Niacin, or vitamin B3, is an essential nutrient obtained from dietary sources, such as meat, fish, cereals, and vegetables [1]. In gram quantities, niacin has been shown to positively affect lipid profiles, lowering triglycerides and low-density lipoprotein cholesterol (LDL-C) levels while raising high-density lipoprotein cholesterol (HDL-C) levels [2, 3, 4]. However, the change in HDL-C caused by niacin is logarithmic, whereas the change in LDL-C is linear [5]. Niacin lowers serum LDL-C through multiple mechanisms, such as inhibiting the peripheral mobilisation of free fatty acids [6], thereby reducing the substrates for the hepatic synthesis of triglycerides and very low-density lipoprotein (VLDL) particles [7], which, in turn, reduces the hepatic conversion of VLDL particles to LDL particles. Additionally, niacin directly interferes with the enzymatic processes that mediate the conversion of VLDL-C to LDL-C [7] and reduces triglyceride synthesis and hepatic lipoprotein secretion by inhibiting diacylglycerol acyltransferase 2 [8]. However, skin flushing is a typical adverse effect associated with niacin. The recommended daily dose for individuals is typically between 15 and 20 mg [9], with pharmacological dosages of up to 3000 mg/day being well-tolerated in treating dyslipidaemia [10].

Historically, the 1975 Coronary Drug Project first recognized niacin’s potential to reduce atherosclerotic cardiovascular events [11]. Next, several early investigations suggested that gram-level niacin therapy could impact cardiovascular risk in secondary prevention, particularly for individuals already affected by cardiovascular disease (CVD) [12]. However, the cardiovascular benefits of niacin therapy remain a subject of debate. The Framingham Heart Study also provided epidemiological support for niacin’s potential to influence CVD through lipid modification pathways, suggesting an inverse relationship between CVD incidence and HDL-C levels [13, 14]. However, the Heart Protection Investigation 2-Treatment of HDL for Reducing the Rate of Vascular Breaks (HPS2-Thrive) investigation, which involved 35,301 patients primarily in secondary prevention trials, was meta-analysed in 2014 and found that adding niacin to statin medication did not significantly alter the death rates from stroke, coronary heart disease, nonfatal myocardial infarct, or all causes [15, 16]. The inconsistent protective effects of niacin observed in existing studies may be attributed to the trial design. Furthermore, the extent to which niacin contributes to these benefits remains unclear. The Institute for Clinical Systems Improvement does not recommend the co-treatment of niacin and statins owing to an elevated risk of side effects without a corresponding decrease in cardiovascular outcomes [17]. However, in the United States, many patients continue to use niacin for other indications approved by the Food and Drug Administration [18].

However, data on the association between niacin levels and CVD mortality are limited. To address these research gaps, this study explored the potential relationship between niacin intake and the risk of all-cause and CVD mortality. This study aimed to provide dietary recommendations that may contribute to improved CVD management.

Our study revealed favorable associations between niacin and cardiovascular events using data from the NHANES 2003–2018. We identified a negative correlation between the population’s prevalence of CVD and niacin levels, which persisted after adjusting for covariates, suggesting niacin’s protective role against CVD development. The cardiovascular protective effect may stem from niacin’s ability to decrease LDL-C and triglycerides and improve lipoprotein function [26]. A meta-analysis published in 2006, encompassing 23 studies, indicated that for every 1% decrease in LDL-C, the incidence of CVD events decreased by nearly 1%, and for every 1% increase in HDL-C, the incidence of CVD events decreased by at least 1%, irrespective of LDL-C reduction [27]. Dose–response analysis revealed a statistically significant and nonlinear trend, with a sharp decline in the ORs at lower doses and a plateau at higher doses. While sex-based differences in CVD incidence were not substantial, a discernible, though statistically non-significant, trend towards reduced CVD prevalence with niacin therapy was observed. While research on the link between niacin and CVD is ongoing, interest in using dietary niacin as an intervention is growing. The Landmark Coronary Drug Project (1966–1975) explored the long-term reliability and effectiveness of niacin and other lipid-altering drugs [28, 29]. Although it showed modest benefits in reducing nonfatal heart attacks, the lack of impact on overall mortality led to the trial being considered neutral and overlooked [28]. In a placebo-controlled study involving 1119 male patients administered 2000 mg of niacin daily and 2789 taking a placebo, the niacin group showed a 26% lower rate of nonfatal heart attacks and a 24% decrease in strokes (p 0.05) [11]. A subsequent meta-analysis of seven trials confirmed momentous drops in stroke, nonfatal heart attacks, coronary revascularization, and transient ischaemic attacks with niacin compared to placebo [30]. Interestingly, it also hinted at a potential but non-significant decrease in cardiac mortality (p = 0.13). It should be noted that the niacin doses in these trials varied [30]. Our investigation examined participants’ baseline and nutritional characteristics based on niacin intake. Despite controlling for several variables, there was no correlation with a lower risk of all-cause or CVD mortality in men. Similarly, a meta-regression analysis of 11 niacin trials [31] linked serum HDL-C levels with a lower probability of CVDs. This may be owing to the independent anti-atherogenic effects of niacin through its antioxidant and anti-inflammatory properties [32].

