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. Author manuscript; available in PMC: 2019 Mar 15.
Published in final edited form as: Int J Cancer. 2017 Nov 16;142(6):1166–1173. doi: 10.1002/ijc.31142

Midlife metabolic factors and prostate cancer risk in later life

Barbra A Dickerman 1, Johanna E Torfadottir 2, Unnur A Valdimarsdottir 1,2,3, Kathryn M Wilson 1,7, Laufey Steingrimsdottir 4, Thor Aspelund 2,5, Julie L Batista 1, Katja Fall 1,6, Edward Giovannucci 1,7,8, Lara G Sigurdardottir 2,9,11, Laufey Tryggvadottir 11, Vilmundur Gudnason 5,9, Sarah C Markt 1,*, Lorelei A Mucci 1,7,*
PMCID: PMC5773388  NIHMSID: NIHMS923990  PMID: 29114858

Abstract

Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n=9,097, enrolled 1967–1987) were followed for incident (n=1,084 total; n=378 advanced; n=148 high-grade) and fatal (n=340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0–4) combining the risk factors: BMI ≥30 kg/m2; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mmHg or taking anti-hypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides was associated with prostate cancer risk. Higher metabolic syndrome score (3–4 vs. 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p-trend=0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.

Keywords: Prostate cancer, metabolic syndrome, BMI, hypertension, triglycerides, fasting blood glucose, diabetes

INTRODUCTION

Metabolic syndrome is a cluster of metabolic risk factors for cardiovascular disease and type 2 diabetes. It has been defined by several groups, including the World Health Organization (WHO) and National Cholesterol Education Program’s Adult Treatment Panel (ATP III),1,2 as a combination of factors related to obesity, high blood pressure, insulin resistance, and dyslipidemia. Increasing evidence suggests metabolic syndrome may play a role in the etiology of certain cancers, such as liver, colorectal, pancreatic, and prostate cancer.3,4 While the exact mechanism is unknown, proposed pathways include metabolic syndrome’s association with hyperinsulinemia, increased circulating IGF-1 levels, and induction of angiogenesis, oxidative stress, DNA damage, and adipokine production.5–7

Many studies of prostate cancer risk have focused on the individual components of metabolic syndrome. Obesity has been linked to lower risk of nonaggressive disease, but higher risk of advanced or fatal prostate cancer.8–10 Type 2 diabetes has been consistently associated with reduced prostate cancer risk, particularly among studies conducted during the prostate-specific antigen (PSA)-screening era.11 Studies of the association between hyperinsulinemia,12–16 blood pressure,17–20 blood lipids18,21–23 and prostate cancer risk and progression have been inconsistent.

Eight prospective studies have examined metabolic syndrome as a constellation of factors and total prostate cancer risk. Five reported positive associations,24–28 one found an inverse association,18 and two were null.29,30 The few studies examining risk of aggressive disease found a positive association between metabolic syndrome and fatal prostate cancer,28 but not advanced disease at diagnosis.29 These aggressive cases may have a different etiology than non-advanced or PSA screen-detected disease.31

We leveraged a unique prospective cohort of Icelandic men to investigate whether a metabolic syndrome score or its individual components were associated with risk of total, advanced, high-grade, or fatal prostate cancer.

MATERIALS AND METHODS

Study population

The Reykjavik Study began in 1967 when residents, born 1907–1935, in the Reykjavik metropolitan area were invited to participate in a prospective cohort study examining risk factors for cardiovascular disease.32–34 Men were recruited in five stages through 1987 (response rates 64–75%), and 9,116 men completed a baseline medical examination, blood collection, and health-related questionnaire. We excluded those diagnosed with prostate cancer before entry (n=19), leaving 9,097 men in this analysis. The study was approved by the Icelandic Ethical Review Board and the Icelandic Data Protection Authority.

