American Journal of Epidemiology © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected].
Vol. 180, No. 7
Letters to the Editor RE: “VITAMIN D DEFICIENCY AND CARDIOVASCULAR EVENTS IN PATIENTS WITH CORONARY HEART DISEASE: DATA FROM THE HEART AND SOUL STUDY” for pharmaceutical drugs, which assume that the agent used in the trial is the only source of the agent, and that there is a linear dose-response relationship. Neither assumption is valid for vitamin D RCTs. The proper way to design such RCTs was outlined recently. The main points include starting with the 25(OH)D concentration–health outcome relation, measuring 25(OH)D concentrations of prospective participants, enrolling only those with values near the low end of the quasilinear region of the relation, supplementing them with sufficient vitamin D3 to increase their 25(OH)D concentrations to the upper end of the quasilinear region of the relation, and remeasuring 25(OH)D concentrations (8). Metaanalyses of vitamin D RCTs have not found any significant reduction of CVD outcomes (9–11). However, 1 RCT from Iran that enrolled women with baseline 25(OH)D concentrations of 7 ng/mL and who were given sufficient vitamin D to increase concentrations to 23 ng/mL found significant reductions in serum total cholesterol, triglyceride, and very-lowdensity lipoprotein levels but not in several other CVD risk factors (12).
The recent paper by Welles et al. (1) reported that serum 25-hydroxyvitamin D (25(OH)D) concentrations were inversely correlated with cardiovascular disease (CVD) events during a median follow-up period of 8 years; however, after further analysis for potential biological mediators, the correlation was no longer significant. It was noted that parathyroid hormone (PTH) may have been responsible for the majority of the attenuation. There may be a problem with this interpretation. First, the follow-up time was long enough that the 25(OH)D concentrations measured at baseline would have changed significantly during the course of the study, thereby reducing the observed change with relation to 25(OH)D. As shown in a pair of papers, the longer the follow-up time, the lower the observed inverse correlation of 25(OH)D with breast and colorectal cancer incidence rates (2) and all-cause mortality rate (3). Nonetheless, the 25(OH)D concentration–relative hazard ratio for CVD events in Figure 1 (1) is in good agreement with a figure for relative risk in a recent meta-analysis (4). However, it might still be worthwhile to present the analyses for 3 ranges of 25(OH)D concentration. Doing so would facilitate comparisons with other studies, such as the Intermountain Heart Collaborative Study, which used 15 and 30 ng/mL as the cutoff values (5). Regarding the possible role of PTH in explaining the findings, it is noted that the 25(OH)D–PTH relation is very tightly controlled with the exception of 1 factor—age. As shown recently, for the baseline mean 25(OH)D concentration of 25.8 ng/mL in the population studied by Welles et al. (1), PTH increases from approximately 25 pg/mL for those less than 20 years of age to 31 pg/mL for those aged 20–40 years, 38 pg/mL for those aged 40–60 years, and 47.5 pg/mL for those older than 60 years (6). Although the results in Tables 2 and 3 in the article by Welles et al. (1) were adjusted for multiple factors, including age in model 1 and PTH in model 4, different results might be found if the age-PTH relations were used to estimate PTH at the time of each CVD event. As for the suggestion to wait for randomized controlled trials (RCTs) before recommending vitamin D supplementation to increase 25(OH)D concentrations to reduce the risk of CVD events, that is probably not necessary. First, the findings regarding vitamin D reducing the risk of CVD generally satisfy the criteria for causality in a biological system. The primary criteria are strength of association, consistent findings in different populations, temporality, biological gradient, plausibility (e.g., mechanisms), and experiment (e.g., RCTs) (7). Not all criteria need be satisfied to claim causality, but the more that are, the better. The main problem with most vitamin D RCTs reported to date is that they were designed on the basis of the guidelines
ACKNOWLEDGMENTS W.B.G. receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, Arkansas), the Sunlight Research Forum (Veldhoven, the Netherlands), and the UV Foundation (McLean, Virginia). Conflict of interest: none declared. REFERENCES 1. Welles CC, Whooley MA, Karumanchi SA, et al. Vitamin D deficiency and cardiovascular events in patients with coronary heart disease: data from the Heart and Soul Study. Am J Epidemiol. 2014;179(11):1279–1287. 2. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level: implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinology. 2011;3(3):199–204. 3. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyvitamin D and all-cause mortality rate. Dermatoendocrinology. 2012;4(2):198–202. 4. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819–829. 5. Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106(7):963–968. 6. Valcour A, Blocki F, Hawkins DM, et al. Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab. 2012;97(11):3989–3995. 757
Am J Epidemiol. 2014;180(7):757–761
758 Letters to the Editor 7. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295–300. 8. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1): 48–54. 9. Myung SK, Ju W, Cho B, et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;346:f10. 10. Autier P, Boniol M, Pizot C, et al. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014; 2(1):76–89. 11. Bolland MJ, Grey A, Gamble GD, et al. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a
trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(4):307–320. 12. Rahimi-Ardabili H, Pourghassem Gargari B, Farzadi L. Effects of vitamin D on cardiovascular disease risk factors in polycystic ovary syndrome women with vitamin D deficiency. J Endocrinol Invest. 2013;36(1):28–32.
