Background Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis. Methods This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration. Findings Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38·8%) were overweight (BMI 25·0–29·9 kg/m2) and 87 (3·4%) were obese (BMI ≥30 kg/m2). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m2) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1·47 [95% CI 1·16–1·88] for overweight men and 2·66 [1·62–4·39] for obese men; ptrend<0·0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991–2007) compared with during the pre-PSA screening era (1982–1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2·38 [95% CI 1·31–4·30]; ptrend=0·008). Compared with men with a BMI less than 25 kg/m2 and low C-peptide concentrations, those with a BMI of 25 kg/m2 or more and high C-peptide concentrations had a four-times higher risk of mortality (4·12 [1·97–8·61]; pinteraction=0·001) independent of clinical predictors. Interpretation Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings. Funding The National Institutes of Health research grants CA42182, CA90598, CA58684, CA34944, CA40360, HL26490, HL34595, the National Cancer Institute of Canada, and the Prostate Cancer Foundation, Santa Monica, CA, USA.

Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis