In our analyses based on a population-based sample nationally representative for Germany, mortality was almost twice as high among adults with T2D as among adults without T2D. Relative risk of death associated with T2D was significantly higher in younger age groups, except for analyses limited to women or diagnosed T2D. The T2D-associated increase in mortality risk tended to be higher for men than women in the case of undiagnosed T2D. YLL due to diagnosed diabetes among adults in Germany in 2010 amounted to approximately 334 000 years without a relevant sex difference.
Results in the context of other studies
Germany
No age-specific estimates of relative mortality associated with T2D from previous German cohort studies are available for comparison with our results. However, corresponding overall estimates from previous studies and this study are compatible despite methodological differences concerning age and sex structure of the samples, diabetes definitions, reference groups, follow-up time, and statistical methods.
The ERFORT study, comprising 1125 men aged 40–59 years from the city of Erfurt, reported age-adjusted hazard ratios (HR) comparing men with diagnosed diabetes with those with normal glucose tolerance (NGT) ranging from 1.86 (1.22 to 2.84) to 2.22 (1.36 to 3.63), depending on duration of follow-up.12 These estimates are slightly higher than our age-standardized MRR for men aged ≥45 years with diagnosed T2D (1.70 (1.10 to 2.63)). The older age range in our sample could explain this difference, as excess mortality declined with age.
The KORA S4 study, comprising a population-based sample of 1466 adults aged 55–74 years from the Augsburg region, reported an age- and sex-adjusted HR comparing persons with diagnosed diabetes with those with NGT amounting to 2.6 (1.7 to 3.8),13 which tends to be higher than the corresponding MRR in our study (1.68 (1.26 to 2.23)).
In the ERFORT study relative mortality was lower among persons with undiagnosed diabetes (HR from 1.48 (1.09 to 1.99) to 1.81 (1.10 to 2.97), depending on duration of follow-up) than among those with diagnosed diabetes, while it was higher for undiagnosed diabetes in the KORA S4 study (HR 2.8 (1.7 to 4.4)) and our analysis (MRR 1.96 (1.41 to 2.71)). A rather unusual definition of undiagnosed diabetes (plasma glucose of >200 mg/dL (>11.1 mmol/L) at 1 hour on oral glucose tolerance testing (OGTT)) in the ERFORT study contrary to definitions of established guidelines applied in KORA S4 (plasma glucose after fasting or at 2 hours on OGTT) and our study (HbA1c) may contribute to this difference.
International
Due to different age and sex structures, comparability of MR and MRR from different countries is limited. Tancredi et al4 followed 435 369 persons with T2D aged ≥18 years in the Swedish National Diabetes Register from 1998 to 2011, a time period corresponding to the follow-up of our study, and compared their mortality with matched controls from the general Swedish population. Lind et al16 used healthcare databases in Ontario, Canada, and The Health Improvement Network database of primary care practices in the UK to calculate annual MR for large samples of adults aged ≥20 years with and without diabetes for the years 1996–2009.
To augment comparability of results, we standardized age-specific MR for adults aged 18/20 to <75 years with and without diabetes published by Tancredi et al and Lind et al and from our data all to the age structure of the official German population as of December 31, 1997 and calculated the corresponding MRR. For the MRR from our data, we compared persons with diagnosed T2D with those without T2D or with undiagnosed T2D to best parallel the condition of register and healthcare databases in the other analyses. Comparison of the standardized MRR thus obtained still needs to consider differences in data sources (register, healthcare database, practice database, survey), diabetes definition, age ranges and groups, and statistical methods. However, the MRR recalculated from our data (1.78 (1.04 to 3.04)) was very similar to that from Sweden (1.77 (1.03 to 3.04)). The MRR obtained for the UK and Ontario using MR averaged for 1998–2009 were higher (2.68 (1.51 to 4.74) and 2.41 (1.28 to 4.53), respectively), yet 95% CI were overlapping between all countries.
Sex differences
Our analysis revealed similar age-standardized MRR for diagnosed T2D among women and men. This might seem surprising, as relative risk of mortality associated with diabetes, especially due to cardiovascular disease, has formerly been reported to be larger among women.3 7 35 36 However, other meta-analyses contradict such sex differences37 38 and SMR in the diabetes registry of the GDR in 1987 did not differ by sex.11 More recently, analyses of excess mortality among US adults between 1997 and 2006 showed no relevant sex difference,6 SMR for women and men in the Danish National Diabetes Register between 1995 and 2006 were almost identical,5 and no interaction between T2D and sex was observed in mortality analyses of data from the Swedish National Diabetes Register.4
Relative mortality associated with total T2D tended to be higher in men than in women in this study. Sex-stratified analyses differentiating between undiagnosed and diagnosed T2D implied that this was mainly due to a higher relative mortality associated with undiagnosed T2D for men than women. A possible explanation for this observation could be a diagnosis earlier in the course of the disease among women than men due to gender differences in the organization and the utilization of preventive healthcare services for younger adults. In Germany, screening for gestational diabetes has been implemented in 2012.39 Among adults 35–44 years of age, men are also significantly less likely than women to participate in free biennial health check-ups for cardiovascular risk factors, offered to people 35 years of age and older who are covered by the statutory health insurance system.40
It has to be considered that the sample size was very small for multiply stratified analyses. Howsoever, young men with undiagnosed T2D might be an important target group for secondary prevention, although further data are needed to clarify potential sex differences in relative mortality associated with undiagnosed and diagnosed T2D.
Variations over age
Several studies in Sweden,4 Denmark,5 the UK,8 16 Canada,9 16 the US,17 and Australia3 reported relative mortality associated with diagnosed diabetes to decrease with increasing age, identifying younger persons to be at especially high risk. Our analyses showed a corresponding trend, although not statistically significant in all subgroups, which was possibly due to the limited number of participants with events resulting in considerable variability especially among younger age groups.
