Effect of vitamin D supplementation on cardiac-metabolic risk factors in elderly: a systematic review and meta-analysis of clinical trials

'Cardiac-metabolic' is a complex disorder characterized by dyslipidemia, hyperglycemia, visceral obesity, and hypertension [1]. The prevalence of cardiac-metabolic disorders has profoundly grown over the past decade [2, 3]. Individuals with cardiac-metabolic disorders are at a development risk for diabetes mellitus (DM) and cardiovascular disease [4]. In recent years, several studies have investigated the effect of essential nutrients on cardiac-metabolic disorders and their risk factor [5, 6]. As a global health problem, “vitamin D” deficiency is extremely prevalent in all age populations, especially in older adults (≥ 60 years old) [7]. Moreover, there has been growing data to prove the extra-skeletal role of vitamin D [8]. Evidence has been concerned with the relation between vitamin D deficiency and the development of DM, metabolic syndrome, cardiovascular disease, autoimmune diseases, and some cancers [8, 9].

A reverse association has been demonstrated between vitamin D levels and multiple pathological outcomes, including cardiovascular diseases [10, 11]. In this regard, some investigations have suggested that vitamin D supplementation (VDS) has therapeutic results on insulin resistance, serum triglycerides, and waist circumference in patients with metabolic syndrome and even in healthy adults [12‐14]. In contrast, a few randomized clinical trials (RCTs) did not show any effectiveness in metabolic profile via VDS [15, 16]. In general, disagreement in the results of studies could be ascribed to differences in terms of methodology, supplementation dose, and populations' characteristics. Moreover, several meta-analyses have examined the impact of VDS on DM, dyslipidemia, body weight, and cardiovascular disease in adults and children and found conflicting results [17‐24].

To the best of our knowledge, there is no comprehensive evidence outlining the effects of VDS on cardiac-metabolic outcomes in the elderly population. Given the critical assessment of the impact of vitamin D in older adults, we aimed to examine the overall effects of VDS on cardiac-metabolic outcomes in the elderly population.

The present meta-analysis finding revealed that VDS compared with placebo improved TC and TG management in the elderly. In contrast, we observed no significant beneficial effects of VDS in overall or subgroup analyses on LDL, HDL, FBS, HbA1c, HOMA-IR, BMI, and WC. Nevertheless, characteristics of the selected trials such as baseline vitamin D, duration of supplementation, and health condition of participants partly influenced the impacts that emerged in some overall findings.

Given the existence of much evidence about the effectiveness of vitamin D in glucose metabolism, some meta-analyses similar to our overall pooled results found that VDS may not improve glycemic indices[23, 41]. While, others [22, 42, 43] proposed that vitamin D could be a useful adjuvant therapy in controlling glycemic parameters in patients with DM or impaired glucose tolerance because it reduces insulin resistance and improves the function of beta cells [44]. Most systematic reviews have evaluated the effects of vitamin D on glycemic parameters in diabetics or adults with impaired glucose tolerance. Our selection criteria were different from the meta-analysis, and we included the elderly population (more than 60 years) with any type of disease. Despite that, the subgroup analysis showed a decrease in glycemic parameters (i.e., insulin concentration, FBS, and HOMA-IR) in DM subgroups; but, because of the few eligible trials, it is not statistically significant.

Further, in terms of the intervention duration, present findings demonstrated that intervention duration ≤ six months significantly improved insulin concentration; however, long-term duration (> 6 months) was associated with increased FBS levels. In line with our findings, some meta-analyses displayed improvement in glycemic control in short-term interventions [22, 41, 45]. Contrary to the results, some studies found that longer intervention durations were associated with more decrease in glycemic parameters [20, 46, 47]. It seems that the effect of the duration of VDS on glycemic control is controversial. This ambiguity may be attributed to the wide diversity between the study's population, health condition, dose, frequency, and baseline vitamin D level.

