Increased kidney cancer risk in diabetes mellitus patients: a population-based cohort study in Lithuania

Abstract

Background

Diabetes is associated with increased risk of various cancers but its association with kidney cancer is unclear. The objective of this study was to evaluate the association between T2DM with or without metformin use and the risk of kidney cancer in a population-based national cohort in Lithuania.

Methods

The cohort was composed of diabetic patients identified in the NHIF database during 2000–2012. Cancer cases were identified by record linkage with the national Cancer Registry. Standardized incidence ratios (SIRs) for kidney cancer as a ratio of observed number of cancer cases in diabetic patients to the expected number of cancer cases in the underlying general population were calculated.

Results

T2DM patients (11,592) between 2000 and 2012 were identified. Overall, 598 cases of primary kidney cancer were identified versus 393.95 expected yielding an overall SIR of 1.52 (95% CI: 1.40–1.64). Significantly higher risk was found in males and females. Significantly higher risk of kidney cancer was also found in both metformin users and never-users’ groups (SIRs 1.45, 95% CI: 1.33–1.60 and 1.78 95% CI: 1.50–2.12, respectively).

Conclusions

The patients with T2DM have higher risk for kidney cancer compared with the general Lithuanian population.

Keywords:

• Urological cancers
• kidney cancer
• metformin treatment
• diabetes
• population-based study

Background

With more than 400,000 new cases in 2018 worldwide, kidney cancer is 14th most common cancer in the world [1]. The latest available Lithuanian population-based analysis of kidney cancer incidence and mortality trends showed that the incidence rates were rising during the period of 1993–2012 with the highest increase in stage I tumors in both, men and women [2]. The widespread usage of ultrasound, computed tomography and magnetic resonance imaging may attribute to the increase of incidence and incidental detection of kidney tumors [3]. In recent years, the incidence of kidney cancer in Lithuania ranks sixth among all cancers (5.56% of new cases in 2018) with the mortality rate of 4.41% [1].

It is already known that obesity and hypertension predispose kidney cancer [4]. Tobacco smoking was classified as Group 1 carcinogen for the cancers of urinary bladder and kidney by the World Health Organization International Agency for Research on Cancer [5]. Occupational exposure and dietary habits are possible risk factors [6]. Another risk factor for kidney cancer might be the presence of another urological carcinomas such as prostate or bladder cancer [7]. Different studies showed the increased risk of kidney cancer in patients with diabetes, however, the association of kidney cancer and diabetes remains not fully understood [8,9]. The role of diabetes mellitus as independent risk factor remains unestablished in the development of kidney cancer, as both diseases share an important risk factor—obesity. Hypogonadal men with low testosterone levels are prone to be overweight or obese due to inflammation of adipose tissue [10] which results in increased risk for T2DM [11,12]. Overweight and obesity have consistently been associated with higher risk of not only diabetes but kidney cancer, as well. The overall pooled results from 18 studies showed that relative risk in obese persons was seven-fold, and for overweight three-fold higher compared to normal weight [13]. Meta-analysis of 24 cohort studies showed, that compared to the normal weight, relative risk of kidney cancer was 1.35 in overweight and 1.76 in obese participants [14].

The main first-line oral medication in treatment of T2DM across all age groups is biguanide group agent metformin. Metformin is widely used for the treatment of diabetes and is associated with decreased diabetes-related morbidity and mortality and with a dose-dependent reduction in cancer risk of various sites, which is shown in randomized controlled trials and population-based studies [15–18]. How metformin use affects the risk of kidney cancer remains unclear. In vivo and in vitro experiments suggested that metformin may have antitumor effects on malignant cells and therefore it could be a potential therapeutic agent for the treatment of renal cancer [19]. An observational study from Taiwan showed significantly lower risk of kidney cancer among metformin users and metformin reduced the risk of kidney cancer in a dose–response pattern [20]. Large scale data from two international studies on the comparative efficacy of diabetes medication and disease outcomes showed no significant effect of metformin on the risk of kidney cancer [21]. Therefore, the association between metformin use in diabetes mellitus patients and kidney cancer risk requires further investigation.

