Effects of vitamin D supplementation on cardiometabolic parameters among patients with metabolic syndrome: A systematic review and GRADE evidence synthesis of randomized controlled trials

Metabolic syndrome (MetS) is defined by the co-occurrence of risk factors for cardiovascular disease and type 2 diabetes, including central obesity, hypertension, dyslipidemia, and hyperglycemia. Low 25-hydroxyvitamin D [25(OH)D] levels are associated with MetS and its components. Vitamin D receptors are widely expressed, suggesting extraskeletal effects of vitamin D on lipid metabolism, glucose homeostasis, and blood pressure regulation. Observational studies and mechanistic data suggest potential benefits of vitamin D on lipids, insulin secretion/sensitivity, and blood pressure; however, evidence from trials is inconsistent. This review aimed to assess randomized controlled trials (RCTs) that simultaneously evaluated the effects of vitamin D supplementation (VDS) on all five MetS components (TG, HDL-c, fasting glucose, blood pressure, waist circumference) in adults with confirmed MetS, to inform clinical decision-making about treating vitamin D deficiency in this population.

Prior epidemiologic and mechanistic research indicates inverse associations between vitamin D status and abdominal obesity and dyslipidemia, and suggests roles of 1,25(OH)2D3 in lipogenesis, lipoprotein lipase activity, insulin secretion, insulin resistance, and renin-angiotensin-aldosterone system modulation. Previous systematic reviews reported heterogeneous findings. A meta-analysis of RCTs focusing only on HDL-c and TG found no effect of VDS on these lipids. Another narrative review combining observational and interventional studies (often without confirmed MetS diagnosis or baseline vitamin D status) suggested possible benefits on blood pressure, abdominal obesity, and glucose metabolism. Many discrepancies are attributed to differences in vitamin D dose, form (D2 vs D3), intervention duration (2–12 months), and geographic settings. Earlier reviews often did not use GRADE; this review extends prior work by including only RCTs with confirmed MetS and assessing all five components with GRADE.

Protocol and registration: Conducted per PRISMA 2020 and SWiM guidelines; protocol registered in PROSPERO (CRD42019123212) and published (DOI: 10.1186/s13643-020-01433-3). Eligibility (PICOS): Adults >18 years with MetS diagnosed by NCEP-ATP III or IDF criteria; Intervention: oral vitamin D2 (ergocalciferol) or D3 (cholecalciferol), administered daily, weekly, or monthly; Comparator: placebo; Primary outcomes: triglycerides (TG) and HDL-c; Secondary outcomes: fasting blood glucose (FBG), blood pressure (BP), and waist circumference (WC). Exclusions: vitamin D combined with other supplements, fortified foods (uncertain dose), active vitamin D analogs [1,25(OH)2D3]. Search strategy: EMBASE, MEDLINE (PubMed), Web of Science Core Collection, Lilacs, Cochrane CENTRAL, ClinicalTrials.gov, and Google Scholar, from 1998 (first WHO MetS definition) to April 2023; no language restrictions; reference lists hand-searched. Study selection: Two reviewers independently screened titles/abstracts in Rayyan, with disagreements resolved by a third reviewer; data extracted using a Cochrane form. Synthesis and analysis: Due to heterogeneity in interventions, outcome measures, and effect metrics, a meta-analysis was not appropriate; results were synthesized narratively per SWiM, describing dose, duration, frequency, population characteristics, and outcomes. Risk of bias: Assessed independently by two authors using Cochrane RoB 2.0 across five domains, with consensus resolution. Certainty of evidence: GRADE was used by three authors to rate certainty for TG, HDL-c, FBG, BP, and WC, with differences resolved by consensus.

