Cardiovascular Disease (CVD) is one of the leading causes of death and disability among adults worldwide, with hyperlipidemia playing a significant role in its development [1]. Statin therapy offers clear benefits, including reducing lipid levels, slowing the progression of atherosclerosis, decreasing cardiovascular events, and is generally regarded as safe and well-tolerated [2]. However, it is essential to recognize that numerous studies and meta-analyses have confirmed the potential risk of statin use in increasing the incidence of new-onset diabetes (NOD) [3, 4, 5, 6, 7]. While the adverse effects of statin-mediated NOD are outweighed by the benefits of statin medications, NOD may negatively impact medication adherence among statin users. The mechanism underlying this population may be related to coenzyme Q10 (CoQ10) [8].

Coenzyme Q10, also known as ubiquinone, is a lipophilic compound that functions similarly to a vitamin and is synthesized endogenously from tyrosine in the human body [9]. CoQ10 acts as a lipophilic antioxidant by neutralizing free radicals, inhibiting lipid peroxidation of biomembranes, and protecting mitochondrial proteins and DNA from oxidative damage [10, 11]. Additionally, CoQ10 binds to the inner mitochondrial membrane, participating in the electron transport chain and oxidative phosphorylation, playing a crucial role in cellular energy synthesis by generating adenosine triphosphate (ATP) [12].

However, factors such as genetics, aging, and statin therapy can decrease its physiological concentration [9, 13]. Notably, low-density lipoprotein (LDL) serves as the primary carrier of CoQ10 in circulation, and is reduced by statin therapy, which may lead to decreased circulating levels of CoQ10 [13]. Furthermore, statins inhibit the synthesis of CoQ10. Insufficient CoQ10 can induce mitochondrial oxidative stress, leading to beta-cell apoptosis, reduced insulin sensitivity, and ultimately manifesting as NOD or poor blood glucose control [9, 14, 15]. Therefore, we hypothesize that appropriate CoQ10 supplementation may help reduce the risk of NOD in individuals taking statin medications.

Previous studies have confirmed that CoQ10 is associated with a reduction of NOD in mice [16, 17], but relevant studies in human population are limited [18, 19]. This study aimed to investigate whether CoQ10 supplementation has a protective effect against new-onset diabetes in a statin-taking population and to explore the dose-response relationship. This will directly address the current research gap and provide insights for future studies targeting NOD.

This study retrospectively included a total of 4394 patients from the NHANES database spanning the years 1999 to 2018, with a median follow-up duration of 86.00 (46.00, 135.00) months. The key finding is that among patients taking statin medications, the simultaneous co-administration of CoQ10 is associated with a reduction in NOD. This correlation remained significant even after adjusting for various confounding factors (p 0.05). Further analyses confirmed that the observed correlation and protective effect is independent of the dosage of CoQ10 supplementation.

While statin therapies are widely utilized in clinical practice, multiple studies have confirmed their association with NOD risk [3, 4, 5, 21, 22, 23], which may be related to CoQ10 deficiency. Research has demonstrated that statin drugs can decrease CoQ10 levels in the blood by 16% to 54% [24]. Two possible mechanisms contribute to the statin-induced reduction in CoQ10. Firstly, statin treatment inhibits the production of mevalonate, an intermediate in CoQ10 synthesis. Secondly, statin drugs lower LDL-C levels, potentially impacting CoQ10 transport. External supplementation of CoQ10 has been shown to elevate the levels of CoQ10 in the blood of patients undergoing statin therapy [24, 25]. Additionally, CoQ10 deficiencies can lead to impaired mitochondrial function and reduced antioxidant capacity, further decreasing insulin secretion and sensitivity, which may contribute to NOD development [25, 26]. Exogenous supplementation with CoQ10 may ameliorate this process [16]. In addition, studies have confirmed that supplementation with CoQ10 improves mitochondrial metabolism, which plays a crucial role in the pathogenesis of diabetes mellitus [19, 27].

Therefore, we hypothesized that exogenous supplementation with CoQ10 might help reduce the occurrence of NOD in those taking statins [28]. In previous animal experiments, Lorza-Gil et al. [16] found that pravastatin-treated hypercholesterolemic LDL receptor knockout mice exhibited decreased insulin secretion, increased islet cell death, and increased oxidative stress. Initiating dietary supplementation of CoQ10 in these mice reversed fasting hyperglycemia, improved glucose tolerance (by 20%), enhanced insulin sensitivity (by $>$2-fold), and fully restored the damage caused by pravastatin-impaired pancreatic glucose-stimulated insulin secretion by 40% [16]. Subsequent in vitro experiments also confirmed that co-treatment of insulin-secreting INS1E cells with CoQ10 protected the cells from pravastatin-induced cell death and oxidative stress. Simvastatin and atorvastatin were even more effective (10- to 15-fold) in inducing dose-dependent INS1E cell death, which was also mitigated by CoQ10 co-treatment [16]. This study demonstrated that statins impair $\beta$-cell redox homeostasis, function, and viability while CoQ10 supplementation protects against the deleterious effects of statins on pancreatic endocrine secretion [16]. However, limited clinical studies have been conducted on the effect of exogenous CoQ10 supplementation on statin-induced NOD. The 2019 LIFESTAT study, which included people using simvastatin for primary prevention, found that the insulin secretory capacity was unaltered by supplementation with CoQ10 (400 mg/day). Although insulin sensitivity remained unchanged, hepatic insulin sensitivity was elevated [29]. Besides, several studies have confirmed that CoQ10 supplementation can reduce glucose and HbA1c levels [25, 26, 30, 31, 32].