Metabolic syndrome assessment

Height, weight, and blood pressure were measured at the baseline in-person examination by research nurses. Fasting blood glucose and serum triglycerides were measured in pre-diagnostic blood collected at the baseline examination as described elsewhere.33 Information on anti-hypertensive use was obtained from a medication inventory recorded by a registered nurse. We obtained information on self-reported history of type 2 diabetes, family history of prostate cancer, smoking, attendance of regular physician health checkups, and attained education from the baseline questionnaire.

To evaluate the individual components of metabolic syndrome, we defined each factor based on current guidelines. Body mass index (BMI) was calculated as weight in kg/height in meters2 and categorized as normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), or obese (≥30 kg/m2);35 75 participants with BMI 16.0 to <18.5 kg/m2 were included in the normal BMI category. Hypertension was categorized as a binary variable due to low case counts among normotensive men: yes if systolic blood pressure (SBP) ≥140 or diastolic blood pressure (DBP) ≥90 mmHg or taking anti-hypertensives, no if SBP<140 or DBP<90 mmHg. Triglyceride categories (<150, 150–199, ≥200 mg/dL) were formulated according to ATP III’s guidelines of normal, borderline high, and high levels.36 Fasting blood glucose/type 2 diabetes categories were formulated based on American Diabetes Association guidelines: normal (<100 mg/dL and no history of diabetes); pre-diabetes (100–125 mg/dL and no history of diabetes); type 2 diabetes (≥126 mg/dL or history of diabetes)37 We also created separate variables to distinguish actual measurements of fasting blood glucose from self-reports of type 2 diabetes.

We calculated a metabolic syndrome score based on the presence or absence of: BMI ≥30 kg/m2 (obese); SBP ≥130 mmHg, or DBP ≥85 mmHg, or taking anti-hypertensives; serum triglycerides ≥150 mg/dL; fasting blood glucose ≥100 mg/dL, or self-reported type 2 diabetes. This score represented a modified version of the ATP III and WHO criteria for metabolic syndrome1 based on the information available in the Reykjavik Study (HDL cholesterol was not measured). Men missing one of the individual criteria (n=898) were assigned to the referent groups, and men missing ≥ two criteria (n=36) were not included in the score calculation. In sensitivity analysis, results were qualitatively similar when men missing one of the individual criteria were excluded from the score calculation.

Outcome ascertainment

Record linkage with the Icelandic Cancer Registry,38 using unique identification numbers, was applied to identify prostate cancers diagnosed in the cohort through December 31, 2014. Cancer registration is mandatory and estimated completeness is very high (99.2%).38 Over 98% of the prostate cancer diagnoses were morphologically verified.38 Information on cause of death was obtained from the Directorate of Health.

Incident prostate cancer was categorized as total (n=1,084), advanced (n=378; clinical stage >T3b or N1 or M1 at diagnosis, or died of prostate cancer during follow-up), high-grade (n=148; Gleason score 8–10), and fatal (n=340). We were missing data on both stage and grade for 336 (31%) cases.

Statistical analysis

We evaluated the association between each of the metabolic risk factors separately and as a composite metabolic syndrome score, with risk of total, advanced, high-grade, and fatal prostate cancer. Follow-up time for each participant accrued from cohort entry to the earliest of the following events: prostate cancer diagnosis (for the incidence analyses) or prostate cancer death (for the mortality analyses), death from other causes, or end of follow-up (December 31, 2014). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). For each metabolic factor, we used plots of log(-log(S(t))) vs. log(t) to verify that the curves were parallel and the proportional hazards assumption was not violated (data not shown). Time since study entry was the underlying time scale. All models were adjusted for entry age (linear and quadratic terms) and stage of cohort entry (1967–68, 1970–71, 1974–76, 1979–81, 1985–87). Fully-adjusted models also included the following potential confounders, measured at baseline: family history of prostate cancer (yes, no), smoking status (never, former, current), regular checkups (yes, no), attained education (primary, secondary, college, university), fasting blood glucose/type 2 diabetes (normal, pre-diabetes, type 2 diabetes), height (quartiles), and BMI (<25.0, 25.0–29.9, ≥30 kg/m2). The metabolic syndrome score model was not adjusted for fasting blood glucose or BMI categories since these variables were part of the score. Categorical variables were modeled as indicators. Models for individual metabolic factors excluded those missing data on the main exposure (BMI: 27, blood pressure: 1, cholesterol: 25, triglycerides: 894, fasting blood glucose/type 2 diabetes: 53). In multivariable models, missing indicators were included for height (n=16) and for BMI and fasting blood glucose when included as covariates in models for other exposures. Those missing data on smoking status (n=1) and education (n=1) were assigned to the referent group.

