Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, accounting for approximately 19.8 million fatalities in 2022 (1). The high prevalence and mortality associated with CVDs pose significant public health challenges, leading to severe consequences such as myocardial infarction, stroke, and heart failure. These conditions often result in long-term disability, diminished quality of life and impose a substantial financial burden on healthcare systems globally (2). As the global burden of CVDs intensifies, addressing modifiable risk factors is crucial for informing effective prevention strategies. Among these factors, improving poor dietary habits and lifestyle choices is essential in mitigating the risk of CVDs, as these modifiable elements, either independently or synergistically, play a pivotal role in disease development.

Vitamin D, a fat-soluble vitamin and steroid hormone, plays an indispensable role in sustaining bone health and mineral metabolism and also exerts extensive effects on the immune and nervous systems, including anti-inflammatory and immunomodulatory properties (3–5). Emerging evidence has linked vitamin D deficiency to various health conditions, including CVDs, diabetes, respiratory disorders, and cancers (6, 7). Despite extensive research, the relationship between vitamin D levels and mortality, whether from all causes, cardiovascular or cancer-specific, remains inconclusive. Although observational studies (8) suggest an association between low vitamin D levels and increased mortality risk, findings from randomized controlled trials (RCTs) have been inconsistent. Some meta-analyses of RCTs (9) have reported no significant reduction in all-cause or cardiovascular mortality with vitamin D supplementation. However, accumulating evidence, including findings from some RCTs and epidemiological studies, suggests a potential benefit in reducing cancer-specific mortality (9, 10) These discrepancies may stem from variations in study design, baseline vitamin D levels, and intervention strategies, necessitating further investigation into the complex relationship between vitamin D and mortality.

Sleep disorders, including insomnia and sleep apnea, are also recognized as significant health issues, with mounting evidence linking them to higher risks of cardiovascular disease, metabolic disorders, and overall mortality (11–16). While some studies have shown that sleep disorders are associated with an increased risk of cardiovascular events (17, 18), other research has observed differing associations across various populations (19, 20), emphasizing the inconsistency in findings and indicating the need for further investigation into the nature of this relationship.

While extensive research has explored the individual impacts of vitamin D deficiency and sleep disorders on health, there remains a glaring gap in the literature regarding their combined effects on adults mortality. This gap is particularly pressing as changes in sleep behavior often lead to altered eating habits, reduced outdoor activity, and decreased sunlight exposure, all of which can contribute to diminished vitamin D synthesis (21, 22). Furthermore, recent meta-analyses (23, 24) have highlighted a notable association between vitamin D deficiency and an increased susceptibility to sleep disorders and have suggested that taking vitamin D supplements may help improve sleep quality. Considering the intricate interplay between vitamin D levels and sleep health, a novel and comprehensive evaluation of their combined effects could offer valuable insights into their impact on cardiovascular disease outcomes, especially for those experiencing both significant sleep disorders and vitamin D deficiency, who are at elevated risk.

To address these gaps, our study aimed to investigate the prevalence of vitamin D deficiency and sleep disorders in a nationally representative cohort of U.S. adults and to evaluate both the individual and combined effects of these factors on cardiovascular, all-cause, and cancer-specific mortality. Utilizing comprehensive NHANES data from 2005 to 2018, this analysis sought to shed crucial light on the combined effects of these prevalent health conditions and their impact on mortality outcomes, thereby offering significant contributions to public health discourse. Moreover, the findings from this study were poised to establish a foundation for future research efforts focused on developing targeted interventions designed to mitigate the health risks associated with vitamin D deficiency and sleep disorders.

This study explored the combined effect of vitamin D deficiency and sleep disorders on mortality risks using a nationally representative cohort of 24,566 U.S. adults. Approximately 34.34% of participants were found to have vitamin D deficiency, while 8.41% had sleep disorders. Over a median follow-up of 9.08 years, both vitamin D deficiency and sleep disorders were individually associated with significantly increased risks of all-cause mortality. However, neither condition alone was significantly associated with cardiovascular or cancer mortality. In the joint analysis, individuals with both conditions exhibited markedly higher risks of all-cause and cardiovascular mortality compared to those with only one or neither risk factor. The combined effect on cancer mortality was not statistically significant. These associations remained robust in sensitivity and subgroup analyses. To the best of our knowledge, this is the first study to investigate the joint effects of vitamin D deficiency and sleep disorders on mortality risks in U.S. adults, underscoring the need to address both factors to mitigate all-cause and cardiovascular mortality in this population.

Growing evidence suggests that the relationship between vitamin D levels and cardiovascular mortality is not uniform, with varying dose–response patterns reported across studies. Our analysis, based on six consecutive NHANES cycles (2005–2018) in adults aged 20 years and older, identified a linear association between vitamin D levels and cardiovascular mortality, indicating that lower vitamin D levels are consistently linked to higher cardiovascular mortality risk. This finding aligns with Mo et al. (30) who similarly reported a linear relationship between serum 25-hydroxyvitamin D concentrations and cardiovascular mortality risk. However, other studies have reported a non-linear association. Notably, a recent NHANES-based analysis spanning a broader timeframe (2001–2018) identified an L-shaped association, suggesting a threshold effect where cardiovascular mortality risk declines primarily at lower vitamin D levels before reaching a plateau (31). These discrepancies may arise from variations in study periods, population characteristics, analytical methodologies, or vitamin D assay standardization. Collectively, these findings underscore the complexity of vitamin D’s role in cardiovascular mortality and highlight the need for further research to refine supplementation strategies, clarify optimal vitamin D thresholds, and delineate the mechanisms underlying these associations.

Building on these findings, our study further supports the notion that both vitamin D deficiency and excessive serum 25(OH)D levels may contribute to increased mortality risk, reinforcing a J-shaped dose–response pattern for all-cause mortality. This pattern has been demonstrated in the CopD study, which reported an increased mortality risk when serum 25(OH)D levels exceeded 50–60 ng/mL (32). Such nonlinearity suggests that while maintaining adequate vitamin D levels is crucial, indiscriminate supplementation may not always yield additional benefits. Recent study recommend a daily vitamin D intake of up to 4,000 IU for normal-weight individuals and 10,000 IU for those with obesity to maintain serum 25(OH)D levels within 30–50 ng/mL (33). While our study suggests potential risks associated with excessive vitamin D levels, prior research indicates that commonly used high-dose supplementation (e.g., 50,000 IU/week) does not necessarily lead to toxicity (34). Despite strong observational evidence linking low vitamin D levels to increased mortality risk (8), RCTs have produced inconsistent findings, particularly regarding all-cause and cardiovascular mortality. Some RCTs (35) have indicated a reduction in all-cause mortality, while others (9, 36) reported no significant impact on all-cause or cardiovascular mortality, though reductions in cancer mortality were observed. These discrepancies may arise from several methodological limitations in RCTs, such as suboptimal trial designs (37, 38), failure to selectively enroll individuals with severe vitamin D deficiency (e.g., <18 ng/mL) which may dilute the potential benefits of supplementation (39), and substantial heterogeneity in baseline vitamin D status, supplementation dosages, and follow-up durations across trials, making it challenging to detect consistent effects (40). Additionally, another critical but often overlooked factor is sunlight exposure, a key determinant of endogenous vitamin D synthesis. Inadequate sun exposure has been linked to increased mortality risk (41), yet many RCTs do not account for individual differences in UVB exposure, potentially leading to misclassification of vitamin D status and underestimation of supplementation benefits. These inconsistencies highlight the need for more targeted RCTs with improved methodological rigor. Optimized trial designs, such as those employed by Rostami et al. (42) and Dawson-Hughes et al. (43), which focus on high-risk populations with severe vitamin D deficiency and tailored intervention strategies, may provide more definitive evidence on the role of vitamin D in mortality outcomes. Additionally, emerging evidence suggests that vitamin D supplementation may be more beneficial when combined with vitamin K intake in managing cardiovascular risk factors (44). However, our study did not assess the role of vitamin K co-supplementation, highlighting the need for future research in this area. Future studies should prioritize these approaches to clarify the potential benefits of vitamin D supplementation in reducing mortality risk.

