Overall And Cause-Specific Mortality in Patients With Type 1 Diabetes Mellitus: A Population-Based Cohort Study in Taiwan From 1998 Through 2014

ABSTRACT 

Background: To investigate all-cause and cause-specific mortality in Taiwanese patients with type 1 diabetes. 

Methods: A cohort of 17,203 patients with type 1 diabetes were identified from Taiwan's National Health Insurance claims from 1998 to 2014. Person years were accumulated for each individual from the date of type 1 diabetes registration to the date of death or the last day of 2014. Age, sex, and calendar year standardized mortality ratios (SMRs) were calculated concerning the general population. Results: In up to 17 years of follow-up, 4,916 patients died from 182,523 person-years. Diabetes (30.15%), cancer (20.48%), circulatory diseases (13.14%), and renal diseases (11.45%) were the leading underlying causes of death. The mortality rate (26.93 per 1,000 person-years) from type 1 diabetes in Taiwan was high, the cause of death with the highest mortality rate was diabetes (8.12 per 1,000 person-years), followed by cancer (5.52 per 1,000 person-years), and circulatory diseases (3.54 per 1,000 person-years). The all-cause SMR was significantly elevated at 4.16 (95% confidence interval, 4.04–4.28), with a greater all-cause SMR noted in females than in males (4.62 vs 3.79). The cause-specific SMR was highly elevated for diabetes (SMR, 16.45), followed by renal disease (SMR, 14.48), chronic hepatitis and liver cirrhosis (SMR, 4.91), and infection (SMR, 4.59). All-cause SMRs were also significantly increased for all ages, with the greatest figure noted for 15–24 years (SMR, 8.46). 

Conclusions: Type 1 diabetes in both genders and all ages was associated with significantly elevated SMRs for all causes and mostly for diabetes per se and renal disease.

Keywords: cohort studies; mortality; standardized mortality ratio; type 1 diabetes; underlying cause of death 

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INTRODUCTION 

Type 1 diabetes mellitus is associated with a high risk of premature death from various acute and chronic causes.1–3 Causes of death in children and young adults with type 1 diabetes are mainly related to acute diabetic complications; meanwhile, the main cause of death in adulthood is related to long-term complications, particularly cardiovascular disease (CVD).4,5 Although the risk of mortality in individuals with type 1 diabetes remains elevated, a declining trend in mortality of the type 1 diabetes population was noted in many parts of the world, such as Norway, Australia, and Sweden.6–8 A meta-analysis of the relative risk (RR) of mortality for type 1 diabetes compared with the general population that included 26 studies with 88 sub-populations found that the overall RR of mortality was 3.82 (95% confidence interval [CI], 3.41–4.29) compared with the general population.9 Observations using data before 1971 had a considerably larger estimated RR (5.80) when compared with the data between 1971 and 1980 (RR 5.06), 1981–1990 (RR 3.59), and those after 1990 (RR 3.11). The recently improved mortality from type 1 diabetes is primarily due to enforced guidelines that emphasize tight glycemic control, blood pressure control, and treatment of dyslipidemia, as well as smoking cessation, in the management of type 1  diabetes.10–12

Recent evidence suggests a reduction in mortality from chronic complications,8 but little change in mortality from acute complications of type 1 diabetes.13 Mortality varies noticeably among countries,4, and countries with a lower incidence of type 1 diabetes have higher absolute and relative mortality than higher incidence countries.6,14 Willi et al15 suggested ethnic disparities in the outcomes of children with type 1 diabetes, with black participants having more diabetic ketoacidosis and severe hypoglycemic events than white or Hispanic participants. A recent systematic review identified 16 studies that showed racial=ethnic minority youth with type 1 diabetes had higher hemoglobin A1c (HbA1c) than Caucasian youth.16 A recent review indicated that South Asian ethnicity with type 1 diabetes has higher mortality than white Europeans due to excess CVD. Type 1 diabetes in South Asians also have significantly higher HbA1c, lower high-density lipoprotein, and lower rates of neuropathy than white Europeans.17

In Taiwan, the annual incidence rate of childhood (<15 years) type 1 diabetes was stable for boys and girls, with a mean annual incidence rate of 5.3 per 100,000 children between 2003 and 2008.18,19 Compared with Western countries, especially the Nordic nations, Taiwan is among the nations with a low incidence rate of type 1 diabetes. However, the mortality of individuals with type 1 diabetes in Taiwan has not been adequately studied. This study aimed to investigate the overall, sex-specific, and age-specific risks of mortality from all-cause and various causes among type 1 diabetes patients in 1998–2014.

METHODS 

The study proposal was approved by the Institutional Review Board of National Cheng Kung University Hospital (No. B-EX- 105-010). A written informed consent was waived because of the deidentification of personal identity.

Data sources

Data analyzed in this study were retrieved from datasets of the National Health Insurance (NHI) program and Taiwan Death Registry (TDR) from 1998 to 2014. The NHI claims datasets store the inpatient and outpatient medical claims of all residents of Taiwan, and the NHI Administration performs quarterly expert reviews on a random sample of medical claims to ensure their accuracy.20 We used several parts of the NHI claim datasets, including the Catastrophic Illness Database (CID) and the Beneficiary Registry which included the sociodemographic characteristics of every individual. Information on type 1 diabetes diagnosis is among the listed catastrophic illnesses in the CID. Individuals who are registered in the CID for type 1 diabetes must report to the NHIA review board a physician's diagnosis certificate and relevant medical records, including examination results, fasting or glucagon-stimulated C-peptide level, anti-GAD antibody level, and history of diabetic ketoacidosis. Type 1 diabetes diagnosis in the CID was previously used to report the incidence of type 1 diabetes in Taiwan.18,19 with a positive predictive rate of 98.3%.19 In Taiwan, all live births and deaths should be registered within 10 days after birth or death as a legal requirement. Death certificates include various information, including demographic variables, underlying cause of death (UCOD), place of death, and marital status. Data quality for TDR has been evaluated and is considered valid and complete.21

Study design We used a retrospective cohort study design that initially included 17,269 individuals with type 1 diabetes registered with CID between 1998 and 2014. After excluding 66 patients with missing information on gender or age at CID registration, this study enrolled 17,203 study subjects. The date on CID registration was regarded as the date of cohort enrollment (ie, cohort entry).

The study patients were linked to the TDR using a unique personal identification number for identifying the patients who died during the study period of 1998–2014. The information on the UCOD was based on the International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM) (1998–2007) or the Tenth Revision (ICD-10-CM) (2008–2014) codes. In the 17 years of observation, 4,916 individuals died, including 2,511 males and 2,405 females.

Statistical analysis 

The person-years observed for each study subject were accumulated from the date of cohort enrollment to date of death or the last day of 2014. Age at enrollment was categorized into 0–14, 15–29, 30–44, and ≥45 years. The person-years were then categorized according to calendar year, gender, and patient's age at different calendar years (ie, before 2003, 2003–2006, 2007–2010, and 2011–2014). The study cohort contributed 182,523 person-years during the follow-up period. The mortality rate was calculated as the number of deaths divided by observed person-years. Survival curves for sex-stratified and age-stratified cumulative survival risk were plotted using the Kaplan-Meier product-limit method and compared using the log-rank test. We compared patients' risks of all-cause and cause-specific mortality to those of the general population with comparable sex and age at specific calendar years. The UCOD analyzed in this study included diabetes, circulatory diseases, malignant neoplasm, renal diseases, violence and accidents, suicide, infection, chronic hepatitis or liver cirrhosis, and chronic obstructive pulmonary disease (COPD). eTable 1 shows the codes for the selected UCOD analyzed in this study. The expected number of deaths for the type 1 diabetes cohort was calculated from the person-year approach using the age group and sex-specific annual mortality rates, concerning the general population of Taiwan. The annual age- and sex-specific population sizes for the general population during the study period were derived from the national annual household registration statistics published by the Ministry of the Interior of Taiwan. The annual average size of the general population during the study period (ie, 1998–2014) was 23,769,198. Overall, sex-specific, and age-specific standardized mortality ratios (SMRs) were calculated. The 95% CI for SMR was estimated using the exact estimation.22 The distributions of UCOD were graphically presented according to age at enrollment, gender, and year of cohort entry. The analysis was performed using SAS (version 9.4; SAS Institute, Cary, NC, USA), and the level of significance was set at α = 0.05.