects. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER NCT01745263.
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Effects of Vitamin D, Omega-3 Fatty Acids and a Home Exercise Program on Prevention of Pre-Frailty in Older Adults: The DO-HEALTH Randomized Clinical Trial.
Gagesch, M, Wieczorek, M, Vellas, B, Kressig, RW, Rizzoli, R, Kanis, J, Willett, WC, Egli, A, Lang, W, Orav, EJ, et al
The Journal of frailty & aging. 2023;(1):71-77
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BACKGROUND The benefits of supplemental vitamin D3, marine omega-3 fatty acids, and a simple home exercise program (SHEP) on frailty prevention in generally healthy community-dwelling older adults are unclear. OBJECTIVE To test the effect of vitamin D3, omega-3s, and a SHEP, alone or in combination on incident pre-frailty and frailty in robust older adults over a follow-up of 36 months. METHODS DO-HEALTH is a multi-center, double-blind, placebo-controlled, 2x2x2 factorial randomized clinical trial among generally healthy European adults aged 70 years or older, who had no major health events in the 5 years prior to enrollment, sufficient mobility and intact cognitive function. As a secondary outcome of the DO-HEALTH trial, among the subset of participants who were robust at baseline, we tested the individual and combined benefits of supplemental 2,000 IU/day of vitamin D3, 1 g/day of marine omega-3s, and a SHEP on the odds of being pre-frail and frail over 3 years of follow-up. RESULTS At baseline, 1,137 out of 2,157 participants were robust (mean age 74.3 years, 56.5% women, mean gait speed 1.18 m/s). Over a median follow-up time of 2.9 years, 696 (61.2%) became pre-frail and 29 (2.6%) frail. Odds ratios for becoming pre-frail were not significantly lower for vitamin D3, or omega 3-s, or SHEP, individually, compared to control (placebo for the supplements and control exercise). However, the three treatments combined showed significantly decreased odds (OR 0.61 [95% CI 0.38-0.98; p=0.04) of becoming pre-frail compared to control. None of the individual treatments or their combination significantly reduced the odds of becoming frail. CONCLUSION Robust, generally healthy and active older adults without major comorbidities, may benefit from a combination of high-dose, supplemental vitamin D3, marine omega-3s, and SHEP with regard to the risk of becoming pre-frail over 3 years.
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Effects of vitamin D, omega-3 fatty acids, and a simple home strength exercise program on fall prevention: the DO-HEALTH randomized clinical trial.
Bischoff-Ferrari, HA, Freystätter, G, Vellas, B, Dawson-Hughes, B, Kressig, RW, Kanis, JA, Willett, WC, Manson, JE, Rizzoli, R, Theiler, R, et al
The American journal of clinical nutrition. 2022;(5):1311-1321
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BACKGROUND The roles of vitamin D, omega-3 fatty acids, and home exercise on fall prevention among generally healthy and active older adults are unclear. OBJECTIVES We tested the effects of daily supplemental vitamin D, daily supplemental marine omega-3s fatty acids, and a simple home exercise program (SHEP), alone or in combination, on the incidences of total and injurious falls among generally healthy older adults. METHODS We performed a 2 × 2 × 2 factorial-design randomized controlled trial among 2157 community-dwelling adults aged 70 years and older, who had no major health events in the 5 years prior to enrolment, recruited from Switzerland, Germany, Austria, France, and Portugal between December 2012 and November 2014. Participants were randomly assigned to supplementation with 2000 international units/day of vitamin D3 and/or 1 g/day of marine omega-3s, and/or a SHEP compared with placebo and/or control exercise over 3 years. The primary endpoint for the present fall analysis was the incidence rate of total falls. Falls were recorded prospectively throughout the trial. Since there were no interactions between treatments, the main effects are reported based on a modified intent-to-treat analysis. RESULTS Of 2157 randomized participants, 1900 (88%) completed the study. The mean age was 74.9 years, 61.7% were women, 40.7% had a serum 25-hydroxyvitamin D concentration < 20 ng/ml, and 83% were at least moderately physically active. In total, 3333 falls were recorded over a median follow-up of 2.99 years. Overall, vitamin D and the SHEP had no benefit on total falls, whilst supplementation with omega-3s compared to no omega-3 supplementation reduced total falls by 10% (incidence rate ratio = 0.90; 95% CI, 0.81-1.00; P = 0.04). CONCLUSIONS Among generally healthy, active, and vitamin D-replete older adults, omega-3 supplementation may have a modest benefit on the incidence of total falls, whilst a daily high dose of vitamin D or a SHEP had no benefit.