- Study selection and characteristics: 13,644 records identified; 9,129 duplicates removed; 4,515 screened; 24 studies deemed eligible; 7 RCTs included. Trials were conducted in Greece (2), Iran, Iraq, China, Thailand, and India; sample sizes 50–120; ages 40–65 years; follow-up 2–12 months; average daily vitamin D dose 700 IU to 8,571 IU. Most used vitamin D3; one used vitamin D2; some included co-interventions (dietary counseling or physical activity); one study co-supplemented calcium. - Vitamin D status: All trials reported significant increases in serum 25(OH)D in intervention groups versus controls across varying dosing protocols. - Lipid profile: Among five studies assessing lipids, only one (Salekzamani 2016; ~7,142 IU/day for 4 months) observed a significant TG reduction (e.g., 269 to 242 mg/dL; p<0.001/p=0.01 reported). No consistent improvements in HDL-c were observed; in one trial (Farag 2019) HDL-c increased only when VDS was combined with endurance physical activity (p=0.029), while TG was paradoxically lower in placebo versus VDS arms (p=0.003). - Waist circumference (WC): Of five studies, only one (Mahmood 2017; ~8,571 IU/day for 6 months) showed a significant WC decrease (p=0.001). Others reported no significant WC changes. - Fasting blood glucose (FBG): Across five studies, VDS did not significantly improve FBG. - Blood pressure (BP): Across four studies, VDS did not significantly improve systolic or diastolic BP. - Risk of bias: Three trials rated low risk of bias; three had some concerns (notably deviations from intended interventions); one had high risk of bias (measurement of outcomes). - Certainty of evidence (GRADE): Very low certainty that VDS decreases TG or increases HDL-c (primary outcomes); low certainty for WC reduction; moderate certainty for effects on FBG and BP (no consistent benefit demonstrated).

This systematic review addressed whether vitamin D supplementation improves all five components of MetS in adults with confirmed MetS. Despite consistent increases in 25(OH)D levels with supplementation, improvements in MetS components were not consistently observed: only isolated benefits were seen for TG (in one study with high daily-equivalent dosing over 4 months) and WC (in one study with high dosing over 6 months). Heterogeneity in dosing regimens, intervention duration, vitamin D form, and co-interventions likely contributed to inconsistent outcomes and precluded meta-analysis. While mechanistic and observational data suggest that vitamin D could favorably influence lipid metabolism, insulin sensitivity/secretion, and blood pressure regulation, clinical RCT evidence in MetS populations remains inconclusive, with generally low to very low certainty for primary lipid outcomes and at best moderate certainty for glycemia and blood pressure, where no consistent benefit was shown. Overall, findings do not substantiate routine VDS as an effective strategy to improve MetS components beyond correcting vitamin D deficiency, and they underscore the need for standardized, adequately powered RCTs with clear therapeutic targets for 25(OH)D levels and harmonized outcome reporting.

Across seven RCTs in adults with MetS, vitamin D supplementation consistently increased serum 25(OH)D but led to significant improvements in only two components—triglycerides and waist circumference—in single studies. Given the low to very low certainty for these findings and lack of consistent effects on fasting glucose, blood pressure, and HDL-c, current evidence does not support VDS as an effective intervention to improve MetS components. Future research should prioritize well-designed, adequately powered RCTs that simultaneously evaluate all MetS components, standardize dosing regimens and durations, set therapeutic 25(OH)D targets, consider phenotypic subgroups, and control for confounding factors (e.g., seasonality, genetics, co-interventions).

- Few RCTs simultaneously evaluated all five MetS components, limiting power and generalizability. - High heterogeneity in vitamin D dose, form (D2 vs D3), dosing frequency, intervention duration, and co-interventions (diet, physical activity, calcium), preventing meta-analysis and hindering between-study comparisons. - Potential baseline imbalances or unclear reporting of baseline vitamin D status between groups in some trials. - Geographic concentration in Eastern countries limits extrapolation to Western populations. - Several trials had some concerns or high risk of bias; overall certainty was low to very low for many outcomes. - Important modifiers of vitamin D status and response (genetic polymorphisms, season, latitude/sun exposure) were not explored in included trials.