We performed a sensitivity analysis for all of our analyses by excluding the first 5 years of follow-up to address potential reverse causation. We also conducted sub-group analyses to examine whether associations between each individual metabolic factor and total prostate cancer risk differed by median entry age (≥52 vs. <52 years) or BMI (≥25 vs. <25 kg/m2) and whether the association between the score and risk differed by entry age. Stratification by entry age allowed us to evaluate the timing of metabolic alterations in relation to prostate cancer, which may be important given the long natural history of this disease. To assess effect heterogeneity, we included product terms of the metabolic factors with age or BMI and assessed statistical significance using likelihood ratio tests.

Analyses were conducted using SAS software, version 9.4 (SAS Institute, Inc., Cary, NC). All statistical tests were two-sided, and p-values <0.05 were considered to be statistically significant.

RESULTS

Men with a higher metabolic syndrome score had a shorter follow-up time and were older, less likely to have completed college, and more likely to be a former smoker and have regular check-ups compared to men with a zero score for metabolic syndrome (Table 1).

Table 1.

Age-standardized characteristics of 9,061 men at entry into the Reykjavik Study (1967–1987) by metabolic syndrome score

Metabolic syndrome score1
0 (N=1,892) 1 (N=5,028) 2–4 (N=2,141)
Mean(SD)
Follow-up time2 (yrs) 26.7 (11.8) 25.8 (12.0) 23.7 (11.8)
Age at entry3 (yrs) 50.6 (7.9) 52.6 (8.7) 53.1 (8.6)
Height (cm) 176.9 (6.1) 176.3 (6.2) 176.5 (6.6)
BMI (kg/m2) 23.9 (2.7) 25.2 (2.6) 28.8 (3.8)
Systolic blood pressure (mmHg) 120.3 (6.2) 143.4 (17.0) 149.4 (18.4)
Diastolic blood pressure (mmHg) 77.5 (4.7) 89.9 (9.1) 93.8 (10.2)
Total cholesterol (mg/dL) 239.4 (40.5) 246.2 (40.9) 253.4 (42.2)
Triglycerides (mg/dL) 83.8 (26.9) 94.9 (36.2) 172.3 (88.0)
Fasting blood glucose (mg/dL) 78.5 (7.6) 81.0 (8.6) 90.4 (23.6)
%
Highest education
 Primary, % 31.5 34.9 33.7
 Secondary, % 45.2 43.6 45.2
 College, % 13.0 12.2 11.6
 University, % 10.3 9.3 9.4
Smoking status
 Never, % 19.2 22.8 19.9
 Former, % 19.5 23.8 25.3
 Current, % 61.2 53.4 54.8
Family history of prostate cancer, % 8.8 8.3 8.7
Regular check-ups, % 20.7 20.2 23.9
Type 2 diabetes4, % 0.0 0.6 9.5
Taking anti-hypertensives, % 0.0 6.6 13.2
Stage of cohort entry3
 1967–68 29.9 23.7 19.2
 1970–71 15.8 27.5 23.5
 1974–76 20.0 23.3 25.4
 1979–81 20.4 14.2 18.5
 1985–87 14.0 11.4 13.4
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Values are means(SD) or percentages and are standardized to the age distribution of the study population.

BMI: Body mass index; SD: standard deviation

1

Cumulative number of risk factors at cohort entry: 1) BMI ≥30 kg/m2; 2) systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or taking anti-hypertensives; 3) serum triglycerides ≥150 mg/dL; 4) fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes. Excludes 36 men missing ≥2 criteria.