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Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial.
Bischoff-Ferrari, HA, Vellas, B, Rizzoli, R, Kressig, RW, da Silva, JAP, Blauth, M, Felson, DT, McCloskey, EV, Watzl, B, Hofbauer, LC, et al
JAMA. 2020;(18):1855-1868
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IMPORTANCE The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear. OBJECTIVE To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults. DESIGN, SETTING, AND PARTICIPANTS Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017. INTERVENTIONS Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270). MAIN OUTCOMES AND MEASURES The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance. RESULTS Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups. CONCLUSIONS AND RELEVANCE Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01745263.
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Effect of daily 2000 IU versus 800 IU vitamin D on blood pressure among adults age 60 years and older: a randomized clinical trial.
Abderhalden, LA, Meyer, S, Dawson-Hughes, B, Orav, EJ, Meyer, U, de Godoi Rezende Costa Molino, C, Theiler, R, Stähelin, HB, Ruschitzka, F, Egli, A, et al
The American journal of clinical nutrition. 2020;(3):527-537
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BACKGROUND Observational studies report higher blood pressure (BP) among individuals with lower 25-hydroxyvitamin D concentration. Whether dosage of vitamin D supplementation has a differential effect on BP control remains unclear. OBJECTIVE The study aimed to determine if daily vitamin D supplementation with 2000 IU is more effective than 800 IU for BP control among older adults. METHODS This randomized, double-blind, ancillary trial of the Zurich Multiple Endpoint Vitamin D Trial in Knee Osteoarthritis enrolled adults aged ≥60 y who underwent elective surgery due to severe knee osteoarthritis. Participants were randomly assigned to receive high dose (2000 IU) or standard dose (800 IU) daily vitamin D3 for 24 mo. Outcomes included daytime and 24-h mean systolic BP. BP variability and serum 25-hydroxyvitamin D concentration were examined in a post hoc and observational analysis. RESULTS Of the 273 participants randomly assigned, 250 participants completed a follow-up 24-h ambulatory BP monitoring (mean age: 70.4 ± 6.4 y; 47.2% men). The difference in daytime mean systolic BP reduction between the 2000 IU (n = 123) and 800 IU (n = 127) groups was not statistically significant (-2.75 mm Hg vs. -3.94 mm Hg; difference: 1.18 mm Hg; 95% CI: -0.68, 3.05; P = 0.21), consistent with 24-h mean systolic BP. However, systolic BP variability was significantly reduced with 2000 IU (average real variability: -0.37 mm Hg) compared to 800 IU vitamin D3 (0.11 mm Hg; difference: -0.48 mm Hg; 95% CI: -0.94, -0.01; P = 0.045). Independent of group allocation, maximal reductions in mean BP were observed at 28.7 ng/mL of achieved serum 25-hydroxyvitamin D concentrations. CONCLUSIONS While daily 2000 IU and 800 IU vitamin D3 reduced mean systolic BP over 2 y to a small and similar extent, 2000 IU reduced mean systolic BP variability significantly more compared with 800 IU. However, without a placebo control group we cannot ascertain whether vitamin D supplementation effectively reduces BP.This trial was registered at www.clinicaltrials.gov as NCT00599807.
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Starch Digestion-Related Amylase Genetic Variants, Diet, and Changes in Adiposity: Analyses in Prospective Cohort Studies and a Randomized Dietary Intervention.