The objective of this study was to evaluate the association between T2DM with or without metformin use and the risk of kidney cancer in a national cohort.

Methods

Dataset

We used the National Health Insurance Fund (NHIF) database to identify T2DM patients. This database contains demographic data and entries on the primary and secondary healthcare services provided, emergency and hospital admissions, and prescriptions of reimbursed medications.

Cancer cases were identified by record linkage with the Lithuanian Cancer Registry which is a nationwide population-based cancer registry that contains personal and demographic information, as well as information on diagnosis of all people diagnosed with cancer in Lithuania since 1978.

Study design and population

A retrospective cohort design was used to examine the relationship between T2DM and kidney cancer risk. The cohort was composed of patients identified in the NHIF database who were diagnosed with diabetes mellitus between 2000 and 2012. Because the diagnoses of admission are registered by healthcare providers into the database, to increase the sensitivity of case definition for diabetes, only patients who had received prescriptions for reimbursed antidiabetic drugs were included. Only patients with the diagnosis of diabetes aged 40 or more years were included. Patients (115,923) diagnosed with T2DM between 2000 and 2012 were identified for this study. Patients with kidney cancer in the entire Lithuanian population diagnosed during study period were identified through the Lithuanian Cancer registry. Lithuanian Cancer Registry, which is a nationwide population-based cancer registry that contains personal and demographic data and information on type of all diagnosed cancer cases in Lithuania since 1978.

Statistical methods

The person-time of observation was computed from the date of the first recorded T2DM diagnosis in the NHIF database until diagnosis of kidney cancer, emigration or end of the observation period (31 December 2016), whichever came first.

We calculated standardized incidence ratios (SIRs) for kidney cancers as a ratio of observed number of cancer cases in people with diabetes diagnosis to the expected number of cancer cases in the underlying general population. Expected numbers were calculated as multiplication of the exact person-years under observation in the cohort by calendar year- and 5-year-age-groups-specific national incidence rates. 95% Confidence intervals for the SIRs were estimated assuming number of observed cases follows Poisson distribution.

We computed SIRs by age of diabetes diagnosis, duration of follow-up until occurrence of kidney cancer and use of metformin. Patients with a first diabetes diagnosis in 2000 also included prevalent cases, therefore they were excluded from analysis by duration of follow-up. Patients who had never been prescribed metformin after entry were defined as never-users; ever-users were defined as those who had been prescribed metformin more than six times and first prescription more than one year before kidney cancer diagnosis.

All statistical analyses were carried out using STATA 11 statistical software (StataCorp. 2009. Stata Statistical Software: Release 11.0. College Station, TX, USA).

Results

In a study cohort of 115,923 patients diagnosed with diabetes mellitus, 598 cases of primary kidney cancer were identified versus 393.95 expected within a period of observation entailing yielding an overall SIR of 1.52 (95% CI: 1.40–1.64) (Table 1).

Table 1. Numbers of observed (Obs) cases of kidney cancers, standardized incidence ratios (SIR) with 95 percent confidence intervals (CI) in diabetes patients.

	Male					Female					Overall
	Obs	Exp	SIR	CI95L	CI95U	Obs	Exp	SIR	CI95L	CI95U	Obs	Exp	SIR	CI95L	CI95U
Overall	302	196.55	1.54	1.37	1.72	296	197.40	1.50	1.34	1.68	598	393.95	1.52	1.40	1.64
Age at diagnosis
<50	46	19.62	2.34	1.76	3.13	20	9.12	2.19	1.41	3.40	66	28.74	2.30	1.80	2.92
50–59	113	60.08	1.88	1.56	2.26	77	44.65	1.72	1.38	2.16	190	104.73	1.81	1.57	2.09
60–69	89	75.00	1.19	0.96	1.46	111	83.37	1.33	1.11	1.60	200	158.37	1.26	1.10	1.45
>70	54	41.85	1.29	0.99	1.68	88	60.26	1.46	1.19	1.80	142	102.11	1.39	1.18	1.64
Metformin
Users	241	157.03	1.53	1.35	1.74	229	165.09	1.39	1.22	1.58	470	322.11	1.46	1.33	1.60
Never-users	61	39.53	1.54	1.20	1.98	67	32.31	2.07	1.63	2.63	128	71.84	1.78	1.50	2.12

Significantly higher risk was found in both male and female diabetic patients in all age groups. The highest risk of kidney cancer was found in patients younger than 50 years SIR 2.30 (95% CI: 1.80–2.92) while the lowest risk was observed in patients aged 60–69 with SIR 1.26 (95% CI: 1.10–1.45).

The analysis revealed, that all diabetic patients had higher risk of kidney cancer in both, metformin users and never-users of metformin groups (SIRs 1.46, 95% CI: 1.33–1.60 and 1.78 95% CI: 1.50–2.12, respectively) compared with the general Lithuanian population.

Discussion

The results of our study demonstrated that the patients in all age groups with T2DM have higher risk for developing kidney cancer. The presence of higher kidney cancer risk in individuals with diabetes in our cohort is in line with results of other studies. The meta-analysis of nine cohort studies [8] indicated that diabetes is associated with a 42% increased risk of kidney cancer. Another meta-analysis of 24 studies showed that diabetes was significantly associated with the increase of kidney cancer risk by about 40% [9]. In our study the overall kidney cancer risk in type 2 diabetes patients was increased by 52%. Both mentioned meta-analyses observed a stronger relation in women, whereas our study did not show higher risk based on the gender of the patients with SIR in males being 1.54 and SIR being 1.50 in females.

The etiology of kidney cancer is still largely unknown, besides obesity, hypertension, and cigarette smoking. Hyperinsulinemia, insulin resistance and increase IGF-1 associated with the risk of developing kidney cancer [22–24]. Cell proliferation is stimulated by hyperinsulinemia and the secretion of IGF-1 through insulin and IGF-1 receptors and apoptosis is inhibited simultaneously [25,26]. Other mechanisms that could affect the development and aggressiveness of kidney cancer are hyperglycemia, inflammatory cytokines such as tumor necrosis factor-α, interleukin-1 and interleukin-6, and reactive oxygen products [27,28]. In diabetes mellitus patients, metformin is usually chosen as the first-line treatment [29]. Also, metformin enhances insulin sensitivity and reduces insulin resistance [30]. The exact mechanisms whereby diabetes may cause kidney cancer remain unclear.

Positive association between diabetes and the risk of kidney cancer was observed and described in other studies [8,9]. However, whether metformin use can affect the risk of kidney cancer remains to be debatable. To the date only four studies reported the impact of metformin treatment on kidney cancer risk. In the observational study from Northern California metformin was not associated with an increase in the risk of kidney cancer [31], while in another observational study from Taiwan metformin use was associated with significantly lower risk of kidney cancer among metformin [20]. Other two clinical trials showed a non-significantly lower risk of kidney cancer associated with metformin use [21]. The results of our study showed that metformin users had significantly increased risk of developing kidney cancer although increase in risk was slightly lower compared to never-users.

The effects of metformin on renal cancer cell growth were investigated in vitro and in vivo xenograft. The results showed that metformin inhibits cell proliferation of renal cancer cells, inhibits cancerous cell colony formation, down-regulates expression of cyclin D1 and induces a G0/G1 cell cycle arrest in cancerous cells, activates adenosine monophosphate activated protein kinase and inhibits mTOR mammalian target of rapamycin signaling in tumor cells and inhibits the growth of 786-O cell xenografts in nude mice and it suggests that metformin may have antitumor effects on malignant cells and therefore it could be a potential therapeutic agent for the treatment of renal cancer [19].

