Our findings suggested an improvement in T1DM patients quality of life (QoL) after supplementation with high doses of cholecalciferol. According to our knowledge, this is the first clinical trial to demonstrate the impact of VD supplementation on HRQoL in this population.
Few studies addressing VD supplementation on HRQol in patients with diabetes have been conducted. Krul-Poel et al. performed a randomized, double-blind, placebo-controlled trial with 275 patients with type 2 diabetes mellitus (T2DM), who monthly supplemented 50,000 IU of cholecalciferol during six months, and found no changes in QoL at the end of the study. Similarly, Mager et al. analyzed the impact of administering different doses of vitamin D3 (2000 IU day or 40,000 IU monthly) for six months in T2DM patients with chronic kidney disease (CKD), and did not detect improvement in their HRQoL. Those results differ from ours since the patients in the present trial received higher doses of cholecalciferol. Furthermore, both studies used cholecalciferol monthly, in contrast to cholecalciferol daily doses in our trial which have a different biological effect (17–19).
Additionally, the improvement of HRQoL in our study was found by analysis of EQ-5D-5L index after supplementation of cholecalciferol for 12 weeks. We noticed a change in the final EQ-5D-5L index using sets of values from all countries available. It was important to unify the 5 dimensions of problems in a single index to obtain our results. It is our knowledge that additional studies are necessary to establish the importance of each dimension for the Brazilian population. For that, are required both a traditional method validation, performed in Brazil in 2015, and a populational study, which has not happened in this country yet (20). However, our findings showed improvement of EQ-5D-5L index using sets of values from countries of different continents, with different populations and the most diverse HDIs, which gives a lot of consistency to our results.
When we analysed each dimension of EQ-5D in this trial, we found an improvement of mobility. Moreover, self-care dimension showed a tendency to be better by the end of VD administration. Those results differ from Raymakers et al, who describe, in a cross-sectional study, a greater impact of anxiety/depression dimension in HRQoL, evaluating 473 patients with T1DM in Ireland. Nonetheless, it is important to notice that in BrazDiab1SG, as described by Felício et al., patients in North and Northeast regions reported lower frequency of anxiety and depression when compared to other brazilian regions. (3, 21). In addition, it is known that geographic aspects, especially temperature and sun exposure, can affect quality of life (22). The consistent improvement of EQ-5D-5L index when evaluated by sets of values from countries that represent almost all geographical regions validates our findings.
It is well known that skeletal muscle fibers carry VD receptors, and their activation is a possible mechanism of muscle growth (17, 23). Biopsy and consistent findings of muscle atrophy were associated with VD deficiency (24). Moreover, Sato et al. (2005) showed that calcium and vitamin D supplementation improves muscle fibers in number and size, as well as the lower members function. Randomized controlled trials and meta-analyses have shown that 25(OH)D supplementation decreases risk of falls and fractures in elderly patients (24–27). Finally, VD deficiency is associated with muscle atrophy, musculoskeletal pain and worse physical function in the general population (28). In our sample, most patients had hypovitaminosis D (VD < 30ng/ml) at the beginning of the study and, by the end of the supplementation, 94% of them had sufficient levels of 25 (OH) D. It could have potentiated extra-skeletal actions of VD (29). Thus, the hypothesis that VD affected mobility and QoL in our study by its direct action on muscle fibers must be considered.
Our results also demonstrated a reduction in albumin excretion at the end of cholecalciferol supplementation. It particularly occurred in the subgroups that improved QoL in post-hoc analysis. In addition, there was a correlation between final 25(OH)D levels and final albuminuria. Felício et al. in a pilot study that analyzed patients with T1DM who received 4,000 and 10,000 units of cholecalciferol for 12 weeks according to their previous 25(OH)D levels found a reduction in prevalence of diabetic kidney disease (DKD) and a correlation between the percentage of VD levels variation and albuminuria after cholecalciferol supplementation (7). There is growing evidence that vitamin D given in high doses can be renoprotective (30, 31). Humalda et al. (2015) performed a systematic review of all randomized clinical trials with calcitriol or paricalcitol as an antiproteinuric intervention. During follow-up, VD active analogs reduced proteinuria by an average of 16%. These results were obtained, in most cases (84%), in patients under chronic treatment of previous conditions with renin angiotensin aldosterone inhibitors, accentuating the capacity of VD analogs to reduce residual proteinuria. Those authors suggest that compensatory increase in renin is a paradoxical event secondary to the use of SARS inhibitors, and can be antagonized by calcitriol (32). Furthermore, Wolfgram et al. (2017) presented a secondary analysis of the cross-sectional study SPRINT (Systolic Blood Pressure Intervention Trial), in which they evaluated a subgroup of individuals with age greater than 75 years. In addition to renal indexes (GFR and albuminuria), participants in this subgroup underwent gait speed assessment, self-assessment of HRQoL with a focus on functional status (EQ-5D), and assessment risk of falling. In the unadjusted model, the decrease in eGFR and increase in categories of albuminuria were associated with worse scores in the three tools. This data raises the hypothesis that VD may also contributes to an improvement in quality of life through its positive effect in DRD (33).
Studies have shown that, among patients with CKD, HRQoL gradually declines as the disease progresses, with the worst HRQoL scores obtained when an advanced stage of kidney disease is reached (34, 35). When CKD coexists with diabetes an accentuated deterioration in HRQoL is expected (36). However, few studies have examined this relationship in the early stages of CKD or attempted to incorporate albuminuria in this assessment. According to Bowling et al., albuminuria may be more sensitive than glomerular filtration rate (GFR) to identify patients with risk of functional impairment, at least in early stages of CKD (37). In our study, abnormal creatinine levels were an exclusion criteria. Therefore, our data reinforce these findings.
The main limitations of our study were short duration (12 weeks) and absence of a placebo control group. Following this study, controlled, double-blind, randomized trials with a placebo group and a longer duration of supplementation should be performed to confirm our findings.