2

Time from enrollment to prostate cancer diagnosis, death, or end of follow-up.

3

Value is not age adjusted

4

Self-reported history or fasting blood glucose ≥126 mg/dL.

In our analysis of individual metabolic risk factors, hypertension (treated or untreated) was associated with a statistically significantly higher risk of total, advanced, and fatal prostate cancer, and a non-significantly higher risk of high-grade prostate cancer compared to no hypertension (normotensive or untreated pre-hypertension) (Table 2). This association was strongest for risk of fatal prostate cancer (HR 1.34; 95% CI: 1.07, 1.68) (Table 2).

Table 2.

Hazard ratios (HR) for the association between metabolic risk factors at cohort entry and prostate cancer risk in the Reykjavik Study, 1967–2014

Risk of total prostate cancer Risk of advanced prostate cancer Risk of high-grade prostate cancer Risk of fatal prostate cancer
Cases Age-adjusted
HR (95% CI)1 		Fully-adjusted
HR (95% CI)2 		Cases Age-adjusted
HR (95% CI)1 		Fully-adjusted
HR (95% CI)2 		Cases Age-adjusted HR
(95% CI)1 		Fully-adjusted
HR (95% CI)2 		Cases Age-adjusted
HR (95% CI)1 		Fully-adjusted
HR (95% CI)2
BMI (kg/m2)
 <25.0 464 1.00 (ref) 1.00 (ref) 170 1.00 (ref) 1.00 (ref) 77 1.00 (ref) 1.00 (ref) 147 1.00 (ref) 1.00 (ref)
 25.0–29.9 528 1.03 (0.91,1.16) 1.03 (0.91,1.17) 173 0.91 (0.74,1.13) 0.90 (0.73,1.12) 60 0.72 (0.51,1.01) 0.71 (0.51,1.00) 159 0.97 (0.77,1.21) 0.96 (0.77,1.20)
 ≥30.0 88 0.91 (0.73,1.15) 0.93 (0.74,1.17) 34 0.95 (0.66,1.38) 0.97 (0.67,1.40) 11 0.74 (0.39,1.40) 0.72 (0.38,1.37) 33 1.12 (0.76,1.63) 1.13 (0.77,1.65)
Hypertension3
 no 512 1.00 (ref) 1.00 (ref) 169 1.00 (ref) 1.00 (ref) 69 1.00 (ref) 1.00 (ref) 148 1.00 (ref) 1.00 (ref)
 yes 572 1.13 (1.00,1.28) 1.16 (1.02,1.31) 209 1.19 (0.97,1.47) 1.23 (1.00,1.53) 79 1.21 (0.87,1.68) 1.32 (0.94,1.86) 192 1.32 (1.06,1.64) 1.34 (1.07,1.68)
Triglycerides (mg/dL)
 <150 796 1.00 (ref) 1.00 (ref) 291 1.00 (ref) 1.00 (ref) 119 1.00 (ref) 1.00 (ref) 261 1.00 (ref) 1.00 (ref)
 150–199 101 1.03 (0.84,1.27) 1.02 (0.82,1.26) 43 1.24 (0.90,1.71) 1.24 (0.89,1.72) 14 0.96 (0.55,1.68) 1.02 (0.58,1.80) 40 1.33 (0.95,1.85) 1.30 (0.92,1.82)
 ≥200 64 1.06 (0.82,1.37) 1.09 (0.84,1.41) 15 0.70 (0.42,1.18) 0.70 (0.41,1.20) 6 0.69 (0.30,1.58) 0.76 (0.33,1.77) 14 0.74 (0.43,1.27) 0.71 (0.41,1.23)
Fasting blood glucose/type 2 diabetes4
 normal 1018 1.00 (ref) 1.00 (ref) 355 1.00 (ref) 1.00 (ref) 138 1.00 (ref) 1.00 (ref) 320 1.00 (ref) 1.00 (ref)
 pre-diabetes 25 0.67 (0.45, 1.00) 0.68 (0.46, 1.02) 10 0.74 (0.39, 1.39) 0.76 (0.40, 1.43) 4 0.88 (0.33, 2.39) 0.96 (0.35, 2.62) 9 0.78 (0.40, 1.51) 0.80 (0.41, 1.55)
 type 2 diabetes 32 1.64 (1.15, 2.34) 1.59 (1.11, 2.27) 13 1.81 (1.04, 3.17) 1.73 (0.98, 3.03) 5 2.20 (0.89, 5.43) 2.32 (0.93, 5.75) 11 1.87 (1.02, 3.44) 1.78 (0.96, 3.28)
Fasting blood glucose, measurements only5
 normal 1033 1.00 (ref) 1.00 (ref) 363 1.00 (ref) 1.00 (ref) 141 1.00 (ref) 1.00 (ref) 326 1.00 (ref) 1.00 (ref)
 pre-diabetes 28 0.69 (0.48, 1.01) 0.70 (0.48, 1.02) 11 0.74 (0.40, 1.34) 0.74 (0.40, 1.35) 4 0.80 (0.30, 2.17) 0.87 (0.32, 2.36) 10 0.79 (0.42, 1.49) 0.79 (0.42, 1.49)
 diabetes 13 1.76 (1.02, 3.05) 1.75 (1.01, 3.03) 3 1.10 (0.35, 3.44) 1.07 (0.34, 3.35) 2 2.55 (0.62, 10.37) 2.72 (0.66, 11.17) 3 1.45 (0.46, 4.54) 1.37 (0.44, 4.30)
Type 2 diabetes, self-report only
 no 1060 1.00 (ref) 1.00 (ref) 367 1.00 (ref) 1.00 (ref) 144 1.00 (ref) 1.00 (ref) 331 1.00 (ref) 1.00 (ref)
 yes 24 1.68 (1.12, 2.52) 1.61 (1.07, 2.43) 11 2.07 (1.13, 3.80) 1.95 (1.06, 3.60) 4 2.33 (0.85, 6.37) 2.39 (0.87, 6.58) 9 1.99 (1.02, 3.89) 1.88 (0.96, 3.70)
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BMI: Body mass index; CI: Confidence interval; SD: standard deviation