William B. Grant (e-mail: wbgrant@infionline.net) Sunlight, Nutrition, and Health Research Center, San Francisco, CA
DOI: 10.1093/aje/kwu215; Advance Access publication: August 22, 2014
© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected].
THE AUTHORS REPLY We appreciate the interest in our work (1) and thoughtful letter by Dr. Grant (2). The first point raised in his letter is the concern that adjusting for baseline levels of parathyroid hormone may not accurately capture mediation at the time of the event. We would like to point out that the difference in age between cases and controls did not change over time. Thus, any effect of age on parathyroid hormone levels would have been the same at baseline as it was at the time of the event. The second point raised in the letter (2) is whether the analysis should be repeated with cutpoints for serum 25-hydroxyvitamin D (25(OH)D) levels of less than 15, 15–30, and greater than 30 ng/mL. We chose the cutpoint of 20 ng/mL because it is both a clinically relevant cutpoint and also corresponds with an empirical cutpoint (based on the spline, Figure 1) (1). As stated in paragraph 2 of our results section, “The question of whether 25(OH)D levels of 20–29.9 ng/mL (often referred to as vitamin D insufficiency) also confer adverse health consequences is currently controversial. Therefore, we performed additional exploratory analyses to compare annual cardiovascular event rates at 3 different 25-OH levels:
Vol. 180, No. 7
Letters to the Editor RE: “VITAMIN D DEFICIENCY AND CARDIOVASCULAR EVENTS IN PATIENTS WITH CORONARY HEART DISEASE: DATA FROM THE HEART AND SOUL STUDY” for pharmaceutical drugs, which assume that the agent used in the trial is the only source of the agent, and that there is a linear dose-response relationship. Neither assumption is valid for vitamin D RCTs. The proper way to design such RCTs was outlined recently. The main points include starting with the 25(OH)D concentration–health outcome relation, measuring 25(OH)D concentrations of prospective participants, enrolling only those with values near the low end of the quasilinear region of the relation, supplementing them with sufficient vitamin D3 to increase their 25(OH)D concentrations to the upper end of the quasilinear region of the relation, and remeasuring 25(OH)D concentrations (8). Metaanalyses of vitamin D RCTs have not found any significant reduction of CVD outcomes (9–11). However, 1 RCT from Iran that enrolled women with baseline 25(OH)D concentrations of 7 ng/mL and who were given sufficient vitamin D to increase concentrations to 23 ng/mL found significant reductions in serum total cholesterol, triglyceride, and very-lowdensity lipoprotein levels but not in several other CVD risk factors (12).