Years of life lost
Our estimates of YLL due to diagnosed diabetes among adults in Germany in 2010 correspond to those from other studies. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2013)41 reports YLL due to diabetes in year 2010 in Germany of 111 497 (98 812 to 136 318) for women and 132 803 (125 687 to 140 868) for men. Using KORA S4/F4, Brinks et al42 extrapolated YLL in Germany due to undiagnosed and diagnosed T2D in year 2010 to have been 137 000 (55 000 to 243 000) for women and 166 000 (81 000 to 278 000) for men. These numbers are of similar magnitude as our estimates of 164 600 (35 000 to 279 300) YLL among women and 169 900 (28 300 to 328 300) among men. The ratio of YLL among women and men was similar across studies (0.84 in the GBD 2013, 0.83 in the KORA S4/F4 study, and 0.97 in our analysis).
Strengths and limitations
As a major strength, the present study was based on a large population-based sample representative of the adult population in Germany with a nearly complete 12-year follow-up for all-cause mortality. Highly standardized interview and examination instruments including HbA1c measurement permitted estimates of diabetes-associated mortality risk for diagnosed and undiagnosed T2D with stratification by age and sex, which so far have not been reported for Germany.
The study also shows limitations. First, the limited number of participants with T2D and events, especially in younger age groups, limits the statistical power and informative value of the study particularly in the stratified analyses.
Second, a weight correcting for several sociodemographic parameters including education was used18 to counteract the selection bias inherent to health surveys. Nonetheless, parts of the population are probably misrepresented, as additional factors (eg, severe illness) may affect survey participation and persons aged 80 years or older or living in institutions (eg, nursing homes, hospitals) were not included in the survey, representing groups with a presumably high mortality and T2D prevalence. Exclusion of participants due to missing data might further have reduced representativeness, although a sensitivity analysis that did not exclude participants without HbA1c measurement in the case of diagnosed T2D did not suggest a relevant bias of results for persons with diagnosed T2D due to exclusions for missing HbA1c measures.
Third, misclassification of T2D status cannot be excluded. To exclude participants with diagnosed T1D, we used an epidemiological definition, for which a previous study showed a high positive predictive value.43 However, exclusion of participants with gestational diabetes or other diabetes types was not possible with the available information. Definition of T2D based on self-reported information without external validation may have resulted in misclassification, although validity of self-reported diabetes has been shown to be high.44–46 Furthermore, among asymptomatic patients, repeat testing is required to confirm the diagnosis of diabetes in the clinical setting.24 In the present study this was not possible and the definition of undiagnosed T2D was based on a single HbA1c measurement. Applying a highly standardized analytic method, as was the case in the present study, overall specificity of HbA1c testing at a diagnostic threshold of ≥6.5% (≥48 mmol/mol) is considered to be high.24 47 It is therefore unlikely that we identified a substantial proportion of false-positive cases. Mortality associated with undiagnosed as well as diagnosed T2D was possibly underestimated, because changes in T2D status over time could not be captured in the present study. Consequently, mortality in relation to incident T2D was attributed to the reference group without T2D at baseline. Furthermore, intervention bias may have contributed to underestimation of diabetes-associated mortality. GNHIES98 study participants received information on baseline examination results, including HbA1c measures; this may have resulted in earlier diagnosis and treatment.
Fourth, YLL could only be calculated for diagnosed T2D as we chose to use recent data without upper age limit from national health interview surveys (GEDA) 2009–2012 for calculation of prevalence data, which are required for estimation of YLL.
Finally, since no detailed reference data for age ≥90 years were available for standardization, the oldest age group (85 to <92 years) of the study sample was standardized to the official German population aged 85–89 years, possibly leading to an overestimation of T2D-associated mortality because the oldest age group with a relatively low excess mortality thus received a relatively low weight.
Implications for future research and health policies
Mortality follow-up based on nationally representative German health surveys permits estimates of mortality associated with T2D in German adults, which cannot be obtained from official mortality statistics or diabetes registers in Germany. The results of the present study demonstrate the importance of improvement in diabetes prevention and quality of care in Germany. As of 2010, adults with diagnosed T2D still had an up to 70% higher all-cause mortality risk compared with persons without diabetes, with an estimated 334 000 YLL due to diagnosed diabetes, which accounts for about 2% among YLL due to all-causes of death.41 In addition, the increase in all-cause mortality risk appears to be at least as high for persons with undiagnosed as for those with diagnosed T2D.
Our estimates provide a baseline for surveillance of diabetes epidemiology and quality of care. In addition to the lifetime lost, the amount and quality of lifetime spent with the disease should also be considered in future analyses. This becomes all the more important as several countries report declining MRR in association with diabetes, suggesting improved survival into old age and hence a potential increase in years spent in disability.2 48
Nationwide initiatives to tackle T2D already exist in Germany, such as the implementation of a disease management program for T2D.49 Further effort is needed to fight risk factors, prevalence, complications, comorbidities, and mortality of T2D, in order to reduce the growing burden of diabetes on health economics, society, and individuals. Effective prevention of diabetes remains a major challenge. Population-based strategies for primary prevention will have a key role in order to foster healthy living and healthy environments. In addition, recently published results of randomized trials have refueled discussion on screening for T2D, as early detection and treatment of diabetes appear to reduce complications and risk of premature death among persons with previously undiagnosed diabetes.50 51 Studies evaluating the impact of T2D screening imbedded in the primary care setting will be crucial in order to ensure effective secondary prevention and hereby reduce mortality risk associated with T2D.
