Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study

Abstract

Background: People with type 1 diabetes are at elevated risk of mortality and cardiovascular disease, yet current guidelines do not consider age of onset as an important risk stratifier. We aimed to examine how age at diagnosis of type 1 diabetes relates to excess mortality and cardiovascular risk.

Methods: We did a nationwide, register-based cohort study of individuals with type 1 diabetes in the Swedish National Diabetes Register and matched controls from the general population. We included patients with at least one registration between Jan 1, 1998, and Dec 31, 2012. Using Cox regression, and with adjustment for diabetes duration, we estimated the excess risk of all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, acute myocardial infarction, stroke, cardiovascular disease (a composite of acute myocardial infarction and stroke), coronary heart disease, heart failure, and atrial fibrillation. Individuals with type 1 diabetes were categorised into five groups, according to age at diagnosis: 0-10 years, 11-15 years, 16-20 years, 21-25 years, and 26-30 years.

Findings: 27 195 individuals with type 1 diabetes and 135 178 matched controls were selected for this study. 959 individuals with type 1 diabetes and 1501 controls died during follow-up (median follow-up was 10 years). Patients who developed type 1 diabetes at 0-10 years of age had hazard ratios of 4·11 (95% CI 3·24-5·22) for all-cause mortality, 7·38 (3·65-14·94) for cardiovascular mortality, 3·96 (3·06-5·11) for non-cardiovascular mortality, 11·44 (7·95-16·44) for cardiovascular disease, 30·50 (19·98-46·57) for coronary heart disease, 30·95 (17·59-54·45) for acute myocardial infarction, 6·45 (4·04-10·31) for stroke, 12·90 (7·39-22·51) for heart failure, and 1·17 (0·62-2·20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26-30 years were 2·83 (95% CI 2·38-3·37) for all-cause mortality, 3·64 (2·34-5·66) for cardiovascular mortality, 2·78 (2·29-3·38) for non-cardiovascular mortality, 3·85 (3·05-4·87) for cardiovascular disease, 6·08 (4·71-7·84) for coronary heart disease, 5·77 (4·08-8·16) for acute myocardial infarction, 3·22 (2·35-4·42) for stroke, 5·07 (3·55-7·22) for heart failure, and 1·18 (0·79-1·77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1·9 (95% CI 1·71-2·11) per 100 000 person-years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17·7 life-years (95% CI 14·5-20·4) for women and 14·2 life-years (12·1-18·2) for men.

Interpretation: Age at onset of type 1 diabetes is an important determinant of survival, as well as all cardiovascular outcomes, with highest excess risk in women. Greater focus on cardioprotection might be warranted in people with early-onset type 1 diabetes.

Funding: Swedish Heart and Lung Foundation.

Conflict of interest statement

Declaration of interests

NS has consulted for Boehringer Ingelheim, Novo Nordisk, Janssen and Eli Lilly, and received grant support from AstraZeneca. BE has received personal fees (advisory panels and/or consultant) from Amgen, AstraZeneca, Boerhringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mundipharma, Navamedic, Novo Nordisk, and RLS Global outside the submitted work, and grants from Sanofi outside the submitted work. SG has received personal fees (lecture fees and research grants) from AstraZeneca, Boerhringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi outside the submitted work. Ar.R has received personal fees from Novo Nordisk.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Life years lost in relation to age at onset of type 1 diabetes

Loss of life year was estimated using separate Cox regressions fitted to persons with type 1 diabetes and their control persons within each age group. Conditional median survival was estimated from the upper limit of each age interval. Life years lost due to diabetes is calculated as the difference (between people with type 1 diabetes and controls) in the expected median survival.

Figure 2. Adjusted Hazard Ratios for All Outcomes, According to Age at T1D Diagnosis

The analyses were based on Cox regression and adjusted was made for preexisting comorbidities, calendar year, income, country of birth, marital status, educational attainment, duration of diabetes. Matched controls serve as reference group for all models.

Figure 3. Adjusted Hazard Ratios for All Outcomes, According to Age at T1D Diagnosis and Stratified by Sex

The analyses were based on Cox regression and adjusted was made for preexisting comorbidities, calendar year, income, country of birth, marital status, educational attainment, duration of diabetes. Matched controls serve as reference group for all models.

Figure 4. Causes of Death According to Age at Diagnosis of type 1 diabetes

Causes of death according death certificates in the Swedish Cause of Death Registry. Causes of death in the registry are classified according to the International Classification of Diseases (ICD), 10th Revision. Only the primary cause of death was assessed. Hence, cardiovascular disease may be a significant contributor to deaths classified as e.g “Endocrine causes”.