Association of frailty with the incidence risk of cardiovascular disease and type 2 diabetes mellitus in long-term cancer survivors: a prospective cohort study

About half of the UK population born after 1960 are expected to be diagnosed with cancer during their lifetime [1]. With the advance of treatment techniques and effective pharmaceutical agents, the 10-year survival rate of cancer patients has reached 50% over the past several decades in the UK [1, 2]. In comparison with the non-cancer population, cancer survivors are at a 13–70% and 17–158% higher risk of developing cardiovascular disease (CVD) [3] and type 2 diabetes mellitus (T2DM) [4], respectively. Moreover, dying of CVD is common among survivors of site-specific cancer (e.g., breast cancer [5] and prostate cancer [6]), and the corresponding probability is even higher than that of dying from cancer per se [7]. Given the adverse effects of CVD and T2DM on survival and quality of life among cancer survivors [8], finding prognostic factors is crucial to help identify the vulnerable subgroup and then implement appropriate disease management and therapeutic interventions in clinical practice [9, 10].

Previous studies on the prognostic factors of cancer survivors have mainly focused on biological biomarkers [11, 12] and lifestyle [13, 14]. Increasing attention has recently been drawn to the accelerated fundamental aging process, which is one of the most significant characteristics of cancer survivors [15, 16]. In other words, these patients experience an accelerated decline in the trajectories of physical, cognitive, and psychosocial morbidities [17], which are largely captured in the concept of frailty. Frailty is characterized by an increased vulnerability to stressor events caused by cumulative diminished reserve and dysregulation in multiple physiological systems [18] and has been widely used as a valid indicator of the aging process in geriatrics and gerontology [19, 20]. There are two principal frailty indicators: the frailty phenotype proposed by Fried et al. (FP_Frailty) [18] and the frailty index (FI) proposed by Mitnitski et al. (FI_Frailty) [21]. Frailty is usually accompanied by the dysregulation of metabolic and endocrine systems [20, 22], which may further contribute to CVD and T2DM in the general population [23, 24]. About 42% (range: 6–86%) of older cancer survivors exhibit frailty [25], and this proportion is nearly four times higher than that in the community-based older population [26]. Although frailty has been used to predict poor outcomes including mortality among cancer survivors [17, 27], it remains unclear whether it increases the risk of CVD and T2DM in this group. If this is the case, screening cancer survivors for frailty, particularly those at an early stage of frailty (which is potentially reversible) [18], may provide opportunities to delay or prevent the occurrence of late comorbidities, and thus improve their quality of life.

In this study, we included 13,388 long-term cancer survivors (diagnosed with cancer five or more years earlier) free of CVD and 6101 long-term cancer survivors free of T2DM at the time of recruitment, based on data from the UK Biobank (UKB). Given that FP_Frailty and FI_Frailty are complementary [28], the present study aimed to evaluate whether both frailty indicators were significantly associated with incident CVD and T2DM in the large samples of long-term cancer survivors (Fig. 1).

In this prospective study of long-term cancer survivors, we demonstrated that frailty was significantly associated with an increased risk of developing CVD and T2DM, although discrepancies existed between frailty indicators. With the number of long-term cancer survivors on the rise, our findings suggest that frailty assessment may help to identify the most vulnerable subgroup at a high risk of subsequent CVD and T2DM, and then deliver appropriate disease management, such as prevention and interventive strategies for frailty.

Emerging evidence suggests that cancer survivors experience accelerated aging, and thus the cumulative effect of aging and cancer-related issues may result in a poor prognosis, including adverse health outcomes and low quality of life [15, 41]. In this study, the estimated prevalence of frailty by two frailty indicators was 5.0–15.7%, which is relatively higher than that in the general population from the UKB (FP_Frailty: 3%) [33], but is comparable to that among other cancer survivors (range: 6%-86%) [25]. The high prevalence of frailty among cancer survivors cannot be merely attributed to their older age relative to the general population (mean age=60.4 years vs. 56.9 years). It may rather reveal a faster functional aging process in cancer survivors [42]. This may be partially explained by cancer-related treatments (e.g., the impact of cytotoxic and genotoxic treatments on normal cells) [43, 44] or the shared physiological mechanisms between cancer and aging (e.g., DNA integrity and stability, epigenetic modifications) [45, 46]. As referred to above, accelerated functional aging in cancer survivors, indicated by two frailty indicators (FP_Frailty and FI_Frailty) in this study, was found to be associated with a higher risk of CVD and T2DM. The biological mechanisms underpinning these associations are complicated and remain unexplored. Since frailty involves the dysregulation of multiple systems, it is likely that cancer or cancer-related treatments drive degeneration and decline in body and multiple functions (e.g., grip strength), and in turn predispose patients to adverse chronic diseases. From the aspect of health implications, our study supports the implementation of frailty assessment to identify long-term cancer survivors that are at higher risk of subsequent CVD and T2DM more than 7 years before their occurrence. This is different from frailty screening due to treatment-related toxicity, which most often occurs before cancer treatment in oncological practice. Conversely, building on the findings of this study, cancer patients may largely benefit from being routinely monitored after treatment for the improved identification, prevention, and intervention of frailty.

