Should We Hold Our Breath for Vitamin D in COPD?

Author(s)
Jennifer N. Clements, PharmD, BCPS, BCACP
Lisa Gibbs, PharmD

Reviewed By
Sharya Bourdet, PharmD, BCPS
Evan Williams, PharmD, MBA, BCPS, BCACP

Citation
Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomized controlled trials. Thorax 2019; 74: 337-345.

The Problem

 

Chronic obstructive pulmonary disease (COPD) exacerbations contribute to mortality, disease progression, worsening quality of life, and increased health care costs. Smoking cessation, appropriate vaccinations, and inhaled pharmacotherapy remain the mainstay of exacerbation prevention, but adjunctive strategies have been investigated to determine if they can reduce exacerbation severity or/and frequency. Respiratory tract infections are a common cause of COPD exacerbations.  While prophylactic antibiotics may play a role, vitamin D supplementation is an attractive option because it may stimulate innate and adaptive immune responses (without contributing to antibiotic resistance).¹ Although severe vitamin D deficiency (25(OH)D <10 ng/mL) has been associated with more frequent exacerbations and hospitalizations in patients with COPD, it is unclear if supplementation actually reduces exacerbation frequency.²

 

What’s Known

 

The Institute of Medicine defines vitamin D deficiency as 25(OH)D less than 20 ng/mL.³ The Endocrine Society guidelines on the treatment and management of vitamin D deficiency recommend vitamin D supplementation to achieve a blood level >30 ng/mL among the general population, particularly for adults with vitamin D deficiency.  These recommendations are primarily based on the evidence that adequate vitamin D stores are needed for bone and muscle health.³ The 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the diagnosis, management, and prevention of COPD do not recommend vitamin D as an adjunctive therapy for prevention of COPD exacerbations due to insufficient evidence.⁴

 

While vitamin D supplementation has been shown to decrease the risk of acute respiratory tract infections and exacerbations requiring steroids in patients with asthma, available data on vitamin D supplementation and COPD exacerbation risk are conflicting.^5,6 The majority of published evidence (observational cohorts, cross-sectional studies, and randomized controlled trials) suggests no association between vitamin D supplementation and COPD exacerbation risk. However, a few trials have shown vitamin D supplementation to be protective against moderate to severe exacerbations in patients with vitamin D deficiency (25(OH)D <20 ng/mL) and in patients with very severe COPD.^7,8

 

What’s New

 

A recent meta-analysis of double-blind, placebo-controlled, randomized controlled trials, sought to determine the effect of vitamin D supplementation on the rate of moderate to severe COPD exacerbations.⁹  From an extensive literature search, 187 studies were evaluated for potential eligibility; from this pool, only four trials met eligibility requirements with a total of 560 participants. One trial was subsequently not included in the analysis due to missing patient data. Of the remaining 472 participants, outcome data was based on 469 participants in three trials. Primary and secondary outcomes are listed in Table 1.⁹

 

Table 1.  Primary and Secondary Outcomes

Primary Outcome

Secondary Outcomes

Rate of moderate or severe COPD exacerbations requiring systemic corticosteroids, antibiotics, or both

Time from first dose of study medication to moderate-severe exacerbation Number of participants with a at least one moderate or severe COPD exacerbation Number of COPD exacerbations requiring admission to emergency room, hospitalization, or both Number of participants with a at least one serious adverse effect, hypercalcemia, or renal stone Mean percent of pulmonary function at the last follow-up Mean body mass index at the last follow-up COPD-related all-cause mortality

 

The participants ranged in age from 40 to 86 years.  A majority were males (66.7%), were white Europeans (97%), and had either Grade 2 (38.97%) or 3 (32.57%) COPD based on spirometry.  The mean baseline 24(OH)D concentration of 18.3 ng/mL.  Oral vitamin D3 supplementation (e.g., cholecalciferol) was given in all 3 studies, but the regimen and the length of treatment varied (See Table 2).

