Cardiovascular Disease, Mortality and Prognostic Factors in Adult-onset Type 1 Diabetes

Introduction Type 1 diabetes (T1D) is traditionally considered as childhood-onset disease while it occurs more often in adults than in children, with a median onset-age of 29 years[1]. There is a scarcity of evidence on mortality (and causes)[2] and cardiovascular diseases (CVD) in adult-onset T1D. Previous studies involving adult-onset T1D mostly included individuals diagnosed before age 30 years[3-8]. Nationwide studies in Sweden found that T1D diagnosed at any age between 0-30 have shorter life expectancy, higher risks of all-cause mortality, CVD mortality, and incident CVD than population controls, and age of T1D onset and HbA1c levels are important risk stratifiers[4,5].

Age at diagnosis is an important factor affecting prognosis of diabetes but evidence on T1D diagnosed after age 30 years is relatively scarce. A study of 35355 incident T1D cases in England and Wales found that the hazard for all-cause mortality in people with T1D was higher than that in people with T2D across all groups of age at diagnosis (from 20-39 years to ≥60 years) but such excess risk was observed in men and not in women[9]. A small Swedish study of 112 adult-onset T1D cases (diagnosed between age 18 and 100 years) indicated no excess mortality in T1D as compared to population controls[10]. In comparison, a recent study of 1573 people with newly diagnosed (at age ≥35 years) adult-onset T1D in Sweden found that these individuals had excess mortality as compared to people with T2D while the CVD incidence was close to that in population controls[11]. It is unclear how mortality and CVD incidence in adult-onset T1D vary by diabetes duration, lifestyle factors, and clinical characteristics (HbA1c, blood pressure, and lipids, etc).

This study aims to investigate the risk of all-cause mortality, cause-specific mortality, and incident CVD in adult-onset T1D, as compared to T2D with comparable age at diagnosis and population controls. We will explore potential modifiable factors including lifestyle and clinical characteristics that contribute to T1D prognosis.

Methods Study population Adult-onset (≥18 years) T1D cases diagnosed in 2006-2020 will be identified from the Swedish National Diabetes Register (NDR: 1996-2020), without conflicting types of diabetes diagnosis (primary diagnosis) in the National Patient Register (NPR; 1995-2021), and with exclusive insulin prescription initiated within the first 6 months of diagnosis and recorded in the National Prescribed Drug Register (NPDR; 2005-2022). We will also include all T2D cases diagnosed at age ≥18 years in NDR in 2006-2020 and without conflicting types of diabetes diagnosis (primary diagnosis) in NPR. The date of diabetes diagnosis will be defined as the date of first diabetes record in NDR (visiting date or self-reported date of diagnosis, whichever comes first), NPR, or the date of first prescription of glucose-lowering drugs in NPDR, whichever comes first. Individuals whose self-reported year of diabetes diagnosis ("debutar") in NDR was earlier than the year of diagnosis as defined above will be excluded. Population controls will be selected from participants who have not any record of diabetes diagnosis in NDR or NPR before the end of follow-up (2021). Each T1D case will be matched for age, sex, county[5] with 50 (the ratio depends on the minimum number of available population controls in each matched stratum) population controls who are still alive at the year of diagnosis in their matched T1D cases. The analysis of CVD and MACE (major adverse cardiovascular events) incidence will exclude individuals with corresponding diagnosis at baseline.

Covariates and prognostic factors Information on sex, year and month of birth, country of birth, and marital status will be obtained from the Total Population Register, while information on education will be obtained from the Longitudinal integration database for health insurance and labor market studies (LISA). NDR provides information on smoking (yes or no), body mass index (BMI), physical activity, HbA1c, blood pressure, lipids profiles, eGFR and albuminuria after diabetes diagnosis. HbA1c within control target will be defined as an HbA1c of <7.0%[12]. Blood pressure within control target will be defined as systolic blood pressure <140 mmHg, and diastolic blood pressure <90 mmHg[13]. A favorable HDL cholesterol level will be defined as HDL >1.0 mmol/l in men and >1.3 mmol/l in women[14]. A low-risk LDL cholesterol level will be defined as LDL <2.6 mmol/l[14]. We will categorize eGFR levels into two groups, namely eGFR ≥60 or <60 mL/min/1.73 m2. Microalbuminuria will be defined as two positive tests from three samples taken within 1 year, with an albumin/creatinine ratio of 3-30 mg/mmol (~30-300 mg/g) or U-albumin of 20-200 μg/ min (20-300 mg/L), and macroalbuminuria as albumin/creatinine ratio >30 mg/mmol (~>300 mg/g) or U-albumin >200 μg/ min (>300 mg/L)[4]. Physical activity is recorded as never, <1 time/week, 1-2 times/week, 3-5 times/week, or daily. Individuals with physical activity >1 time/week will be defined as having regular physical activity. We will obtain information on use of anti-hypertensive drugs (ATC codes: C02, C03, C04, C07, C08, C09) and statins (ATC codes: C10A, C10B) from NPDR. Information on insulin regimens (insulin pump or short-acting insulin combined with long-acting insulin) will be retrieved from NDR and NPDR.