In the current study, using data from three large longitudinal cohorts, we examined the impact of three-year changes in FPG status on the incidence of all-cause, CV, and cancer mortality in more than 14,000 participants, without initial T2DM over two decades of follow-up. Our principal findings are as follows: 1) using the IFG-ADA, women who experienced incident IFG, persistent IFG, or progression from IFG to T2DM showed an increased risk of all-cause mortality; however, in men, the excess risk was observed only for those who converted to T2DM. Compared to men, women who remained in IFG status had a 24% higher risk for all-cause mortality. Using IFG-WHO, results were generally the same, except for incident IFG in women and IFG conversion to T2DM in men, which were no longer significant. 2) Regarding CV mortality, only among women, conversion to T2DM in IFG-ADA/WHO and NFG-WHO conferred increased risk. 3) For cancer mortality, based on IFG-ADA, NFG to IFG/T2DM and IFG to IFG categories were associated with a significantly greater risk in women only.
Concerning all-cause mortality, we found that IFG-ADA in different conditions, regardless of the conversion to T2DM, was a significant predictor for mortality events among women. In line with our findings, the Hoorn Study previously found that compared to individuals with baseline NFG, those who converted to T2DM during the six-year change from IFG-ADA and IFG-WHO had a higher risk of all-cause mortality in the age and sex-adjusted analysis (11). However, in contrast to our findings, the researchers found that IFG status was associated with a higher risk of all-cause mortality only among those who converted to T2DM within a mean follow-up of 6.4 years.
Despite the irrefutable importance of hyperglycemia duration in developing diabetes-related macro- and microvascular complications (22), little is known about this issue in the pre-diabetes state. A retrospective cohort of the Korean National Health Insurance Service showed that the newly developed IFG-ADA was associated with an increased risk of all-cause mortality, mainly attributable to male participants and the elderly (8). On the other hand, the current study also demonstrated that the newly developed IFG-ADA was significantly associated with all-cause and cancer mortality events among non-elderly women.
Regarding CV mortality, we observed more than a two-fold higher risk associated with the IFG-ADA conversion to T2DM, in the presence of well-known CVD risk factors, in women; when we used IFG-WHO, NFG conversion to T2DM also showed a significant risk. The Hoorn Study also found that conversion to T2DM from IFG-ADA/WHO was associated with more than a two-fold increased risk of CV mortality adjusted for age and sex (11). A collaborative meta-analysis of 102 prospective studies found that the risk of CHD for T2DM was higher in women than in men, at 40–59 years than in the elderly population, and with fatal versus non-fatal disease (23). What is more, Cai et al. (24) showed that pre-diabetes conferred an increased risk of composite CVD in the general population by 15%; however, no gender difference was found; additionally, the composite CVD risk associated with IFG was significantly higher in women with the prevalent atherosclerotic CVD than in men.
As another important finding, we demonstrated that women with persistent IFG during three years still had a higher risk for mortality events. By focusing on clinical trials, current evidence is not consistent or compelling regarding the effect of T2DM prevention on the risk of CVD or mortality (25). Recently, the Diabetes Prevention Program Outcomes Study researchers found that neither metformin nor lifestyle intervention reduced major CVD events over 21 years despite long-term prevention of T2DM (26). Hence, given the balance among benefits, risks, and costs of prevention, we speculate that prevention strategies might need to be considered earlier before subjects experience IFG, especially among women.
In this study, for the first time, we assessed the effects of the directions of FPG on the risk of cancer mortality. Generally, despite the absence of gender interaction, we found that women with IFG-ADA had a much higher risk of cancer mortality. Huang et al. (27), in a meta-analysis of 16 prospective studies, found a 15% increased risk of incidence and mortality of cancer associated with pre-diabetes; following subgroup analysis, men showed a higher risk than women; however, no gender interaction was identified. A meta-analysis of 19 239 302 people from 121 cohorts showed that T2DM was a risk factor for all-site cancer (incidence or fatal) in both sexes, with a significantly higher risk in women than in men by about 6% (28). Findings from our study imply that even a single exposure to IFG-ADA puts women at a higher risk of cancer mortality, even after returning to normal FPG.
Current literature shows signals of sex differences for the outcomes in subjects with abnormal glucose levels (29–31). Wang et al. (32), in a systematic review and meta-analysis, showed that compared to men with the same condition, women with T2DM had about 60% and 13% greater risk of CHD and all-cause mortality, respectively, although there was significant heterogeneity between studies; however, no such difference was observed for cancer mortality. The underlying reasons for these differences over the aging lifespan are less well-understood; differences in traditional CV risk factors do not explain the higher risk of CV mortality associated with T2DM in women compared to men (33). Recently, we found that compared to men, women had greater exposure and burden of multiple risk factors before the onset of T2DM; the issue contributes to a higher CVD risk of T2DM among women. In the current study, we extend the previous research by showing that being in IFG status was associated with more than 20% higher risk for all-cause mortality among women compared to men.
Strengths And Limitations
Our study has several important strengths. First, a longitudinal population-based design over two decades of follow-up, with a large population size using data from three established cohorts, provided a diverse study population to improve generalizability. Second, including a substantial number of individuals without T2DM and CVD allowed us to analyze associations between all categories of changes in FPG status and risk of all-cause mortality separately in men and women. Third, careful adjustment for well-known CVD risk factors was performed in our data analysis. Finally, for the first time, we highlighted sex difference in the impact of FPG change on the risk of all-cause and cause-specific mortality events.
The results of our study need to be interpreted in the context of several limitations. First, the glycated hemoglobin A1c (HbA1c) and 2-h post-load glucose (2h-PG) data were unavailable for all three cohorts, which may have led to the misclassification of T2DM and normoglycemia among participants. Second, study participants with IFG may have developed type 2 diabetes during the follow-up after the three years of examination. Hence, we did not exclude the possibility that the observed risks might be attributable to the development of T2DM during longer follow-ups. Third, although we adjusted our analyses for a wide variety of known covariates as appropriate for each outcome, residual confounding inherent in the observational studies, such as physical activity, nutritional status, and socioeconomic status, may alter the results. Fourth, we did not have enough events in the NFG to T2DM category for CV and cancer mortality events resulting in unstable effect sizes with wide confidence intervals. Fifth, data for cancer mortality analysis was only available for two cohorts, ARIC and TLGS. And last but not least, considering the age span of the study population, our findings might not be extrapolated to individuals > 60 years of age.
In summary, among over 14,000 individuals free of T2DM and prevalent CVD, we examined the association between an approximately three-year change in IFG status with mortality events, with apparent sex differences in this pathway. Among women, the IFG status, whether as persistent, incident, or progression to T2DM, had a significant risk for all-cause mortality events in the presence of CVD risk factors. Moreover, the unfavorable impact of IFG was seen even among women who did not convert to T2DM status. However, in men, the excess risk was observed only for those who converted to T2DM. Additional work is needed to validate our findings and provide further information on the sexual dimorphism in the effects of glycemic directions on mortality events, the issue emphasized in precision medicine.