In this historical cohort study we found that adults (aged 35 years and above) with newly diagnosed diabetes have an overall 38% increased risk for all-cause mortality compared to individuals without diabetes. This is higher than the 15% (95% CI 9–22%) increased risk for mortality reported by a Scottish population based study of individuals aged 35 and older with new onset diabetes, after adjusting for deprivation status and previous cardiovascular disease [
18]. The population of that study was older than in our study (45% and 35% respectively were older than 65 years) which may explain the lower diabetes-associated mortality risk observed. Studies from the UK, Canada, and the US [
3,
8,
19,
20] found that individuals with prevalent diabetes had an almost twofold increased risk for mortality compared to individuals without diabetes. Other studies conducted in Israel, Sweden and the Netherlands found lower relative risks, of <1.5 [
2,
4,
9]. Comparing between studies is difficult due to differences in populations, in methodologies (the use of Cox regression vs. standardized mortality rates) and in the co-variates included in the multivariate analysis. In addition, due to the finding that age and gender modify the risk, overall estimates of the effect of diabetes on mortality are specific to study populations, since they are influenced by variations in population composition. The increased risk for mortality associated with diabetes was only partially explained by baseline risk factors (in the multivariate model the risk was attenuated by 18% from 1.56 to 1.38). Moreover, due to the insidious course of diabetes, its damage to the micro and macro vasculature often starts years before diabetes is diagnosed [
21]. It is possible then, that some of the baseline comorbidities that we included in the multivariable model (e.g. ischemic heart disease and renal failure) were, in effect, caused by the diabetes, so they mediated the mortality risk and did not confound it. Therefore, the actual diabetes-related mortality risk may be somewhere between 1.38 and 1.56. Our finding of a higher diabetes associated risk for mortality among women as compared to men especially in the age group of 35–44 years is congruent with other reports [
3,
4,
22‐
24]. Diabetes is a known risk factor for cardiovascular events [
25] and was hypothesized to attenuate the female natural protection against cardiovascular complications [
26,
27]. Similar to previous studies [
3,
4,
22‐
24,
28] we report that the relative risk for mortality associated with diabetes decreased with age. This may be due to higher background mortality in older ages, or due to a survivor bias, i.e. a less severe course of diabetes that develops in those who survive to older age. Yet, even in those patients who were 75 years and older the risk remained pronounced, similar to a recent work from Taiwan [
29]. Moreover, in the elderly, the lower relative risk translates to an addition of a larger number of deaths associated with diabetes, due to the high background mortality of this age group.
We found that the increased risk for mortality was already evident shortly following the diagnosis of diabetes as can be seen by the early separation of the survival curves (Fig.
1). Similarly, in the Cardiovascular Health Study, the diagnosis of diabetes among individuals aged 65 years and older was associated with a HR of 2.3 for mortality within the first 2 years after the diagnosis [
10]. An immediate risk for mortality was also found among Danish males [
30]. Taken together, this suggests that the mortality risk associated with the hyperglycemic state is not mediated solely through atherosclerotic pathways. The mortality associated with diabetes may be influenced by risk factors that are closely linked with hyperglycemia. One such possibility is insulin resistance, which was previously reported to be associated with cardiovascular events [
31]. The finding that diabetes is associated with an increased risk for mortality at any age should be considered when prescribing medications for primary prevention of cardiovascular events, that have been reported to increase the risk for diabetes [
32,
33]. This highlights the need to tailor treatments according to patient characteristics. The strengths of this study include the population-based design together with the usage of a large and valid electronic database with few dropouts. This minimizes the potential for selection and information biases. Another advantage is the comparison to individuals free of diabetes that belong to the same population as those with diabetes. Yet; our study has a few limitations. The data did not include information regarding the type of the diabetes; though by limiting the study population to patients diagnosed with diabetes at age 35 years and older the proportion with type 1 diabetes was presumably small [
34]. The non-diabetes group may have included individuals with undiagnosed diabetes, as the disease can be asymptomatic for years. In a different project we found that 60% of MHS members at the age 35 years and older had their glucose tested at least once a year (data not published), so the prevalence of undiagnosed diabetes is expected to be low in this population. Similarly, it is possible that some individuals in the control group developed diabetes later on, causing some misclassification of the exposure, but the expected effect of this (if any) is to cause underestimation of the true risk. Another limitation was the fact that we did not have baseline BMI data and any data regarding important risk factors for mortality including physical activity, sedentary lifestyle and nutritional habits, which may differ between individuals with and without diabetes. In addition, we lacked data about the baseline level of important risk factors for mortality in diabetic patients including Hba1c, cholesterol and triglycerides [
35,
36], and about the level of glucose or blood pressure control. In conclusion, our finding of 38% increased diabetes associated risk for mortality shows that despite the major advances in diabetes care and the introduction of new treatments, onset of diabetes still carries a significant increased risk for mortality. Furthermore, the increased risk was observed at all ages even among the elderly aged 75 years and above. These findings highlight the need to allocate resources to diabetes primary prevention and improved care in all ages.