Data regarding the association between hyperlipidemia and cancer risk are heterogeneous.24 Higher risks of colon, prostate, and testicular cancers have been reported in patients with hyperlipidemia in previous research.24 By contrast, studies have reported that patients with hyperlipidemia have lower risks of stomach, liver, and hematopoietic/lymphoid tissue cancers.24 This population-based cohort study demonstrated that patients with hyperlipidemia exhibited a 37–51% increased risk of bladder cancer compared with their non-hyperlipidemia counterparts. The prevalence of hyperlipidemia is high in adults (37% for men and 40% for women).25 The data from this study thus should have profound clinical impact.
The association of hyperlipidemia with the risks of some types of cancer differs between men and women.24 A large population-based study (Metabolic syndrome and Cancer project) showed that hyperlipidemia has an inverse relationship with the risks of liver cancer, pancreas cancer, nonmelanoma of the skin, and lymph/hematopoietic tissue cancer among men and with the risks of gallbladder cancer, breast cancer, melanoma of the skin, and lymph/hematopoietic tissue cancer among women.26 In the present study, subgroup analyses revealed that men with hyperlipidemia had a 36–54% increased risk of bladder cancer compared with men without hyperlipidemia. Notably, the risk of bladder cancer was not significantly different between women with hyperlipidemia and women without hyperlipidemia. These data further highlight that hyperlipidemia increases the subsequent risk of bladder cancer in men but not in women. Therefore, gender has different impacts on the risk of cancer, including bladder cancer, in hyperlipidemia patients. The possible mechanisms may relate to the distinct body fat distribution and energy utilization patterns between men and women, and the storage of fat in visceral adipose tissue and visceral obesity in men have been linked to carcinogenesis.12,27 Although bladder cancer is not defined as an endocrine-related cancer, the association of the androgen/androgen receptor with bladder cancer development has been reported.28 The androgen receptor has been found in bladder tissue, and the downregulation of androgen receptor expression suppresses bladder cancer growth in vitro and in vivo.28,29 Thus, the association between the androgen/androgen receptor and bladder cancer has been evaluated. Shiota et al demonstrated that androgen deprivation therapy decreases the risk of bladder cancer in patients with prostate cancer.30 In a prospective cohort study, finasteride, a 5-alpha reductase inhibitor that reduces the dihydrotestosterone level, was associated with a reduced incidence of bladder cancer.31 According to the findings of previous studies and our study, sex hormones may play a role in the different risks of bladder cancer in hyperlipidemia patients. Additional studies are required to ascertain the underlying mechanisms.
Subgroup analyses further revealed that young adult men aged 20–39 years in the hyperlipidemia cohort exhibited an up to 5.45-fold increased risk of bladder cancer compared with those in the non-hyperlipidemia cohort. However, the risk of bladder cancer was not significantly different between men aged older than 40 years in the hyperlipidemia cohort and those in the non-hyperlipidemia cohort. These data further highlight that hyperlipidemia increases the subsequent risk of bladder cancer, especially in young adult men. A hyperlipidemia diagnosis in young adults increases the subsequent risk of coronary heart disease due to the increased duration of exposure to hyperlipidemia.11 Cancer often takes years to be diagnosed after initial exposure to a carcinogen.32 Obesity and a high-fat, low-vegetable diet may represent risk factors for carcinogenesis.33 Adolescent obesity has been linked to an increased subsequent risk of cancer.34 Metabolic dysregulation in early life plays an integral role in carcinogenesis.34 The results of our study reveal that hyperlipidemia development in young adulthood (aged 20–39 years) increased the subsequent risk of bladder cancer. According to our finding, early-onset hyperlipidemia is a risk factor for bladder cancer in men.
According to previous studies, many factors influence the risk of bladder cancer. For example, DM is associated with an increased incidence and mortality of bladder cancer in both men and women.15 In patients on dialysis for end-stage renal disease, the risk of bladder cancer is increased and is higher in women.19 Obesity increases the risk of bladder cancer linearly according to the body mass index.17,35 COPD is associated with poor survival in elderly patients with bladder cancer.18 Female patients with hypertension are at an increased risk of bladder cancer,36 and untreated hypertension is associated with a decreased risk of bladder cancer.16 Aspirin is associated with a decreased recurrent risk of bladder cancer.20 NSAIDs, especially ibuprofen, and metformin are associated with reduced bladder cancer risk.21,22 Rosiglitazone and pioglitazone are associated with an increased risk of bladder cancer in patients with diabetes.23 In this study, the aforementioned confounders significantly differed between the two cohorts, except for pioglitazone. The impact of these confounders was controlled for through propensity score adjustment. After controlling for these potential confounders, the risk of bladder cancer was higher in the hyperlipidemia cohort than in the non-hyperlipidemia cohort and in men than in women in the hyperlipidemia cohort.
Our population-based study showed the association of hyperlipidemia with the risk of bladder cancer. Whether controlling the serum lipid level can prevent the risk of bladder cancer is unclear; further evaluation is thus required. Furthermore, this study has some limitations. First, smoking is a major risk factor for bladder cancer;5 this information is lacking in the NHIRD. Because smoking is the most important causative factor for COPD,37 we used COPD as a confounder to decrease the bias of this study. Second, the dietary factor is important for the risk of bladder cancer;38 information on lifestyle, physical activity, and dietary habits are lacking in the NHIRD. Third, data on the serum lipid level (such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) are unavailable in the NHIRD. Fourth, direct evidence is lacking for the cause–effect relationship between hyperlipidemia and the risk of bladder cancer. Prospective randomized clinical trials should be conducted to obtain more precise information.