In NHS with up to 26 years of follow-up, we documented 12,555 deaths, of which, 2,458 were cardiovascular deaths, and 5,780 were cancer deaths. Among the cancer deaths, 1,605 were from breast cancer, 547 from colorectal cancer, and 1,280 from lung cancer. In the HPFS with up to 20 years of follow-up, there were 8,678 deaths, of which 2,746 were CVD deaths, and 2,960 were cancer deaths. Among cancer deaths, 335 cases were from colorectal cancer, 563 from lung cancer, and 416 from prostate cancer.
Both men and women who had higher overall and animal low-carbohydrate scores had higher BMI and more likely to be current smokers, but lower intakes of fruits and vegetables (). Conversely, those with higher vegetable low-carbohydrate score tended to have higher alcohol and whole grain intake. 1986 was chosen for consistency of data for men and women.
Age adjusted baseline lifestyle and 1986 dietary characteristics of participants according of deciles of low carbohydrate score*
After adjusting for potential confounders, we observed a modest but statistically higher risk for all-cause mortality with the animal low-carbohydrate score (HR comparing extreme deciles of animal score for HPFS=1.31, 95% CI=1.19-1.44, p trend<0.001; for NHS: HR=1.17, 95% CI=1.08-1.26, p trend<0.001) (). The pooled HR was 1.23 (95% CI=1.11-1.37, p trend=0.051). In both cohorts, similar inverse associations were observed between the vegetable score and all-cause mortality, with the pooled HR comparing extreme deciles=0.80 (95% CI=0.75-0.85, p trend<0.001).
Hazard ratios (95% CI) for all-cause mortality by deciles of low carbohydrate scores
For CVD mortality, a modest but statistically significant direct association was observed with the overall low-carbohydrate score in men only (). However, the animal-based score showed a direct association in the pooled analysis (HR=1.14, 95% CI=1.01-1.29, p trend=0.029 for animal score). Results for the vegetable-based score were similar for men and women, and the pooled HR for CVD mortality was 0.77 (95% CI=0.68-0.87, p trend<0.001) for extreme deciles.
Hazard ratios (95% CI) for cardiovascular mortality by deciles of low carbohydrate scores
For total cancer deaths, a statistically significant direct association was observed with the overall low-carbohydrate score in men (HR comparing extreme deciles1.32, 95% CI=1.11-1.57, p trend<0.001) (). A slightly stronger association was observed with the animal low-carbohydrate score in men (HR=1.45, 95% CI=1.23-1.72, p trend<0.001). However, the same association was weaker in women and did not reach statistical significance in the sensitivity analysis when smoking and physical activity was modeled in finer categories. In addition, no association was observed with the vegetable low-carbohydrate score in either men or women.
Hazard ratios (95% CI) for cancer mortality by deciles of low carbohydrate scores
A direct association was observed between the animal low-carbohydrate score and colorectal cancer death when data were combined (HR comparing extreme quintiles=1.31, 95% CI=1.06-1.62, p trend=0.048) (table 5, online appendix
). In both cohorts, the overall and animal low-carbohydrate scores were positively associated with lung cancer mortality, with the pooled hazard ratio for the overall low-carbohydrate score of 1.22 (95% CI=1.05-1.42, p trend=0.003) comparing top to bottom quintiles (table 5
). The vegetable low-carbohydrate score was not associated with lung cancer deaths. After adjusting for risk factors relevant to specific cancers, none of the low-carbohydrate scores was associated with breast cancer or prostate cancer death.
Additional adjustment for physical examinations to reduce the possibility of confounding by late detection and hence more fatal diseases showed similar results. We also repeated our analysis with continuous updating dietary information even after diagnosis of chronic diseases, but adjusted for the self-reported diagnosis in the regression models. In both cohorts, neither the relative risks nor the p-values were changed. Bonferroni correction for multiple comparison for gender-specific analysis did not change the conclusion of the results for all-cause, CVD, or cancer mortality, and statistically significant associations remained significant.
Less than 25% of either NHS or HPFS participants missed more than 2 FFQs during the follow-up period. However, results for the animal and vegetable low carbohydrate scores remained statistically significant when the multiple imputation procedure was used to account for missing data. In NHS, the HR for a 10 point increase in the animal score was 1.09 (p<0.0001) for total mortality and the corresponding HR in HPFS was 1.06 (p=0.0003). Using baseline dietary data and after adjusting for measurement error in diet, conclusions for the overall low-carbohydrate diet score and total mortality were not materially changed. For example, HR for 10 points increase in baseline overall score was 1.04 (p=0.38) for corrected data and 1.01 (p=0.65) for uncorrected data in NHS. In HPFS, HR for 10 points increase in the baseline overall score was 1.20 (p<0.0001) for corrected data and 1.10 (p=0.0004) for uncorrected data. The test for proportional hazard assumption for total mortality analysis was not significant (p= 0.42 for NHS and p = 0.45 for HPFS).