How to design and compare clinical trials of vitamin D supplementation and mortality rate
“Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment.” (1). There could be two explanations for this finding: one, that vitamin D supplementation does not reduce the risk of death; or two, that the clinical trials reviewed in this paper were not properly designed to evaluate the role of vitamin D supplementation in reducing risk of death. As I will show, the evidence favors the second explanation.
Most vitamin D clinical trials are based on the model for pharmaceutical drugs. The two basic assumptions of such trials are: one, that the trial is the only source of the agent; and two, that there is a linear dose-response relationship. Neither assumption is satisfied for vitamin D. In addition, many trials include many participants with reasonably high 25-hydroxyvitamin D [25(OH)D] concentrations and give only modest vitamin D doses. Observational studies on the effect of vitamin D on health outcomes are generally based on serum 25(OH)D concentrations, so it makes sense that clinical trials should be, too. Ideally, all candidate participants would have serum 25(OH)D concentration measured, those with low concentrations would be included, they would be given vitamin D3 doses calculated to raise concentrations enough to reduce adverse health outcomes determined from observational studies (2), (3), (4).
An example of a clinical trial that was not well designed is that of The Vitamin D and Omega-3 Trial (VITAL) (5). Over 25,000 healthy volunteers were included with one half receiving 2000 IU/d vitamin D3 while the other half received a placebo. As shown in the online supplement to that paper, the mean baseline 25(OH)D concentrations for the 395 males and 441 females who provided values were 28 ng/ml (males) and 32 ng/ml (females), rising to 40 ng/ml (males) and 44 ng/ml (females) after one year of taking 2000 IU/d vitamin D3. To compare these values with observational studies, we can use the results of a meta-analysis of 32 observational studies (6). It found a decrease of the all-cause mortality rate hazard ratio (HR) from 1.9 at 0-9 ng/ml to 1.2 at 20-29 ng/ml, 1.1 at 30-39 ng/ml and 1.1 at 40-49 ng/ml. Using these values and the 25(OH)D concentrations in the online supplement for VITAL, a reduction in mortality rate of about 15% with a 95% confidence interval (CI) of ±20% might be expected. However, in VITAL, for the entire group, the HR for the treatment arm was 0.99 (95% CI, 0.87 to 1.12). However, had the baseline 25(OH)D concentration been 15 ng/ml and the achieved 25(OH)D concentration 40 ng/ml, the expected HR would be 0.65 (95% CI, 0.45 to 0.85). In fact, for African Americans in VITAL, the HR was 0.77 (95% CI, 0.59 to 1.01). The baseline and achieved 25(OH)D concentrations for the 154 African Americans who provided values were 25 and 40 ng/mL. Also, the hazard ratio for those with BMI <20 kg/m was 0.76 (95% CI, 0.63 to 0.90), suggesting that if participants had lower baseline 25(OH)D concentrations and a vitamin D3 dose greater than 2000 IU/d were used, there would have been a greater chance of finding a significant reduction in all-cause mortality rate for the entire group. Another recent paper also made the point that low baseline 25(OH)D concentration was a very important consideration for clinical trials investigating the role of vitamin D in reducing mortality rate (7).
A better way to consider the results of vitamin D clinical trials is the use of individual participant data as done for acute respiratory tract infections (8). This meta-analysis found that the best results were found for participants with baseline 25(OH)D concentrations <10 ng/ml.
In conclusion, it is hoped that future vitamin D clinical trials will be based primarily on 25(OH)D concentrations designed to evaluate the findings from observational studies and that meta-analyses will also consider treatment outcomes based on individual serum 25(OH)D concentrations rather than on unspecified vitamin D doses vs. placebo.
References
1. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.
2. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutrition reviews. 2014;72(1):48-54.
3. Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PloS one. 2017;12(5):e0176448.
4. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. The Journal of steroid biochemistry and molecular biology. 2018;177:266-9.
5. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. The New England journal of medicine. 2019;380(1):33-44.
6. Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, et al. Meta-analysis of All-Cause Mortality According to Serum 25-Hydroxyvitamin D. American journal of public health. 2014;104(8):e43-50.
7. Brenner H, Jansen L, Saum KU, Holleczek B, Schottker B. Vitamin D Supplementation Trials Aimed at Reducing Mortality Have Much Higher Power When Focusing on People with Low Serum 25-Hydroxyvitamin D Concentrations. The Journal of nutrition. 2017;147(7):1325-33.
8. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
Competing interests:
I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA)
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How to design and compare clinical trials of vitamin D supplementation and mortality rate
“Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment.” (1). There could be two explanations for this finding: one, that vitamin D supplementation does not reduce the risk of death; or two, that the clinical trials reviewed in this paper were not properly designed to evaluate the role of vitamin D supplementation in reducing risk of death. As I will show, the evidence favors the second explanation.
Most vitamin D clinical trials are based on the model for pharmaceutical drugs. The two basic assumptions of such trials are: one, that the trial is the only source of the agent; and two, that there is a linear dose-response relationship. Neither assumption is satisfied for vitamin D. In addition, many trials include many participants with reasonably high 25-hydroxyvitamin D [25(OH)D] concentrations and give only modest vitamin D doses. Observational studies on the effect of vitamin D on health outcomes are generally based on serum 25(OH)D concentrations, so it makes sense that clinical trials should be, too. Ideally, all candidate participants would have serum 25(OH)D concentration measured, those with low concentrations would be included, they would be given vitamin D3 doses calculated to raise concentrations enough to reduce adverse health outcomes determined from observational studies (2), (3), (4).
An example of a clinical trial that was not well designed is that of The Vitamin D and Omega-3 Trial (VITAL) (5). Over 25,000 healthy volunteers were included with one half receiving 2000 IU/d vitamin D3 while the other half received a placebo. As shown in the online supplement to that paper, the mean baseline 25(OH)D concentrations for the 395 males and 441 females who provided values were 28 ng/ml (males) and 32 ng/ml (females), rising to 40 ng/ml (males) and 44 ng/ml (females) after one year of taking 2000 IU/d vitamin D3. To compare these values with observational studies, we can use the results of a meta-analysis of 32 observational studies (6). It found a decrease of the all-cause mortality rate hazard ratio (HR) from 1.9 at 0-9 ng/ml to 1.2 at 20-29 ng/ml, 1.1 at 30-39 ng/ml and 1.1 at 40-49 ng/ml. Using these values and the 25(OH)D concentrations in the online supplement for VITAL, a reduction in mortality rate of about 15% with a 95% confidence interval (CI) of ±20% might be expected. However, in VITAL, for the entire group, the HR for the treatment arm was 0.99 (95% CI, 0.87 to 1.12). However, had the baseline 25(OH)D concentration been 15 ng/ml and the achieved 25(OH)D concentration 40 ng/ml, the expected HR would be 0.65 (95% CI, 0.45 to 0.85). In fact, for African Americans in VITAL, the HR was 0.77 (95% CI, 0.59 to 1.01). The baseline and achieved 25(OH)D concentrations for the 154 African Americans who provided values were 25 and 40 ng/mL. Also, the hazard ratio for those with BMI <20 kg/m was 0.76 (95% CI, 0.63 to 0.90), suggesting that if participants had lower baseline 25(OH)D concentrations and a vitamin D3 dose greater than 2000 IU/d were used, there would have been a greater chance of finding a significant reduction in all-cause mortality rate for the entire group. Another recent paper also made the point that low baseline 25(OH)D concentration was a very important consideration for clinical trials investigating the role of vitamin D in reducing mortality rate (7).
A better way to consider the results of vitamin D clinical trials is the use of individual participant data as done for acute respiratory tract infections (8). This meta-analysis found that the best results were found for participants with baseline 25(OH)D concentrations <10 ng/ml.
In conclusion, it is hoped that future vitamin D clinical trials will be based primarily on 25(OH)D concentrations designed to evaluate the findings from observational studies and that meta-analyses will also consider treatment outcomes based on individual serum 25(OH)D concentrations rather than on unspecified vitamin D doses vs. placebo.
References
1. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.
2. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutrition reviews. 2014;72(1):48-54.
3. Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PloS one. 2017;12(5):e0176448.
4. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. The Journal of steroid biochemistry and molecular biology. 2018;177:266-9.
5. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. The New England journal of medicine. 2019;380(1):33-44.
6. Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, et al. Meta-analysis of All-Cause Mortality According to Serum 25-Hydroxyvitamin D. American journal of public health. 2014;104(8):e43-50.
7. Brenner H, Jansen L, Saum KU, Holleczek B, Schottker B. Vitamin D Supplementation Trials Aimed at Reducing Mortality Have Much Higher Power When Focusing on People with Low Serum 25-Hydroxyvitamin D Concentrations. The Journal of nutrition. 2017;147(7):1325-33.
8. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
Competing interests: I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA)