Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials

Nutrition & Diabetes REVIEW ARTICLE www.nature.com/nutd OPEN Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials Kabelo Mokgalaboni 1✉ , Given. R. Mashaba1, Wendy N. Phoswa1 and Sogolo. L. Lebelo1 1234567890();,: © The Author(s) 2024 BACKGROUND: The beneficial effects of folate have been observed under different conditions, but the available evidence on inflammation and reduction of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) is limited. The study aimed to explore the effects of folate on inflammation and homocysteine amongst individuals with T2DM. METHODS: PubMed, Scopus, and Cochrane Library were used to search for evidence. A random-effect model meta-analysis through Review Manager (version 5.4) and metaHun was performed. Results were reported as standardized mean differences (SMD) and 95% confidence intervals graphically using forest and funnel plots. RESULTS: Data from 9 trials with 426 patients living with T2DM were analyzed. Folic acid supplementation significantly revealed a large effect size on homocysteine levels compared to placebo, SMD = −1.53, 95%CI (−2.14,−0.93), p < 0.05. Additionally, we observed a medium marginal effect size on C-reactive protein (SMD = −0.68, 95%CI (−1.34, −0.01), p = 0.05). However, no significant effect on tumor necrosis factor-α (SMD = −0.86, 95%CI (−2.65, 0.93), p = 0.34), and interleukin-6 (SMD = −0.04, 95%CI (−1.08, 1.01), p = 0.95) was observed. CONCLUSION: Evidence analyzed in this study suggests that folic acid supplementation in T2DM reduces homocysteine and may mitigate CVDs. However, its effect on inflammation is inconclusive. Nutrition and Diabetes (2024)14:22 ; https://doi.org/10.1038/s41387-024-00282-6 INTRODUCTION Type 2 diabetes mellitus (T2DM) is a condition that elevates blood glucose, also known as hyperglycemia [1]. Patients living with T2DM are at higher risk of developing cardiovascular diseases (CVD) than healthy individuals [2]. The prevalence of diabetes worldwide in 2021 was estimated to be 10.3% and this is continually rising with estimated projections of around 12.2% in 2045 [3]. The main factors that exacerbate the development of CVD in T2DM include but are not limited to hyperinsulinemia, obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, and homocysteinemia [4]. Inflammation is a central feature in T2DM, contributing to CVD among patients with T2DM. For instance, an increased circulating plasma C-reactive protein (CRP) [5, 6] is noted in patients with T2DM, which may further increase the risk of CVD. Moreover, T2DM are more likely to develop hyperhomocysteinemia primarily due to folate and vitamin B12 deficiency [7, 8]. It is noteworthy to indicate that patients with T2DM who rely on metformin to control hyperglycemia often develop hyperhomocysteinemia, which further makes them susceptible to CVDs [9]. Previous studies have reported a link between homocysteine and inflammation [10–12]. For instance, evidence from preclinical and clinical studies demonstrated an association between homocysteine and proinflammatory responses [10, 13]. Homocysteine is an amino acid associated with the risk of CVD if its level is elevated in the body [14]. Although homocysteine and inflammation markers are frequently detected at the same time, they are not correlated as they have revealed an inverse relationship in previous scientific evidence [8, 15]. We anticipate that measuring them simultaneously will improve the overall interpretation and understanding of their correlation in T2DM. Due to their contribution to the development of CVDs in T2DM, an approach that can reduce the circulating levels of inflammatory markers and homocysteine in T2DM can be important to ameliorate inflammation, halt cardiovascular-related complications amongst T2DM and further reduce morbidity and mortality. It is important to note that T2DM medications widely used to control hyperglycemia in T2DM are available; however, their longterm may result in vitamin B12 and folate deficiency [16, 17]. Recent evidence has shown that folate deficiency is associated with an increased level of homocysteine, increasing the risk of CVD in T2DM [18, 19]. The above shortfalls for drugs and related side effects have prompted an exploration of dietary supplements and macronutrients in alleviating cardiovascular-related complications in T2DM. Other examples include vitamin D [20], and folate, a natural form of vitamin B9 due to its pleiotropic effects in diabetes and fewer side effects than other expensive and toxic therapies [21]. Folate is primarily found in green leafy vegetables and plays a role in cell division and synthesis of nucleic acids [22]. 1 Department of Life and Consumer Science, College of Agriculture and Environmental Sciences, University of South Africa, Florida Campus, Roodepoort, South Africa. ✉email: Received: 21 November 2023 Revised: 9 April 2024 Accepted: 10 April 2024 K. Mokgalaboni et al. 2 Table 1. Eligibility criteria according to PICOS. PICOS Population/Participants of interest Adults (18+ years) with type 2 diabetes mellitus Intervention Folate/folic acid/vitamin B9 for a period of 2 to 26 weeks Comparator/control Placebo/standard treatment Outcomes Changes in homocysteine and inflammation Study design All Randomized controlled trials (cross-over, parallel, open-labeled, single and double-blinded) PICOS population, intervention, comparator/control, outcome and study design. Folate has been explored by previous studies on inflammation, focusing on CRP levels in patients with T2DM. However, the findings reported by various studies are contradictory [23, 24]. While Fatahi et al. [25] through meta-analysis, demonstrated a positive effect of folate on inflammation, the results must be treated with caution as only CRP as a marker of inflammation was assessed, and this might introduce bias, as it is difficult to conclude on the severity of inflammation based on one biomarker. Sato has reported no effect of 20 mg of folic acid on CRP and IL-6 as markers of inflammation in T2DM [15]. Additionally, the findings by Kaye et al., [26] suggest that folic acid may reduce the homocysteine levels in T2DM. However, completely different results were reported in a randomized, placebo-controlled, crossover trial where there was no significant difference between folic acid and placebo groups on homocysteine [27]. Thus, the current study aims to systematically review and meta-analyze data from RCT to evaluate the effect of folic acid/folate on the level of homocysteine and inflammation in T2DM adult patients to rule out any inconsistencies observed in previous evidence. Furthermore, this review and meta-analysis also indicate the effective doses of folic acid/folate therapy that can alleviate inflammation among patients living with T2DM. METHODOLOGY This systematic review and meta-analysis are prepared and reported us (...truncated)