Cardiorespiratory fitness in adolescence and risk of type 2 diabetes in late adulthood in one million Swedish men: nationwide sibling controlled cohort study

Abstract

Objective: To examine the association between adolescent cardiorespiratory fitness and risk of type 2 diabetes in late adulthood, including the potential influence of unobserved familial confounding on the association.

Design: Nationwide sibling controlled cohort study.

Setting: Swedish Military Service Conscription Register, Sweden, 1972-95, with Multi-Generation Register for identifying full siblings. National Patient Register and Prescribed Drug Register for data on diagnoses of type 2 diabetes, deaths from National Cause of Death Register, and Statistics Sweden for emigration and socioeconomic data.

Participants: 1 124 049 Swedish men who participated in mandatory military conscription examinations with completed standardised cardiorespiratory fitness testing. Participants were followed up until 31 December 2023.

Main outcome measures: Type 2 diabetes, defined as a composite endpoint of diagnosis in inpatient or specialist outpatient care and dispensation of antidiabetic drug treatment, until 31 December 2023.

Results: 1 124 049 men, including 477 453 full siblings, with a mean age of 18.3 (standard deviation 0.7) years at baseline were included. During follow-up, 115 958 men (10.3%) and 48 089 full siblings (10.1%) had a first type 2 diabetes event at a median age of 53.4 (interquartile range 47.6-59.3) years. Cardiorespiratory fitness was categorised into deciles (referred to as groups, with group 1 being the lowest fitness level and group 10 the highest). In a cohort analysis, the adjusted hazard ratio in fitness group 2 versus fitness group 1 was 0.83 (95% confidence interval (CI) 0.81 to 0.85), with a difference in the standardised cumulative incidence at age 65 years of 4.3 (95% CI 3.8 to 4.8) percentage points, decreasing to a hazard ratio of 0.38 (0.36 to 0.39; incidence difference 17.8 (17.3 to 18.3) percentage points) in fitness group 10. When comparing full siblings, and thus controlling for all unobserved shared behavioural, environmental, and genetic confounders, the association was replicated, but with a reduction in magnitude. The hazard ratio in fitness group 2 was 0.89 (95% CI 0.85 to 0.94; incidence difference 2.3 (1.3 to 3.3) percentage points) and 0.53 (0.50 to 0.57; incidence difference 10.9 (9.7 to 12.1) percentage points) in fitness group 10. Hypothetically moving all participants in fitness group 1 to fitness group 2 was estimated to prevent 7.2% (95% CI 6.4% to 8.0%) of events at age 65 years in the cohort analysis versus 4.6% (2.6% to 6.5%) in the full sibling analysis, whereas hypothetically moving all participants to fitness group 10 was estimated to prevent 35.6% (34.1% to 37.0%) versus 24.3% (20.5 to 28.0) of events. Indications of effect modification by overweight status were found, where the association was smaller in those with overweight than in those without overweight, particularly in the full sibling analysis.

Conclusions: The findings indicate that adolescent cardiorespiratory fitness could be important in the development of type 2 diabetes in late adulthood, but conventional observational analysis might give biased estimates of the magnitude of the effect.

Keywords: Diabetes mellitus; Endocrinology; Epidemiology; Preventive medicine; Public health; Sports medicine.

Figure 1. Hazard ratio for type 2 diabetes across restricted cubic splines of cardiorespiratory fitness in the cohort and full sibling analyses. Estimates were obtained with flexible parametric survival models, extended to a marginalised between-within model in the full sibling cohort, with baseline knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th centiles of the uncensored log survival times, and with age as the underlying timescale. The knots for the splines of fitness were placed at the 5th, 35th, 65th, and 95th centiles. The referent was set to the median value of fitness group 1 (202 watt max). The models were adjusted for age at conscription, year of conscription, body mass index, parental education, and parental income. For graphical purposes, the x axis was limited to span from the first to the 99th centile of the exposure distribution. CI=confidence interval

Figure 2. Standardised cumulative incidence of type 2 diabetes for the whole follow-up period by levels of cardiorespiratory fitness in the cohort and full sibling analyses. Cardiorespiratory fitness was categorised into deciles (referred to as groups, with group 1 being the lowest fitness level and group 10 the highest). Estimates were obtained with flexible parametric survival models, extended to a marginalised between-within model in the full sibling cohort, with baseline knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th centiles of the uncensored log survival times, and with age as the underlying timescale. All models were adjusted for age at conscription, year of conscription, body mass index, parental education, and parental income. Confidence intervals were omitted for clarity because they are shown in figure 3, as well as in figure 1 and table 2

Figure 3. Difference in standardised cumulative incidence of type 2 diabetes at age 65 years by levels of cardiorespiratory fitness in the cohort and full sibling analyses. Cardiorespiratory fitness was categorised into deciles (referred to groups, with group 1 being the lowest fitness level and group 10 the highest). Estimates were obtained with flexible parametric survival models, extended to a marginalised between-within model in the full sibling cohort, with baseline knots placed at the 5th, 27.5th, 50th, 72.5th, and 95th centiles of the uncensored log survival times, and with age as the underlying timescale. Fitness group 1 (lowest fitness) was the referent. Values in parentheses show the median fitness in each group. All models were adjusted for age at conscription, year of conscription, body mass index, parental education, and parental income

Figure 4. Post-estimated hazard ratio for type 2 diabetes across restricted cubic splines of cardiorespiratory fitness within strata of overweight status in the cohort and full sibling analyses. Estimates were obtained with flexible parametric survival models, extended to a marginalised between-within model in the full sibling cohort, in the total sample, and subsequently post-estimated within strata of overweight status using standardisation (G formula). Baseline knots were placed at the 5th, 27.5th, 50th, 72.5th, and 95th centiles of the uncensored log survival times, and with age as the underlying timescale. The knots for the splines of fitness were placed at the 5th, 35th, 65th, and 95th centiles. The referent was set to the median value of fitness group 1 (202 Wmax). The models were adjusted for age at conscription, year of conscription, parental education, parental income, overweight status, and product terms between overweight status and fitness groups. For graphical purposes, the x axis was limited to span from the first to the 99th centile of the exposure distribution. CI=confidence interval