Concerning lipid profile, our findings agree with the results of most previous meta-analyses revealed that vitamin D could be a valuable treatment to decrease TC and TG. In addition, a significant reduction was shown in TG in the short-term intervention (≤ 6 months) studies, patients with DM and low levels of baseline vitamin D. Dibaba et al. (2019), in a comprehensive meta-analysis found administration of vitamin D diminish TC, TG, and LDL cholesterol, while the improvements were more noticeable in patients with vitamin D deficiency [18]. Another meta-analysis reported that treatment with vitamin D has a beneficial impact on TC; lowering LDL in diabetics and patients with insufficient vitamin D and shorter duration was significant. However, there was no positive effect on TG and HDL cholesterol [48]. In Mirhosseini et al. meta-analysis vitamin D administration improved cardiac-metabolic parameters such as lipid profile. Also, the improvement effect of vitamin D was noticeable in trials with less than six months of intervention and patients with baseline serum vitamin D levels < 50 nmol/l [22]. Wang et al. provided that vitamin D changed LDL cholesterol but not TG, TC, and HDL cholesterol. As well as, the effect on LDL-C was more evident in the short-term intervention duration [49]. However, a recent meta-analysis of 4 RCTs that evaluate the impact of vitamin D on lipid profile in adults with metabolic syndrome has shown no significant effect on lipid profile following supplementation [17]. In the present study, probably due to insufficient studies, no statistically meaningful change was seen in LDL and HDL cholesterol.

It is considered that an inverse association was seen between serum vitamin D levels and serum lipid profile [10, 50]. Several possible reasons may explain the role of vitamin D in modifying lipid profiles. Vitamin D might increase lipoprotein lipase activity and mRNA in adipocytes and lower serum TG levels [51, 52]. Also, it decreases the absorption of fatty acid via improving calcium absorption, and the formation of insoluble calcium-fatty acid complexes in the bowel leading to a diminution cholesterol concentration [53].

There were masses of evidence outlining the emphasis of vitamin D on human health and diseases [54, 55]. Many studies have revealed that impaired vitamin D levels may result in multiple pathological outcomes, including obesity, hypertension, cardiovascular diseases, and DM [56, 57]. Studies have demonstrated that older papulation are highly at risk of severe vitamin D deficiency [58]. The effectiveness of vitamin D in preventing chronic diseases, including metabolic syndrome and cardiovascular diseases, has received extra attention in recent years [54, 59]. Several studies suggested that vitamin D deficiency or insufficiency increases the risk of all-cause mortality in elderly participants, even before the onset of DM and cardiovascular diseases [60]. The result of a meta-analysis demonstrated that serum vitamin D levels of 75 to 87.5 nmol/L (or 30 to 35 ng/mL) are associated with the lowest mortality rate [61]. Taking into expanding the elderly population in the world, the importance of chronic disease and its complications in the population increases. Therefore, as a cheap and safe treatment, vitamin D might prevent morbidities and fracture events in the elderly [62]. As mentioned above, in our study, vitamin D administration has a therapeutic effect on some cardiac-metabolic parameters, though no beneficial effect was observed on BMI or WC. The inverse relationship between BMI and vitamin D status has been provided in numerous pieces of evidence [13, 63]. However, the vitamin D effects on anthropometric measures are controversial. A recent meta-analysis indicates no significant impact on the BMI and WC of healthy adults [64]. With regard to that, a few RCTs investigated vitamin D impacts on anthropometric measures in the elderly.

This is the first systematic review examining the VDS effects on cardiac-metabolic outcomes in the elderly population (≥ 60 years) to the best of our knowledge. We conducted a comprehensive literature search that included all possible related eligible studies. Also, Subgroup and sensitivity analysis was executed to mitigate the study's heterogeneity. Finally, there was no evidence of significant publication bias in most of the study's outcomes, except in TC and FBS. After using Trim and fill method, the overall effect size of vitamin D on TG remained unchanged. The study has some limitations; First, we found only 11 eligible studies in this meta-analysis, clearly underlining the lack of adequate investigation of the elderly population in this issue. Second, even after performance subgroup analysis, we could not diminish potential heterogeneity in some outcomes such as TG. The third limitation is that data on WC and BMI was available in few studies, thus precluding evaluation of the role of vitamin D on anthropometric measures.

This study suggests that VDS may improve TC, TG, and insulin concentration in the elderly, especially in short-term intervention duration and in patients with vitamin D deficiency and diabetes. Although the number of studies on this issue is minimal, nonetheless, the finding of this study will enhance our understanding of the importance of vitamin D in the elderly population as well as potentially provide the best evidence-based practical interventions to improve vitamin D-related cardiac-metabolic diseases in the elderly people. Due to, the high heterogeneity between included studies the study results must be interpreted with caution, and large and well-designed RCTs are necessary to validate the review findings.