 

Table 2.  Vitamin D Regimens for Included Trials

	Dosing Regimen	Length of Treatment	Total Dose of Vitamin D
Regimen 1	100,000 International Units (IU) orally per month	12 months	1,200,000 IU
Regimen 2	120,000 IU orally every other month	12 months	720,000 IU
Regimen 3	1200 IU orally per daily	6 months	220,000 IU

 

Overall, oral vitamin D3 supplementation did not reduce the rate of moderate or severe COPD exacerbations (1.85 versus 1.97 events [placebo] per person per year, p-value = 0.52).⁹ When adjusted for age, sex, and severity of COPD, the findings were unchanged –there was no discernable reduction in the rate of COPD exacerbations with vitamin D supplementation (adjusted incidence rate (aIRR) 0.94, 95% confidence interval 0.79 to 11.12).  In a subgroup analysis, only participants who had a baseline 25(OH)D concentration below 10 ng/mL (aIRR 0.55, 95% CI 0.36 to 0.84) appeared to benefit from vitamin D supplementation and this benefit remained after adjustments for age, sex, and severity of COPD.⁹

 

Among all secondary outcomes, supplementation with oral vitamin D3 did not provide any statistically significant benefit, compared to the placebo.  However, supplementation appeared to be safe and did not lead to serious adverse events, such as hypercalcemia or renal stones.  Lastly, participants with an end-study 25(OH)D concentration ≥30 ng/mL did appear to benefit any more than those who did not achieve this recommended target.⁹

 

Our Critical Appraisal

 

This meta-analysis has several strengths.  The authors followed the PRISMA-P (preferred reporting items for systematic reviews and meta-analysis protocols) guidelines and conducted one- and two-step analyses for the primary and secondary outcomes.  In addition, the data was adjusted for age, sex, and severity of COPD. 

 

However, there were several limitations. First, while the literature search was comprehensive, only three trials were actually included in the analysis. It is unknown whether data from the excluded study (with an additional 88 patients) would have added sufficient power to detect a statistically significant difference in the primary outcome. Regardless, participants in the included studies were not representative of the global COPD population. Females constituted only a third of the participants. Very few of the participants were non-Europeans.  Patients with darker pigmentation often have lower 25(OH)D concentrations and thus may benefit from vitamin D supplementation the most. While the authors attempted to account for several factors in their adjusted analysis, they could not control for other confounders that could influence the rate of COPD exacerbation, such as the COPD treatment regimen, vaccinations, concomitant infections, or season.

 

Another significant limitation is the varying vitamin D treatment regimens and durations used in the included studies. Treatment of vitamin D deficiency (less than 10 to 20 ng/mL) in North American typically involves high doses (e.g. 50,000 IU per week) of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) given for 8 to 12 weeks before re-assessing 25(OH)D concentrations.¹⁰

 

Due to the limited number of included trials, the authors were unable to produce a funnel plot to determine whether publication bias was a factor. While the meta-analysis supports the use of vitamin D supplementation in individuals with severe vitamin D deficiency (25(OH)D <10 ng/mL), these patients would likely receive vitamin D supplementation for other reasons (e.g. bone and muscle health).  The stringent inclusion criteria for this meta-analysis may have excluded potentially relevant data. An ongoing randomized clinical trial on vitamin D supplementation to prevent COPD exacerbation may bring some clarity.  Moreover, additional high-quality data could be included in a future meta-analysis to increase statistical power and improve the generalizability of these results.

 

The Bottom Line

 

Vitamin D supplementation is not warranted for all patients with COPD to prevent exacerbations. However, this meta-analysis suggests there may be a possible protective benefit among patients with severe vitamin D deficiency. Screening for and treating vitamin D deficiency in patients who have COPD would be reasonable, particularly in those who’ve had an exacerbation requiring hospitalization.

 

The Key Points

• Vitamin D plays a role in immune regulation.
• Vitamin D supplementation may be beneficial in patients, with or without COPD, who are clearly deficient.
• A recently published meta-analysis found that supplementation with vitamin D in patients with severe vitamin D deficiency (25(OH)D <10 ng/mL) significantly reduced the rate of COPD exacerbations.
• In patients with COPD, it would be reasonable to measure 25(OH)D concentrations and supplement patients who are deficient in order to decrease fall and fracture risk as well as COPD exacerbations.

 

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.