In a 2011 randomised controlled trial (RCT), 3414 patients diagnosed with coronary heart disease who underwent simvastatin treatment were randomly allocated to either the niacin or placebo group [33]. The participants received simvastatin at doses ranging from 40 to 80 mg, with or without ezetimibe at 10 mg/d, to attain LDL-C levels between 40 and 80 mg/dL. After a 3-year follow-up, no significant advantage was observed in the primary endpoint of composite CVD (95% CI: 0.87–1.21, HR: 1.02; p = 0.79). However, the niacin cohort exhibited a notable elevation in median HDL-C levels compared to those of the placebo group and reductions in triglyceride and LDL-C levels compared to those at baseline. Furthermore, a random-effects meta-analysis of 23 RCTs indicated that niacin did not significantly affect mortality but was associated with adverse outcomes. These included the frequency of nonfatal or fatal infarctions of the heart, cardiovascular or non-cardiovascular death, and the frequency of nonfatal or fatal strokes [26]. A recent study reported that niacin did not negatively affect cardiovascular outcomes during secondary prevention [34]. Moreover, in individuals not taking statin medication, niacin monotherapy was associated with a lower risk of cardiovascular events (relative risk: 0.51, 95% CI: 0.37–0.72; proportional risk: 0.74, 95% CI: 0.58–0.96; stroke: relative risk: 0.74, 95% CI: 0.59–0.94; acute coronary syndrome: and revascularization) [34]. This study did not demonstrate a link between niacin intake and a decreased risk of cardiovascular morbidity or death. However, the sex-stratified analysis revealed a positive association between niacin intake and both CVD and all-cause mortality. Interestingly, females appeared to benefit from higher niacin intake levels, as evidenced by a lack of marked variability in CVD and all-cause mortality compared to males. Further studies are necessary to understand the root cause of this disparity in the impact of niacin consumption based on sex.

Clinical trials have identified various adverse effects associated with niacin, ranging from common symptoms, such as skin flushing and itching, to more severe conditions, such as heart failure, musculoskeletal and gastrointestinal issues, diabetic complications, and new-onset diabetes [30]. Despite these side effects, niacin remains the most potent agent currently available for enhancing HDL levels, exhibiting the ability to increase HDL levels by as much as 30–35%, even in individuals with extremely low HDL levels [35]. Surjana et al. [36] demonstrated the role of niacin in inhibiting carcinogenesis and DNA damage in various cancers, including oral, colon, breast, and lung cancers. Recent clinical research has revealed a correlation between niacin consumption and a lower risk of developing squamous cell carcinoma [37]. These findings hold significance for clinicians for several reasons. Firstly, statin-treated patients often face a residual risk of CVD. Secondly, evidence suggests that improving prognosis beyond lowering LDL-C levels may be beneficial. Furthermore, niacin could be an appealing alternative for an estimated 10% of patients who cannot tolerate or have contraindications to statin therapy [38]. Thirdly, research suggests females may benefit more than males from higher niacin intake levels in reducing CVD mortality. The present study had several limitations. Firstly, potential errors and inaccuracies in diet assessments could introduce uncertainty. Secondly, the presence of residual confounding factors is inherent in observational studies. Although adjustments have been made to various covariates to minimise this issue, complete elimination remains challenging. Thirdly, the self-reported 24-h recalls used to collect dietary data might be susceptible to recall bias. While this method is widely employed by trained interviewers [39, 40], it is essential to acknowledge this limitation. Finally, the scarcity of comprehensive CVD data, particularly regarding mortality data, owing to the relatively small number of deaths is recognised. Large-scale investigations such as clinical studies can provide substantial evidence of the relationship under investigation.

Increased dietary niacin intake is associated with CVD incidence but does not show a substantial correlation with all-cause mortality in the overall population. However, it is noteworthy that an intake of 30.401 mg/d of niacin lowers the risk of all-cause death in females. In addition, a higher niacin intake of 21.302 mg/d or more appears to have a protective effect against CVD mortality, specifically in females, but with no such observed impact in males. Overall, increasing niacin supplementation may help reduce cardiovascular risk in high-risk female patients. However, further prospective studies are required to clarify whether increased niacin intake reduces the risk of CVD mortality in females.

All data generated or analyzed during this study are included in this published article.

Conceptualization, LS, YS and AZ; Analyzed the data, ML, SJ, JZ, KY, YZ, EY, XZ and LS; Statistical analysis and drafting of the manuscript, LS, YZ, JZ, KY and YC; Writing—review and editing, ML, SJ, EY, XZ, AZ and YS. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Not applicable.

The current study was supported by the Yunnan Fundamental Research Projects (grant no. 202301AY070001-028).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2511410.