1

Adjusted for age at cohort entry (deciles) and stage of entry (categorical).

2

Additionally adjusted for family history of prostate cancer (yes, no), smoking status (never, former, current), regular checkups (yes, no), education (primary, secondary, college, university), fasting blood glucose categories (normal, pre-diabetes, type 2 diabetes), height (quartiles), and BMI (<25.0, 25.0–29.9, ≥30.0 kg/m2).

3

Hypetension: yes if SBP ≥140 mm Hg or DBP ≥90 mm Hg or taking anti-hypertensives, no if SBP <140 mmHg or DBP <90 mmHg.

4

Fasting blood glucose/type 2 diabetes: normal: <100 mg/dL; pre-diabetes: 100 to <126 mg/dL; type 2 diabetes (fasting blood glucose ≥126 mg/dL or self-reported history of diabetes).

5

Fasting blood glucose: normal: <100 mg/dL; pre-diabetes: 100 to <126 mg/dL; diabetes ≥126 mg/dL.

Type 2 diabetes was associated with a higher risk of total (HR 1.59; 95% CI: 1.11, 2.27), advanced (HR 1.73; 95% CI: 0.98, 3.03), high-grade (HR 2.32; 95% CI 0.93, 5.75), and fatal (HR 1.78; 95% CI: 0.96, 3.28) prostate cancer compared to normal fasting blood glucose with no history of diabetes (Table 2). Pre-diabetes was associated with a lower risk of total prostate cancer (HR 0.68; 95% CI: 0.46, 1.02) (Table 2). This pattern was similar for more aggressive prostate cancer (Table 2). Similar estimates were found when looking at measurements of fasting blood glucose and self-report of diabetes separately (Table 2). Neither BMI nor triglycerides were significantly associated with prostate cancer risk (Table 2).