The recent paper by Welles et al. (1) reported that serum 25-hydroxyvitamin D (25(OH)D) concentrations were inversely correlated with cardiovascular disease (CVD) events during a median follow-up period of 8 years; however, after further analysis for potential biological mediators, the correlation was no longer significant. It was noted that parathyroid hormone (PTH) may have been responsible for the majority of the attenuation. There may be a problem with this interpretation. First, the follow-up time was long enough that the 25(OH)D concentrations measured at baseline would have changed significantly during the course of the study, thereby reducing the observed change with relation to 25(OH)D. As shown in a pair of papers, the longer the follow-up time, the lower the observed inverse correlation of 25(OH)D with breast and colorectal cancer incidence rates (2) and all-cause mortality rate (3). Nonetheless, the 25(OH)D concentration–relative hazard ratio for CVD events in Figure 1 (1) is in good agreement with a figure for relative risk in a recent meta-analysis (4). However, it might still be worthwhile to present the analyses for 3 ranges of 25(OH)D concentration. Doing so would facilitate comparisons with other studies, such as the Intermountain Heart Collaborative Study, which used 15 and 30 ng/mL as the cutoff values (5). Regarding the possible role of PTH in explaining the findings, it is noted that the 25(OH)D–PTH relation is very tightly controlled with the exception of 1 factor—age. As shown recently, for the baseline mean 25(OH)D concentration of 25.8 ng/mL in the population studied by Welles et al. (1), PTH increases from approximately 25 pg/mL for those less than 20 years of age to 31 pg/mL for those aged 20–40 years, 38 pg/mL for those aged 40–60 years, and 47.5 pg/mL for those older than 60 years (6). Although the results in Tables 2 and 3 in the article by Welles et al. (1) were adjusted for multiple factors, including age in model 1 and PTH in model 4, different results might be found if the age-PTH relations were used to estimate PTH at the time of each CVD event. As for the suggestion to wait for randomized controlled trials (RCTs) before recommending vitamin D supplementation to increase 25(OH)D concentrations to reduce the risk of CVD events, that is probably not necessary. First, the findings regarding vitamin D reducing the risk of CVD generally satisfy the criteria for causality in a biological system. The primary criteria are strength of association, consistent findings in different populations, temporality, biological gradient, plausibility (e.g., mechanisms), and experiment (e.g., RCTs) (7). Not all criteria need be satisfied to claim causality, but the more that are, the better. The main problem with most vitamin D RCTs reported to date is that they were designed on the basis of the guidelines
ACKNOWLEDGMENTS W.B.G. receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, Arkansas), the Sunlight Research Forum (Veldhoven, the Netherlands), and the UV Foundation (McLean, Virginia). Conflict of interest: none declared. REFERENCES 1. Welles CC, Whooley MA, Karumanchi SA, et al. Vitamin D deficiency and cardiovascular events in patients with coronary heart disease: data from the Heart and Soul Study. Am J Epidemiol. 2014;179(11):1279–1287. 2. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level: implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinology. 2011;3(3):199–204. 3. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyvitamin D and all-cause mortality rate. Dermatoendocrinology. 2012;4(2):198–202. 4. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819–829. 5. Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106(7):963–968. 6. Valcour A, Blocki F, Hawkins DM, et al. Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab. 2012;97(11):3989–3995. 757
Am J Epidemiol. 2014;180(7):757–761
758 Letters to the Editor 7. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295–300. 8. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1): 48–54. 9. Myung SK, Ju W, Cho B, et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;346:f10. 10. Autier P, Boniol M, Pizot C, et al. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014; 2(1):76–89. 11. Bolland MJ, Grey A, Gamble GD, et al. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a
trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(4):307–320. 12. Rahimi-Ardabili H, Pourghassem Gargari B, Farzadi L. Effects of vitamin D on cardiovascular disease risk factors in polycystic ovary syndrome women with vitamin D deficiency. J Endocrinol Invest. 2013;36(1):28–32.
William B. Grant (e-mail: wbgrant@infionline.net) Sunlight, Nutrition, and Health Research Center, San Francisco, CA
DOI: 10.1093/aje/kwu215; Advance Access publication: August 22, 2014
© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected].
THE AUTHORS REPLY We appreciate the interest in our work (1) and thoughtful letter by Dr. Grant (2). The first point raised in his letter is the concern that adjusting for baseline levels of parathyroid hormone may not accurately capture mediation at the time of the event. We would like to point out that the difference in age between cases and controls did not change over time. Thus, any effect of age on parathyroid hormone levels would have been the same at baseline as it was at the time of the event. The second point raised in the letter (2) is whether the analysis should be repeated with cutpoints for serum 25-hydroxyvitamin D (25(OH)D) levels of less than 15, 15–30, and greater than 30 ng/mL. We chose the cutpoint of 20 ng/mL because it is both a clinically relevant cutpoint and also corresponds with an empirical cutpoint (based on the spline, Figure 1) (1). As stated in paragraph 2 of our results section, “The question of whether 25(OH)D levels of 20–29.9 ng/mL (often referred to as vitamin D insufficiency) also confer adverse health consequences is currently controversial. Therefore, we performed additional exploratory analyses to compare annual cardiovascular event rates at 3 different 25-OH levels:
