We show that the presence of the full MetS according to the NCEP definition at age 50 is a risk factor for clinically relevant or advanced stages of prostate cancer over 34 years of follow-up. Results for the MetS according to the IDF definition were of similar magnitude, however not statistically significant. Few of the men in the study presented with clinically non-advanced or non-aggressive prostate cancer. The components of the MetS predominately responsible for the finding appear to be abdominal obesity, and a high serum triglyceride level. The findings become more evident when accounting for the competing risk of early death due to the MetS. High fasting blood glucose, high blood pressure and a low HDL cholesterol level are only marginally associated with the conditional probability of prostate cancer whereas smoking is not.
The ULSAM cohort used in this study is population based, homogeneous as regards ethnic background and standardized for age of the participants at baseline. The participants have been thoroughly characterized regarding the components of the MetS, smoking status and occurrence of prostate cancer. The participation rate is high and the data on individual follow-up of up to 34 years is almost complete through linkage to personal hospital records and nationwide registers with high coverage. In addition, less than 2% of the prostate cancer cases are screening detected and our results thus mainly pertain to clinically relevant prostate cancer with a high risk of progressive disease.
While the ULSAM cohort is relatively small and modest or weak associations may go undetected, its annotation is unprecedented in details and precision. It is indeed similar in size to other studies published on the relationship between a fully characterized MetS and prostate cancer and the follow-up is considerably longer. The measurements for diagnosing the full MetS used for the present study were made at only one point in time, on average 25 years before diagnosis, a design feature shared with most studies in the field. However, several of the components of the MetS reflect long-term life style habits which will not likely vary significantly over time, once established in middle aged men. Any misclassification of men who after the age of 50 have established the MetS would most probably lead to an underestimation of the risks observed rather than overestimate them.
There may be several reasons why previous cohort studies have come to divergent conclusions regarding the MetS and prostate cancer risk. This may be attributed to a number of factors, among these, the different definitions of the MetS used and the effects of competing factors are probably the most important. The four generally accepted definitions used to define the MetS have been put forth by the World Health Organization (WHO), NCEP, the European Group for the Study of Insulin Resistance (EGIR) and IDF. None of these can yet be considered the gold standard, since they emphasize different aspects of the MetS. This may in part explain differences in the results in the various studies. Furthermore, several investigators used modified versions of these definitions (2
) or only selected parts of these definitions (4
). We feel that a more important reason for equivocal results is the lack of consideration given to the effect of competing risks; many men with the MetS will not live to an age when prostate cancer risk is highest but will die early from other causes leaving an excess risk of risk of prostate cancer undetected.
The commonly used statistical analyses assume that censored individuals have the same risk of the event under study as those observed until the endpoint (35
). When an exposure is associated both with risk of early death and the disease under study, especially when the outcome is increasing in frequency with age, this criterion is not fulfilled (35
). We used a conditional probability method described by Pepe (32
) to try to circumvent such a possible violation of the assumptions underlying the standard techniques and revealed that the full metabolic syndrome and key elements of the MetS are linked to prostate cancer risk.
Further reasons for diverging results in previous studies may be differences in age at baseline measurement and length of follow-up, e.g. measurements vary from those done early in life (7
) to those in the elderly close to or at the time of diagnosis of prostate cancer (4
). Some of the published studies on prostate cancer detected outside PSA screening end their follow-up before the mean age of diagnosis for non-screening detected prostate cancer (2
), thereby studying only a younger part of the prostate cancer spectrum.
Our findings are in line with those of Laukkanen et al (3
) who in their younger cohort found that men with a modified WHO definition of the MetS had a 1.9 fold higher relative risk (CI 1.1-3.5) of developing clinically relevant prostate cancer later in life. They considered the effects on the estimates due to high morbidity and mortality in men with diabetes and excluded these men. Lund-Håheim et al (2
) studied modified components of the MetS according to NCEP in a large cohort and found a weak positive relation to prostate cancer with an increased relative risk of 1.56 (CI: 1.21-2.00). The weak associations may be due to this cohort being young. The median age at the end of follow-up was 73, which is below the mean age of diagnosis for clinically detected prostate cancer in our cohort. Tande et al (6
) observed in a cohort study on comparatively young and overweight American men, a lower relative risk of developing prostate cancer of 0.77 (CI: 0.60-0.98) in men with the MetS (NCEP). The study had a 50% participation rate. The cases were identified by a combination of questionnaire and registry findings and the prostate cancers were to an unknown extent screening detected.
Martin et al (7
) used a revised NCEP definition of the MetS and found little evidence of a relationship between the MetS or most of the components thereof and later clinically relevant prostate cancer, RR= 0.91 (CI: 0.77-1.09). Their study included 29 364 men with an average age of 50 years followed for a mean of 9.3 years, i.e. mainly men of ages with low prostate cancer risk. Competing risks were not considered. The only significant finding was a positive relationship between elevated blood pressure and prostate cancer. Prostate cancer in the young may in 30-40% of cases be associated with dominantly inherited genetic traits with high penetrance (36
) and less influenced by metabolic factors. In two previous studies on the relationship between type 2 diabetes mellitus and prostate cancer risk, even though they did not take competing risk of mortality into consideration an increased risk of prostate cancer was observed in men with lower BMI in one study (37
) but not in the other one (38
). These studies did not take competing risk of death into account when analysing the relationship to prostate cancer which is a cancer typically diagnosed at higher ages and further that type 2 diabetes is a condition with an expected shorter life span due to an increased risk of cardiovascular death mediated by elevated blood glucose.
Our results indicate that life style factors giving rise to the metabolic syndrome according to either the NCEP or the IDF definition, in particular abdominal obesity, increase the risk of clinically relevant prostate cancer once the competing risk of dying from other outcomes of the MetS has been taken into account. If this is substantiated in further studies, it will not only be an important public health message, but will also prompt research to further understand the underlying mechanisms and to find out whether a reversal of the MetS components, e.g. obesity, will attenuate the risk. The findings also call for a methodological development to better analyze competing risks for risk factors with complex effects, e.g. our findings indicate that smoking is indeed a risk factor for prostate cancer which is still unclear (39
) plausibly owing to its being a relatively weak risk factor in a disease that mainly occurs late in life while also leading to a high risk of premature death from other causes as CVD and lung cancer.