Heianza, Y, Zhou, T, Yuhang, C, Huang, T, Willett, WC, Hu, FB, Bray, GA, Sacks, FM, Qi, L
Diabetes. 2020;(9):1917-1926
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Salivary amylase, encoded by the AMY1 gene, is responsible for the digestion of carbohydrates. We investigated associations of AMY1 genetic variations with general and central adiposity changes considering dietary carbohydrate intake among 32,054 adults from four prospective cohort studies. A genetic risk score (GRS) was calculated based on nine AMY1 single-nucleotide polymorphisms, with higher AMY1-GRS indicating higher activity of salivary amylase. We meta-analyzed interactions between AMY1-GRS and dietary intake for changes in general and central adiposity over 5.5-10 years. We found that carbohydrate food intake significantly altered associations of AMY1-GRS with changes in BMI (P interaction = 0.001) and waist circumference (P interaction < 0.001). Results were consistent and significant in female cohorts rather than in male cohorts. Among women, higher AMY1-GRS was associated with more increases in adiposity if dietary carbohydrate food intake was high, while higher AMY1-GRS was associated with less gains in adiposity when the dietary intake was low. Also, in a 2-year randomized dietary intervention trial, associations of AMY1-GRS with changes in weight (P interaction = 0.023) and waist circumference (P interaction = 0.037) were significantly modified by carbohydrate intake. Our results suggest the importance of precision nutrition strategies considering participants' genetic adaptation to carbohydrate-rich diets in regulating general and central adiposity.
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Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease.
Manson, JE, Cook, NR, Lee, IM, Christen, W, Bassuk, SS, Mora, S, Gibson, H, Gordon, D, Copeland, T, D'Agostino, D, et al
The New England journal of medicine. 2019;(1):33-44
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BACKGROUND It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. METHODS We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. RESULTS A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSIONS Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).
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Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance).
Morales-Oyarvide, V, Yuan, C, Babic, A, Zhang, S, Niedzwiecki, D, Brand-Miller, JC, Sampson-Kent, L, Ye, X, Li, Y, Saltz, LB, et al
Journal of the National Cancer Institute. 2019;(2):170-179
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BACKGROUND Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients. METHODS We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided. RESULTS High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability. CONCLUSIONS Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.
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Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer.
Manson, JE, Cook, NR, Lee, IM, Christen, W, Bassuk, SS, Mora, S, Gibson, H, Albert, CM, Gordon, D, Copeland, T, et al
The New England journal of medicine. 2019;(1):23-32
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BACKGROUND Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear. METHODS We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo. RESULTS A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed. CONCLUSIONS Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).
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Substituting brown rice for white rice on diabetes risk factors in India: a randomised controlled trial.
Malik, VS, Sudha, V, Wedick, NM, RamyaBai, M, Vijayalakshmi, P, Lakshmipriya, N, Gayathri, R, Kokila, A, Jones, C, Hong, B, et al
The British journal of nutrition. 2019;(12):1389-1397
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India has the second largest number of people with type 2 diabetes (T2D) globally. Epidemiological evidence indicates that consumption of white rice is positively associated with T2D risk, while intake of brown rice is inversely associated. Thus, we explored the effect of substituting brown rice for white rice on T2D risk factors among adults in urban South India. A total of 166 overweight (BMI ≥ 23 kg/m2) adults aged 25-65 years were enrolled in a randomised cross-over trial in Chennai, India. Interventions were a parboiled brown rice or white rice regimen providing two ad libitum meals/d, 6 d/week for 3 months with a 2-week washout period. Primary outcomes were blood glucose, insulin, glycosylated Hb (HbA1c), insulin resistance (homeostasis model assessment of insulin resistance) and lipids. High-sensitivity C-reactive protein (hs-CRP) was a secondary outcome. We did not observe significant between-group differences for primary outcomes among all participants. However, a significant reduction in HbA1c was observed in the brown rice group among participants with the metabolic syndrome (-0·18 (se 0·08) %) relative to those without the metabolic syndrome (0·05 (se 0·05) %) (P-for-heterogeneity = 0·02). Improvements in HbA1c, total and LDL-cholesterol were observed in the brown rice group among participants with a BMI ≥ 25 kg/m2 compared with those with a BMI < 25 kg/m2 (P-for-heterogeneity < 0·05). We observed a smaller increase in hs-CRP in the brown (0·03 (sd 2·12) mg/l) compared with white rice group (0·63 (sd 2·35) mg/l) (P = 0·04). In conclusion, substituting brown rice for white rice showed a potential benefit on HbA1c among participants with the metabolic syndrome and an elevated BMI. A small benefit on inflammation was also observed.