Conclusions
The current analysis provides a quantitative estimate of the premature mortality associated with pre-diabetes and diabetes. It reveals that adjusted life expectancy of middle-aged individuals with pre-diabetes, and diabetes, is 2 and 8 years shorter than of individuals with normoglycemia, respectively. YPLL was greater in women, in younger individuals (<60 years) and in those with moderate overweight. As expected, diabetes was associated with the highest YPLL in this long-term cohort study when compared with individuals with normoglycemia.
The main outcome of this study, namely that pre-diabetes is associated with a shorter life span as compared with normoglycemia but higher as compared with overt diabetes, is supported by other reports, although some differences exist. In line with our findings, the National Health Interview Survey (NHIS) sample reveals that American women lost more life years than men in both white and black individuals with diabetes.11 In a Canadian population, diabetes was also found to be associated with a greater loss of life expectancy in women than in men.12 In addition, life years lost associated with diabetes declined with older age. We found YPLL to be 10 years greater in diabetes versus normoglycemia for individuals aged <60 years, but of only 6 years among the older individuals. Narayan et al13 also reported similar findings. In the Japanese NIPPON DATA80 Study, a 7–9 years shorter life expectancy was found in participants with diabetes as compared with those without diabetes, and 2–4 years for participants with IGT compared with those without diabetes.14 In contrast to our findings of greater YPLL in women with pre-diabetes than in men, Japanese men with IGT had a shorter life expectancy than women with IGT.
Whether the higher YPLL of patients with pre-diabetes is due to their aberrant glycemic state associated with higher morbidity and mortality or emergence of overt diabetes with time is not clear. The Australian Diabetes, Obesity, and Lifestyle Study found increased mortality for patients with IFG and IGT with a median of 5.2 years’ follow-up.15 This relatively short time period suggested that progression to diabetes is a less likely factor for the increased mortality associated with pre-diabetes and underscores the inherent risk of pre-diabetes. Similarly, the Framingham Offspring Study showed that pre-diabetes and especially early-onset pre-diabetes confers increased propensity for death, mainly from cardiovascular causes without ever progressing to diabetes.16 On the other hand, during the 23 years of follow-up in the Da Qing Diabetes Prevention Study, the higher death rate compared with matched cohort without diabetes of the IGT group was attributed to the high 79% progression rate to diabetes mellitus.17 This latter finding underscores the great potential for mortality reduction when delaying the onset of diabetes by preventing the progression of pre-diabetes to diabetes. A lifestyle intervention in individuals with pre-diabetes from the Da Qing Diabetes Prevention Study increased life expectancy by an average of 1.44 years.18
Taken together, these data suggest that both factors—inherent risk conferred by pre-diabetes per se together with progression from pre-diabetes to diabetes—may play a role in reducing the life span of persons with pre-diabetes. Our midterm analysis performed after 2 decades of follow-up supports this notion, demonstrating increased mortality for the group with pre-diabetes advancing to diabetes and less so for the individuals with stable pre-diabetes. In addition, the observed gradient of progression rate from pre-diabetes to diabetes according to pre-diabetes criteria, that is, IFG, IGT or both, may be associated with differential YPLL. This was not examined in the present study due to the relatively small groups. In the present study, 12% reverted from pre-diabetes, mostly IFG, to normoglycemia, during a 20-year follow-up, with a relatively low mortality rate of 45% by the end of follow-up. Although the cause for this reversion is unknown, the latter finding may be in accordance with lifestyle intervention studies such as the Finnish Diabetes Prevention Study,19 the Malmo Study20 and the Diabetes Prevention Program,21 consistently showing a reduction in diabetes incidence as well as a decrease in cardiovascular risk factors associated with early mortality. Other interventions, such as drug therapy and bariatric surgery, have proven effective in prevention of progression to diabetes.22–26 Most drugs, excluding metformin, had only modest benefit, with no mortality or cardiovascular advantage.22–25 Although bariatric surgery had better diabetes prevention rates compared with drugs, it lacks proven mortality/cardiovascular benefit and has a considerable adverse effect profile.26
The association of mortality with obesity among people with diabetes is not clear. While previous reports did not find differences in life expectancy between people with diabetes with or without obesity,27 in this study the largest number of YPLL was observed in the mild-overweight group (BMI 25.0–26.9 kg/m²) in both individuals with pre-diabetes and diabetes. Our finding is in accordance with the American NHIS 1997–2000 survey demonstrating that the largest YPLL associated with diabetes was found in the overweight for most of the age, sex and race groups.11 The lowest number of YPLL observed among the obese individuals, when comparing pre-diabetes, diabetes, and normoglycemia, may be a result of other obesity-related comorbidities.
Our study has several limitations. Glycemic state was examined at baseline and may have changed over the years of follow-up until death occurred. Although we performed a midterm analysis, it included only part of the GOH cohort, mainly of survivors. Thus, we were unable to analyze stable pre-diabetes versus that progressing to diabetes and its association with YPLL for the entire cohort. Nevertheless, this midterm analysis most probably reflects an underestimation of the magnitude of the association between dysglycemia and YPLL. Although a 100-gram glucose load was used instead of the standard 75 g, it was found to have little effect on glucose levels.28 Higher rates of pre-diabetes, of 48% were observed in the present study, compared with other Western population reports of 30%–34%.17 29 This may affect the external validity to other populations. Cohort ethnic imbalance, including ~25% Yemenites, known for the extremely high proportion of diabetes and pre-diabetes,30 may explain cohort pre-diabetes proportions. However, the estimated YPLL reported herein were adjusted for ethnic origin, as well as sex, age, smoking, BMI, and blood pressure. Cause-specific mortality could not be examined in the current study due to lack of available data on cause of death. Finally, some of the cohort members were still alive at end of follow-up, and an imputation strategy was applied to allow the use of the full data set while avoiding the risk of survival (selection) bias. Our sensitivity analysis revealed that the estimated YPLL with and without these individuals is showing a similar pattern.
This study has several strengths. While most studies on life expectancy in relation with dysglycemia focused on diabetes, our study reports YPLL in association with both pre-diabetes and diabetes. The data used in the current study were collected and laboratory tests were performed under standard conditions for purposes of a follow-up study, increasing the validity of the data. Availability of information on additional risk factors is another advantage of the present study. In addition, glycemic state definition was based on both fasting and OGTT in accordance with present major guidelines; our cohort is comprised of both men and women and was randomly drawn from the Central Population Registry. Finally, in regard to mortality, the length of follow-up is exceptionally long, providing high event rates (death) and better YPLL assessment.
The exceptionally long 4-decade follow-up of our cohort provided a unique opportunity to determine the association between various stages of dysglycemia and YPLL over an ordinary life span. Our study reveals that adjusted life expectancy of middle-aged individuals with pre-diabetes is shorter than of individuals with normoglycemia. These findings are especially relevant in view of the rising worldwide prevalence of pre-diabetes within younger age groups and underscore the crucial importance of delaying progression from pre-diabetes to diabetes by either lifestyle modification or drug therapy to reduce the YPLL in this high-risk group.