As a combination of factors, a higher metabolic syndrome score (3–4 vs. 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p-trend=0.08), although this finding was not statistically significant (Table 3). The metabolic syndrome score was not significantly associated with risk of total, advanced, or high-grade prostate cancer (Table 3).

Table 3.

Hazard ratios (HR) for the association between metabolic syndrome score at cohort entry and prostate cancer risk in the Reykjavik Study, 1967–2014

Metabolic syndrome score1
0 1 2 3–4 P-trend
Total prostate cancer risk
 No. cases 234 617 189 40
 Age-adjusted HR (95% CI)2 1.00 (ref) 1.10 (0.94,1.28) 1.13 (0.93,1.37) 0.98 (0.70,1.37) 0.45
 Fully-adjusted HR (95% CI)3 1.00 (ref) 1.11 (0.95,1.30) 1.15 (0.94,1.39) 0.99 (0.71,1.39) 0.38
Advanced prostate cancer risk
 No. cases 72 226 64 16
 Age-adjusted HR (95% CI) 1.00 (ref) 1.25 (0.95,1.63) 1.20 (0.85,1.68) 1.21 (0.70,2.08) 0.33
 Fully-adjusted HR (95% CI) 1.00 (ref) 1.26 (0.96,1.65) 1.20 (0.86,1.69) 1.21 (0.70,2.10) 0.31
High-grade prostate cancer risk
 No. cases 32 85 27 4
 Age-adjusted HR (95% CI) 1.00 (ref) 1.12 (0.74,1.70) 1.24 (0.74,2.09) 0.78 (0.27,2.21) 0.75
 Fully-adjusted HR (95% CI) 1.00 (ref) 1.14 (0.76,1.73) 1.25 (0.75,2.10) 0.81 (0.28,2.29) 0.70
Risk of prostate cancer-specific mortality
 No. cases 62 205 57 16
 Age-adjusted HR (95% CI) 1.00 (ref) 1.34 (1.01,1.79) 1.31 (0.91,1.88) 1.53 (0.88,2.66) 0.09
 Fully-adjusted HR (95% CI) 1.00 (ref) 1.36 (1.02,1.82) 1.32 (0.91,1.89) 1.55 (0.89,2.69) 0.08
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CI: Confidence interval

1

Cumulative number of risk factors at cohort entry: 1) BMI ≥30 kg/m2; 2) systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or taking anti-hypertensives; 3) serum triglycerides ≥150 mg/dL; 4) fasting blood glucose ≥100 mg/dL or self-reported type 2 diabetes.

2

Adjusted for age at cohort entry (continuous) and stage of entry (categorical).

3

Additionally adjusted for family history of prostate cancer (yes, no), smoking status (never, former, current), regular checkups (yes, no), education (primary, secondary, college, university), and height (quartiles).

We found suggestive, but not statistically significant, effect heterogeneity (pheterogeneity=0.07) by entry age for the association between the metabolic syndrome score and total prostate cancer risk: score 3–4 vs. 0, HR 0.46 (95% CI: 0.22, 0.99) for men <52 years and HR 1.27 (95% CI: 0.86, 1.88) for men ≥52 years (Figure 1; Supplementary Table 1). Men <52 years old at entry were less likely to have pre-diabetes (3.5 vs. 4.1%, respectively) or diabetes (1.4 vs. 3.9%, respectively) compared to older men. No significant effect heterogeneity by age or BMI was found for any individual metabolic risk factors (data not shown).

Figure 1.

Figure 1

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Associations were similar in sensitivity analyses excluding the first 5 years of follow-up (data not shown).

DISCUSSION

In our prospective study of 9,097 Icelandic men with an average 25 years of follow-up, hypertension and diabetes were associated with an increased risk of total and aggressive prostate cancer. We found no significant associations between other individual metabolic risk factors (BMI or triglycerides) and total or aggressive prostate cancer. As a collection of metabolic risk factors, the metabolic syndrome score was associated with an increased risk of fatal prostate cancer, although this finding was not statistically significant.

Hypertension was associated with higher prostate cancer risk, with the strongest association noted for fatal disease. Results of prior studies of blood pressure and prostate cancer have been inconsistent. A cohort study of 336,159 Swedish men found that elevated blood pressure was associated with a lower risk of incident prostate cancer and higher risk of fatal prostate cancer (HR 1.14 for BP ≥160/100 vs. <140/90 mmHg; 95% CI: 0.99, 1.38).39 Some studies have suggested an increased risk of total or advanced prostate cancer with elevated blood pressure,17,20,27 while others have reported no association.18,19,26 Studies of blood pressure lowering medications (e.g. beta-blockers, ACE-inhibitors) suggest a null or inverse association with prostate cancer risk.40 The incorporation of anti-hypertensive use into our definition of hypertension thus does not explain our findings. Findings for total prostate cancer must be considered in light of the potential for uncontrolled confounding by PSA screening or diagnostic intensity.

We found an unexpected increased risk of total and aggressive prostate cancer among men with type 2 diabetes compared to men with normal fasting blood glucose and no history of diabetes. Most prior studies have shown diabetes to be associated with a lower risk of total prostate cancer, with a meta-analysis of 19 studies estimating a relative risk of 0.84 (95% CI: 0.76, 0.93).11 A study of 820,900 individuals in 97 prospective studies (including the Reykjavik Study) estimated a lower risk of similar magnitude (HR 0.89, 95% CI: 0.71, 1.10) for prostate cancer-specific mortality, comparing those with diabetes (based on self-report, medication use, and/or fasting glucose ≥126 mg/dL) versus without, although this inverse association was not statistically significant.41 However, the evidence has been inconsistent with two recent cohort studies in Asian populations among 494,630 and 22,458 men reporting positive associations between diabetes diagnosis codes and risk of total prostate cancer42 and self-reported diabetes and risk of advanced prostate cancer.43 The US-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial also found positive associations between diabetes and aggressive prostate cancer among men who were lean or highly physically active.44 Conflicting results might be related to variation in the prevalence of genetically or behaviorally defined subgroups within different populations. For example, a variant in the TCF2 gene is associated with both diabetes and prostate cancer risk.45 Evidence is inconsistent for the influence of diabetes on prostate cancer prognosis. A recent meta-analysis found that pre-existing diabetes was associated with a 29% increased risk of prostate cancer-specific mortality (RR 1.29, 95% CI: 1.22, 1.38).46 While detection bias has been hypothesized to explain observed positive associations when duration between diabetes assessment and cancer detection is short,47 our positive findings persisted after eliminating the first 5 years of follow-up. We are unable to rule out the possibility that these findings are due to chance, due to a low prevalence of type 2 diabetes in this study population (2.7%).

Our findings of an inverse association between pre-diabetes and prostate cancer risk is more consistent in magnitude and direction with prior findings of overt diabetes and prostate cancer.11 Those with pre-diabetes at entry may have gone on to develop overt diabetes over the course of follow up. Alternatively, men with pre-diabetes at entry may have sought out dietary, lifestyle, or pharmaceutical interventions to prevent overt diabetes, and these strategies may be linked to lower prostate cancer risk.48 Also, high insulin levels have been implicated in prostate cancer risk and aggressiveness,12–15 and diabetics at entry would likely have had more severe or a longer duration of insulin resistance than pre-diabetics, which may partially explain the discrepant associations. Overall, our results suggest that the link between diabetes and prostate cancer at different disease stages is complex. This warrants further investigation in large, prospective studies with ample follow-up and repeated measures of diabetes.

