We hypothesized that diets characterized by a high glycemic index and glycemic load are associated with an increased risk of total cancer, on the basis of previous suggestive findings from cohort studies that indicated harmful effects of glycemic index for premenopausal (25
) and postmenopausal (26
) breast cancer and of glycemic load for endometrial (28
), ovarian (29
), and colorectal (30
) cancer. However, our findings suggest that glycemic index and glycemic load are not strongly associated with cancer incidence. For total cancer, we found evidence of a slightly increased risk for men who consumed high glycemic index foods, but this quintile 5 confidence interval included 1, and we actually found a modest, decreased risk of total cancer for women and men with high glycemic load diets. Further analyses showed, however, that glycemic index was positively related to total cancer only among women and men with a high body mass index, and glycemic load was inversely related to total cancer only among women and men with a low body mass index.
Our glycemic index data are consistent with an explanation based on the Nurses' Health Study, which suggests that those of higher body mass index who are inactive are likely to be more susceptible to the carbohydrate quality of the foods they consume because of a strong insulin response to high glycemic index foods (32
). However, this explanation does not explain the inverse glycemic load and total cancer associations that we saw in low body mass index women and men. Given the low magnitude and direction of the relative risks observed for glycemic index and glycemic load, respectively, it is possible that these exposures are not directly involved in the etiology of cancer but, rather, track with diet and lifestyle patterns associated with cancer risk.
Site-specific associations for glycemic load in our study were largely null, demonstrating consistency with past cohort study results for postmenopausal breast cancer (25
), premenopausal breast cancer (26
), colorectal cancer (31
), stomach cancer (44
), endometrial cancer (45
), and pancreatic cancer (regarding results for men) (32
). A few site-specific associations were significant, although multiple comparisons explain their significance given their exploratory nature, and many disappeared in subanalyses with more careful control for confounders, thus weakening support for the effects of glycemic index and glycemic load.
The inverse glycemic load–ovarian cancer relation that we observed was contrary to findings in the National Breast Screening Study (26
). We investigated confounding by oral contraceptive use, but this adjustment strengthened the association, arguing against oral contraceptive use as an explanation for our results. Menopausal hormone therapy use was positively associated with ovarian cancer in the NIH–AARP cohort (51
). Although use of menopausal hormone therapy was carefully adjusted for in our multivariate models, since the glycemic load–ovarian cancer relation was not significant among women who never used menopausal hormone therapy, confounding by use of this therapy may be an explanation for this finding. Neither this association nor the glycemic load–pancreatic association in women was significant when we stratified by body mass index or excluded the first 2 years of follow-up.
The positive glycemic index–colorectal cancer and inverse glycemic load–myeloma associations observed in women did not have significant quintile 5 confidence intervals. The positive glycemic index–colorectal cancer association in women and positive glycemic index–stomach cancer association in men disappeared when the analysis was restricted to never smokers. Among men, the positive glycemic index–colorectal cancer association disappeared when stratified by red meat intake and otherwise remained significant only among those with a high body mass index or who had never smoked.
To our knowledge, the remaining site-specific associations have not been previously investigated in cohorts. The positive glycemic index–bladder cancer association among men disappeared when we stratified by smoking and simultaneously controlled for smoking status, dose, and time since quitting smoking, suggesting residual confounding by smoking. The positive glycemic index–esophageal cancer association in men became null when we stratified by red meat and otherwise was significant only among men who had a high body mass index or a high saturated fat intake, or who were former or current smokers. The glycemic load–liver cancer association in women may have been the result of residual confounding, as the association was not present when we restricted the analysis to never smokers.
At present, there is no current literature to support a rationale for the direction of inverse associations that we observed for glycemic index among men for brain cancer and non-Hodgkin's lymphoma (which became null when we stratified by body mass index).
With almost 500,000 participants, 50,000 cancer cases, and 3,078,866 person-years of follow-up, the NIH–AARP Diet and Health Study is well powered to detect differences in cancer incidence if they truly exist. Follow-up of the cohort based on linkage to cancer registries and mortality databases, with approximately 90% sensitivity for incident cancers (20
), reduced the likelihood that our overall results reflected bias due to differential follow-up, and the exposure preceded the onset of cancer enabling us to prevent against recall bias. Moreover, there was a wide range of glycemic load, allowing for sufficient variability in this exposure for a difference to be seen.
Our study is limited, however, by the narrow range of glycemic index values in the NIH–AARP cohort. The majority of glycemic index values centered around the middle of the theoretical range for glycemic index (i.e., 0–100), which may have precluded our ability to detect the effects of different levels of glycemic index unless it is a powerful determinant of disease risk at middle values (52
Additionally, systematic, multivariate measurement error from imprecise dietary measurement may have occurred (53
) and affected the hazard ratios and covariate estimates obtained (54
). It is possible that reporting of energy intake differed by body mass index status (55
), which was not captured in this study. Despite strong follow-up (mean = 6.89 years) of the cohort at the time of this analysis, our assessment of diet may also not have captured the cancer-relevant period of exposure, given cancer's potential for long latency and our modeling based on median quintiles of dietary glycemic load at baseline, when participants were already aged over 50 years. Our study also characterized glycemic index and glycemic load as individual exposures, because past research suggested that the exposures alone might be surrogate markers of insulin load. Our findings reflect their direct effect on cancer incidence.
To date, few glycemic index and glycemic load analyses have provided evidence of meaningful associations with cancer risk. The small magnitude of the inverse and the positive significant relative risks that we observed suggest that glycemic index and glycemic load might not be as useful in predicting cancer incidence as other chronic diseases. In diabetics (56
), low glycemic index and glycemic load predicted better glycemic control in the majority of feeding studies (4
). An increased risk of non-insulin-dependent diabetes mellitus was seen in the Nurses' Health Study for high versus low glycemic index and glycemic load (61
) and in the Health Professionals Follow-Up Study for glycemic index (62
). This evidence reveals the importance of these concepts in guiding food choice among diabetics in the context of other nutritional indicators (63
). Glycemic load has also been associated with increased risk of coronary heart disease in the Nurses' Health Study (64
) and with cardiovascular disease in a Dutch cohort (65
). Our findings do not rule out the insulin resistance hypothesis, but rather they suggest that glycemic index and glycemic load are not major contributors to aspects of insulin resistance that might influence cancer risk (66
In summary, analysis of the NIH–AARP cohort did not provide strong evidence that diets high in glycemic index and glycemic load are associated with cancer incidence. With a widening understanding of the complex interactions involved in cancer etiology and that food is not consumed in isolation, we believe that identification of the role of glycemic load as part of an overall healthy dietary pattern (67
) may enable examination of the broader diet–cancer relation.