Regarding sleep disorders, our study found a significant association with all-cause mortality, consistent with prior research (15, 45). However, we did not observe statistically significant associations with cardiovascular or cancer-specific mortality, contrasting with reports from some studies (12, 46, 47) that identified such associations. These inconsistencies across studies may be attributed to the complex nature of sleep as a concept, differences in study populations, geographic variations in daily light exposure, limited statistical power in smaller studies, or potential biases in measurement techniques. Mechanistically, sleep disorders are known to promote systemic inflammation, elevating levels of C-reactive protein and interleukin-6, which are associated with increased mortality risk (45, 48). Moreover, sleep disorders may adversely affect health outcomes by influencing lifestyle factors such as physical activity, smoking, and alcohol consumption. For instance, prolonged sleep duration might reduce the time available for engaging in health-promoting activities, like physical activity (49, 50). In this study, we observed significantly lower physical activity levels in the sleep disorder group, further supporting this hypothesis. Overall, our findings reinforce the role of sleep disorders as a significant health risk factor, highlighting the need for heightened public awareness and targeted interventions to improve sleep health.

A systematic comparison of joint and interaction analyses offers a more nuanced understanding of how these two risk factors jointly influence mortality. We found that the combined effect of vitamin D deficiency and sleep disorders significantly increased both all-cause and cardiovascular mortality, and these associations remained robust across various subgroups. Furthermore, our findings persisted even after excluding participants with follow-up periods of less than 3 years, reinforcing the reliability of the results. This evidence offers valuable epidemiological insights for guiding public health policies and clinical interventions, emphasizing the need to optimize vitamin D levels and improve sleep quality to reduce early mortality risk associated with these modifiable factors. Although our additive and multiplicative interaction analyses did not reach statistical significance, this outcome suggests that capturing these complex interactions may require more extensive studies or more sensitive statistical methods. It also highlights the importance of not only focusing on the independent effects of single risk factors but also delving into the joint management of multiple risk factors. A review of randomized controlled studies has emphasized that such strategies, including nutrition counseling, dietary changes, addressing sedentary behavior, promoting physical activity, avoiding tobacco exposure, and minimizing long-term glucocorticoid therapy, could effectively manage multiple health risks (51). Overall, these findings underscore the necessity of integrating multiple health factors into comprehensive management strategies within clinical and public health practices, providing new avenues for enhancing population health and extending life expectancy.

Subgroup analyses revealed that the combined effects of vitamin D deficiency and sleep disorders on cardiovascular mortality remained consistently significant across various subgroups, particularly among individuals without hyperlipidemia or cardiovascular disease. Notably, the joint effects were more pronounced in individuals with a normal BMI, which aligns with prior research (52), indicating that the cumulative impact of vitamin D deficiency on cardiovascular mortality is most evident in normal-weight individuals. This heightened sensitivity may be attributed to the more evident protective cardiovascular effects of vitamin D in individuals with a normal BMI, such as improved endothelial function and blood pressure regulation (53). Conversely, the metabolic disruptions associated with obesity, including chronic inflammation and insulin resistance, could attenuate the impact of vitamin D deficiency on cardiovascular outcomes (54). Regarding cancer mortality, although the joint effects of vitamin D deficiency and sleep disorders were not statistically significant in our analysis, accumulating evidence suggests that BMI may modify the relationship between vitamin D and cancer outcomes. The VITAL study demonstrated that vitamin D supplementation significantly reduced the incidence of cancer in individuals with BMI <25 but not in those with higher BMI (55), supporting the hypothesis that vitamin D’s protective effects are more pronounced in individuals with lower BMI. A secondary analysis further revealed that vitamin D supplementation was associated with a reduced risk of advanced cancer, particularly among participants with BMI <25 (56). The attenuated effect of vitamin D in individuals with higher BMI may be explained by differences in vitamin D distribution. While previous studies suggested that sequestration of vitamin D in adipose tissue reduces its bioavailability (57), emerging evidence indicates that volumetric dilution—whereby the larger distribution volume in obese individuals results in lower circulating vitamin D concentrations—may be a more plausible mechanism (58). This dilution effect likely reduces the physiological availability of vitamin D, potentially contributing to the weaker association between vitamin D status and cancer mortality observed in individuals with obesity. Additionally, recent findings by Muñoz and Grant (10) reinforce the role of vitamin D in reducing cancer mortality, emphasizing the importance of maintaining adequate vitamin D levels, particularly among individuals with lower BMI. Collectively, these findings underscore the need for further research to elucidate BMI’s role as a key modifier in the relationship between vitamin D and cancer outcomes, which may inform future precision-based supplementation strategies.

Several biological pathways may account for the observed joint effects of vitamin D deficiency and sleep disorders on all-cause and cardiovascular mortality, necessitating further exploration. Firstly, vitamin D plays a critical role in regulating circadian rhythms and maintaining sleep quality, particularly in brain regions like the hypothalamus, where its receptors are abundantly expressed (59, 60). Deficiency in vitamin D may disrupt the function of these brain regions and lower melatonin levels, potentially leading to sleep disorders and consequently increasing risks of all-cause and cardiovascular mortality (22, 61). Moreover, vitamin D deficiency is associated with immune system dysregulation and chronic inflammatory responses, promoting elevated levels of inflammatory mediators such as TNF-α, IL-1, and prostaglandin D2, which are closely linked to sleep regulation (62, 63). Furthermore, vitamin D deficiency can alter gut microbiota composition, potentially disrupting B vitamin metabolism and reducing pantothenic acid production, which is essential for immune regulation (64). This imbalance may impair immune function and promote a pro-inflammatory state associated with atherosclerosis and autoimmunity (65). Given the strong link between chronic inflammation and cardiovascular disease, these immune disturbances may further heighten cardiovascular risks in individuals with both vitamin D deficiency and sleep disorders (66). Additionally, disruptions in the gut microbiota—closely linked to immune and cardiovascular health—may further compound the risk of cardiovascular mortality in individuals with vitamin D deficiency and sleep disorders (67). However, within the complex pathology of cancer, these mechanisms might be overshadowed by other factors such as genetic predisposition, tumor type, disease stage, and treatment modalities (68, 69), making it challenging for current study designs to capture these complex interactions. Additionally, individual variability and the heterogeneity of cancer types may further complicate the impact of vitamin D deficiency and sleep disorders on cancer mortality, particularly among patients with different biological characteristics. This variability could contribute to the absence of significant joint or interactive effects observed in our overall analysis. A limitation of this study is the presence of unmeasured variables that may influence both vitamin D levels and sleep disorders, such as long-term medication use or psychosocial factors, which could potentially confound the results. Therefore, future research should aim for more comprehensive control of confounding factors and consider employing more advanced statistical and bioinformatics methods to gain a deeper understanding of the complex effects of vitamin D deficiency and sleep disorders on cancer mortality.

This study possesses several notable strengths. It is the first to examine the combined effects of vitamin D deficiency and sleep disorders on mortality, addressing a significant gap in existing literature. Using a large, nationally representative sample from NHANES, alongside the prospective design and extended follow-up period, enhances the robustness and generalizability of our findings. Additionally, extensive adjustments for potential confounders in sensitivity and subgroup analyses further strengthen the validity of our results, providing a comprehensive understanding of these associations. However, several limitations should be acknowledged. First, all exposures and confounders were measured at baseline, and any changes during the follow-up period were not captured, which could affect the observed associations. Second, our exposure variables relied primarily on self-reported data, which may be subject to recall bias and random measurement errors, potentially leading to underestimating the true magnitude of the associations. Moreover, although sleep disorders were assessed by physicians, the absence of detailed reporting on the specific nature hindered further in-depth analysis, limiting our ability to explore the multidimensional nature of sleep disturbances. Third, despite careful consideration of multiple confounding factors, the observational nature of the study design means that residual confounding and reverse causality cannot be entirely ruled out. We attempted to mitigate the impact of reverse causation by excluding patients who died within the first 3 years of follow-up in our sensitivity analysis, yet this limitation warrants caution. Finally, although the NHANES sample was substantial, it may not fully represent the U.S. population, as the participants were self-selected, limiting our findings’ generalizability to other regions of the U.S. and to other countries.

In summary, this population-based cohort study underscores the significant joint effect of vitamin D deficiency and sleep disorders on all-cause and cardiovascular mortality risk. The implications of this research are promising, as addressing both vitamin D status and sleep health may offer a more comprehensive approach to reducing mortality risk in clinical practice and public health interventions. The potential for future research to build on our findings, focusing on longitudinal studies with repeated measurements and personalized supplementation strategies, offers hope for further advancements in this field.