Men with hypogonadism are at increased risk for developing T2DM [11,12]. Additionally, not only testosterone but also progesterone serum levels should be examined as it influences testosterone biosynthesis [32]. Testosterone replacement therapy (TRT) is beneficial for stoping prediabetes progression to diabetes [33]. For those who already have T2DM, TRT helps to reach the goal of losing weight which is usually not achieved in hypogonadal men even with the balanced diet and exercise [34,35]. Also, TRT helps to normalize glucose levels in blood [33–35], positively afffects libido, erectile function and cardiovascular conditions [11,12,36]. Furthermore, a study by Yassin et al. [37] showed that TRT might have a positive effect against high-grade prostate cancer in hypogonadal males, even though a number of different guidelines recommend against TRT for patients who have increased risk for prostate cancer. Secondary hypoganadism due to androgen deprivation therapy and diabetes in patients with prostate cancer increased the risk of bone fractures [38]. Altogether, testosterone and progesterone serum levels should be examined in males with T2DM and TRT should be considered as a treatment option.

Multidisciplinary approach is required in order to decrease the incidence of various cancers that could be avoided. This includes general physicians, urologists and endocrinologists working together as a team. Identifying late-onset hypogonadism, which could result in T2DM if untreated, and treating those patients early could help not only in preventing diabetes but also the risk of developing cancers associated with T2DM in the future could be decreased.

The main strength of our population-based cohort study is that we analyzed the national data via the record linkage of National Health Insurance fund and Lithuanian Cancer Registry which allows to cover whole Lithuanian population. Also, since the NHIF database holds the records of all prescriptions, the analysis of risk by antidiabetic drugs use was made possible.

However, there are several limitations of our study, as well. First of all, other possible potential cofounders such as body mass index (BMI), smoking and comorbidities were not assessed. Secondly, the group of metformin never-users includes those patients who have never used any antidiabetic drugs and those who use different antidiabetic drug combinations without metformin which makes it difficult to interpret the results of metformin never-users group.

In conclusion, this population-based cohort study showed that patients with T2DM have higher risk of kidney cancer compared with the general Lithuanian population. In metformin users the risk of kidney cancer remained significantly higher than in general Lithuanian population.

Acknowledgements

AP and GS contributed to the study conception and design. AP and GS contribute to the acquisition of data. AP and GU analyzed and interpreted data. GU drafted the manuscript. DLU, AD, LZ, RS and GS critically revised the manuscript. AP and GU provided statistical analysis. GS supervised the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data from NHIF database and cancer registry was accessed via the Laboratory of Cancer Epidemiology of National Cancer Institute.

Additional information

Notes on contributors

Greta Undzyte

G. Undzyte is a medical student at Lithuanian University of Health Sciences in Kaunas, Lithuania. Fields of interest—male reproductive health, urological cancers. A. Patasius, MD in urology and junior researcher at the Laboratory of Cancer Epidemiology, works on cancer screening projects and cancer epidemiology research. D. Linkeviciute-Ulinskiene is a doctoral student at Vilnius University, Faculty of Medicine, and MD in endocrinology. Her interests are interdisciplinary research, diabetes and cancer epidemiology. L. Zabuliene, MD, PhD, is a consultant in endocrinology and associate professor at Vilnius University, Faculty of Medicine. She is a co-author of over 40 interdisciplinary research articles in the field of diabetes mellitus, obesity, and cancer. R. Stukas, PhD, is a head of the department of Public Health at Vilnius University. He is a co-author of more than 100 research articles with the main focus being lifestyle and dietary effects on health. A. Dulskas, MD, PhD, is a surgical oncologist at National Cancer Institute. His research focuses on colorectal cancer, metformin effects on cancer, cancer epidemiology. G. Smailyte, PhD, is the Head of the Laboratory of Cancer Epidemiology of the National Cancer Institute in Vilnius, Lithuania. She is a co-author of over 100 research articles in the field of cancer epidemiology, cancer risk factors and cancer prevention.