Given the limited number of studies investigating CoQ10 supplementation in the context of NOD among statin-using populations, we must refer to related studies for insights into CoQ10 dosage. In statin-related studies, Fedacko et al. [33] found significant improvement in statin-related myopathy with a CoQ10 dosage of 200 mg/day over three months. Similarly, another study demonstrated that CoQ10 supplementation (240 mg/d for 22 months) markedly reduced the incidence of statin-related fatigue (from 84% to 16%) and myalgia (from 58% to 6%) [34]. Additionally, several studies have shown that CoQ10 supplementation at a dose of 150 mg/day or 200 mg/day for three months significantly improves fasting blood glucose and HbA1c levels [30, 31, 32]. This study found no statistically significant correlation between CoQ10 dosage and the incidence of NOD. We attribute this finding to several factors: (1) The retrospective design of this study posed several limitations, particularly with the small number of participants taking CoQ10 and the broad range of CoQ10 dosages, which may have obscured statistical differences. (2) The study relied on the average CoQ10 dose taken in the past month, which may not accurately reflect the total CoQ10 exposure over the entire period of statin therapy. We recommend future well-designed randomized controlled trials to explore the dose-response relationship between CoQ10 and NOD in statin users. Identifying the optimal dosage would provide a practical and effective means to prevent NOD in this population. A key strength of this study is that this is the first to leverage the NHANES database to investigate the association between exogenous CoQ10 supplementation and NOD in a statin-using population. The NHANES database’s robust sampling methodology, combined with the appropriate use of statistical weighting, allows the findings of this study to extend beyond the sampled cohort, and to be generalized to the entire U.S. population using statins. This broad generalizability enhances the sensitivity and reliability of the study’s conclusions, making its findings particularly valuable for public health applications.

Despite the aforementioned strengths, this study does have notable limitation. As a retrospective study, it is inherently constrained by the reliance on observational data, making it difficult to establish causality between CoQ10 supplementation and NOD—we can only infer a correlation. Furthermore, the small sample size of participants taking CoQ10, compared to those who were not, may have increased the margin of error in the statistical analysis of CoQ10’s effects. Additionally, several continuous variables in the analysis do not follow a normal distribution. This deviation necessitated the use of non-parametric tests, reducing the statistical power of some comparisons. Another limitation is the lack of data on the total duration of CoQ10 administration and serum CoQ10 concentrations, which could have provided more precise insights into CoQ10’s role. These limitations are common in retrospective analyses, and we hope that well-designed randomized controlled trials in the future will further explore the qualitative and quantitative relationships between CoQ10 supplementation and NOD risk in statin users.

The opportunity presented by this study is its suggestion of a potentially effective approach for preventing NOD in individuals who require statin therapy, but are concerned about the risk of developing NOD. This could enable more patients to benefit from the cardiovascular protective effects of statins without fear of adverse metabolic effects. Additionally, this research sets a foundation for future randomized controlled trials to further investigate the dose-response relationship between CoQ10 supplementation and NOD, providing a clear direction for subsequent studies.

In individuals taking statins, CoQ10 supplementation is associated with a reduced risk of developing NOD. This relationship remains statistically significant even after adjusting for confounding factors (p 0.05). Interestingly, the effect of CoQ10 on reducing NOD risk does not appear to be influenced by the dosage of CoQ10.

Data described in the manuscript comes from the official NHANES website at https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx. If needed, the corresponding author can provide the relevant R code upon request. This study is an observational retrospective study, and according to the Clinical Trial Registration Statement from the International Committee of Medical Journal Editors (ICMJE), registration is not required for purely observational studies.

XRH designed the study, analyzed the data, and drafted the manuscript. JXL and YZG contributed to the data analysis. YFL and WZ assisted in the interpretation of the data. NQL and AMD contributed to the conception and design of the study, critically reviewed the manuscript for important intellectual content, and approved the final version for publication. All authors contributed to the editorial revisions of the manuscript. All authors have read and approved the final manuscript. All authors have made substantial contributions to the work and agree to be accountable for all aspects of the research.

We use NHANES database, which is a well-established public database, participants signed informed consent forms, and the project was approved for ethical review. The data used in this article involves multiple ethics approval numbers, as detailed in the supplementary materials.

This work was supported by grants from the National Key R&D Program of China [grant number 2022YFC3602400 and 2022YFC3602405] and the Key Projects of the National Health Commission [grant number 2020-ZD13].

The authors declare no conflict of interest.