The positive association of FI_Frailty with incident T2DM was observed, and a series of sensitivity analyses confirmed the robustness of the findings. Nevertheless, we found a null association for FP_Frailty, which is interesting. Firstly, our findings support the differences in predicting outcomes between FP_Frailty and FI_Frailty as demonstrated in previous studies [47‐49]. For instance, compared with FP_Frailty, FI_Frailty based on the accumulation of deficits has a relatively stronger association with mortality [47]. Moreover, FI_Frailty was found to identify vulnerable individuals even in a robust subgroup that was categorized by FP_Frailty [50]. These discrepancies may be partially explained by the broader spectrum of health-deficit accumulation measured by FI_Frailty which represents a closer risk profile to the clinical condition [28]. In the clinical setting, the choice of frailty measurements should balance the implementation feasibility and prediction performance. Second, to ensure the precision of incident T2DM, we used primary care data covering about half of the UKB sample, rather than linked hospital data, to identify these incident cases [30]. The null association may be induced by the low statistical power due to the limited sample size determined at the practice level. Third, because FP_Frailty we constructed in this study was adapted from the original definition [18], thus, there may be misclassification. Future research is required to help understand the associations between different frailty indicators and the risk of incident T2DM in long-term cancer survivors.

According to the findings of this study, cancer patients at the pre-frail stage may be a potential subgroup to be targeted. First, over 40% of cancer survivors were identified as pre-frail in our study. Second, not only pre-frailty but also the very early stage of frailty (e.g., a FI score between 0.1 and 0.2) were positively associated with incident CVD and T2DM. Third, as an intermediate transition stage from robust to frailty, the pre-frail stage has the potential to be intervened [18]. For instance, physical exercise training and nutrition supplementation were found to prevent the progression from pre-frailty to frailty [51, 52]. Moreover, these strategies have shown beneficial effects on physical performance and health-related quality of life in pre-frail adults [52, 53]. Hence, taking advantage of the potential intervention opportunity to successfully delay or reverse frailty may have a significant impact on the long-term prognosis of cancer survivors at the early stage of frailty. Nevertheless, evidence on the cost-effectiveness of interventional programs targeting pre-frailty is scarce. On the other hand, our findings still need to be validated. Thus, more efforts are needed to balance resource allocation with health benefits.

The significant strengths of our study included the large sample size of cancer survivors with long follow-up. Furthermore, we applied two widely used frailty indicators; FP_Fraity emphasized frailty as a physical function, while FI_Frailty focused on the accumulation of health defects for the whole organism. In addition, a series of sensitivity analyses were performed to confirm the validity of the findings.

Some limitations in this study should also be noted. First, the information on the stage, grade, and treatment of cancers was unavailable, restricting the exploration of their potential influence on the results. Second, the dataset included limited numbers of cancers other than breast cancer or colorectal cancer; thereby, we were unable to evaluate the effect of cancer type on the findings. Third, we used primary care data to define incident T2DM; however, more than half of cancer survivors did not have primary care data, which may result in low statistical power. Our findings require confirmation when the primary care data was expanded to all the UKB participants in the future. Fourth, the FP_Frailty components we used were adapted from the original definitions. For instance, slow gait speed was assessed by self-reported usual walking pace, which was less reliable than objectively measured gait speed; weight loss was not specified as unintentional. Finally, the majority of UKB participants were White and lived at a higher socioeconomic level [54], and thus, our sample was less representative of all long-term cancer survivors in the UK. A recent study has shown that cancer prevalence in UK Biobank was almost similar to that in the Secure Anonymised Information Linkage (SAIL) databank (an unselected population from Wales) (6.22% vs 5.78%), as was the hazard ratio for all-cause mortality (1.99 vs 1.86) [55]. Also, the frailty prevalence of our sample was comparable to that in the literature [25]. These observations suggest a reduced magnitude of sample selection bias to some extent. However, we caution that our estimates of associations may be subject to collider bias to a lesser extent [56]. Future research on other populations is warranted to validate our results.

Among long-term cancer survivors, we established that frailty—even at the very early stage, was positively associated with the incidence risk of CVD and T2DM, although there were discrepancies between frailty indicators. While further research is required to validate our findings, they suggest that routine monitoring, prevention, and interventive programs of frailty among cancer survivors may help to prevent late comorbidities and, eventually, improve quality of life. Especially, interventions are recommended to target those at an early stage of frailty when healthcare resources are limited.