BMI has been inversely associated with nonaggressive prostate cancer but positively associated with aggressive disease and progression.8–10 However, we found no associations between BMI at entry and risk of total, advanced, high-grade, or fatal prostate cancer. This may be due to a limited number of obese participants at study entry or due to unmeasured weight change over time.49 Lastly, we found no association between triglycerides and prostate cancer risk, which is in line with several other studies.18,25,26,29

To our knowledge, Haggstrom et al conducted the only prior study to examine a composite score of metabolic syndrome factors and risk of prostate cancer-specific mortality, reporting a positive association (RR 1.13 per 1-unit increase of the composite metabolic z score; 95% CI: 1.03, 1.25; mean age 44 years at entry).28 Two other cohort studies from the US and Norway reported no association between a composite score of metabolic factors and risk of total, advanced, and high-grade prostate cancer.29,30 Martin et al. conducted the only prior study to prospectively examine risk of advanced disease at diagnosis, reporting no association between metabolic syndrome and risk of localized or advanced disease.29 An earlier study conducted in Norway and three additional Scandinavian cohorts all found metabolic syndrome to be positively associated with risk of total prostate cancer.24–27 These studies differed in size, analytic approach, and definition criteria for metabolic syndrome.

Among men <52 years old at entry, we observed an inverse association between metabolic syndrome score and total prostate cancer risk. This association is unlikely to be driven by pre-diabetes as men <52 years old at entry were less likely to have pre-diabetes than older men. These findings are generally consistent with a US-based study that reported a 23% reduced risk of prostate cancer (95% CI: 0.60, 0.98) among men with metabolic syndrome (≥3 vs. <3 components).18 The age distribution was similar to the current study, though their inverse findings were among all men aged 45–65 years at entry and the two populations differed by ethnic/racial composition and PSA testing practices. Alternatively, our results may be due to chance as only 7 prostate cancers were identified in the highest risk group among men <52 years old.

Several limitations should be noted. Metabolic risk factors were measured only once at cohort entry, so we were unable to assess changes over time. We were missing data on stage and grade for 31% of cases, which may have reduced our power to detect an association for aggressive prostate cancer if one exists. In addition, censoring deaths due to causes other than prostate cancer (e.g. cardiovascular disease) may have induced a selection bias if the metabolic factors under study were associated with the competing event and there were shared common causes of the competing event and the prostate cancer outcome. However, we attempted to address this by adjusting for the most plausible common causes of both cardiovascular disease and prostate cancer, such as fasting blood glucose, BMI, and age. Also, the Caucasian background of these men may limit the generalizability of our findings to more diverse groups of men. Finally, we cannot rule out the possibility that our incidence findings might be partially explained by PSA testing, although our population was not subject to routine PSA testing.50 We were able to adjust for the frequency of regular checkups to account for varying degrees of diagnosis opportunity.

Strengths of our study include its long duration of follow-up, population-based sample, and complete and reliable outcome data obtained through registry linkage. A comprehensive physical exam and questionnaire were completed at cohort entry, allowing us to define our exposures using both physiological measures and self-report and to adjust for many potential confounders.

In conclusion, we found that midlife hypertension and diabetes were associated with a higher risk of total and aggressive prostate cancer. Metabolic syndrome as a combination of factors was associated with a higher risk of fatal prostate cancer, though this finding was not statistically significant. Future studies are needed to explore potential biologic mechanisms linking metabolic factors to prostate cancer and potential synergy among them, particularly for aggressive disease.

Supplementary Material

Supp TableS1

Novelty and Impact.

In this study, the authors investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a unique prospective cohort of Icelandic men. Findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.

Acknowledgments

Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (T32 CA09001 to BAD, SCM, JLB), the American Institute for Cancer Research (to JLB), the Nordic Health-Whole Grain Food (HELGA; to JLB, LS, JET). This project was supported in part by the Dana-Farber/Harvard Cancer Center SPORE in Prostate Cancer (P50 CA090381).

We are indebted to Meir J. Stampfer for his contributions to this work.

Footnotes

Conflict of Interest: JLB is currently employed by Sanofi-Genzyme (Cambridge, MA).

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Supplementary Materials

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