Cardiorespiratory Fitness in Adolescence and Risk of Type 2 Diabetes in Late Adulthood: A Nationwide Sibling-Controlled Cohort Study.

Background: The importance of adolescent cardiorespiratory fitness for long-term risk of type 2 diabetes (T2D) remains poorly investigated, and whether the association is influenced by unobserved familial confounding is unknown. Methods: We conducted a sibling-controlled cohort study based on all Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 around the age of 18, and who completed standardized cardiorespiratory fitness testing. The outcome was T2D, defined as a composite endpoint of diagnosis in inpatient or specialist outpatient care, or dispensation of antidiabetic medication, until 31 December 2023. Findings: 1 124 049 men, of which 477 453 were full siblings, with a mean age of 18.3 years at baseline were included. During follow-up, 115 958 men (48 089 full siblings) experienced a first T2D event at a median age of 53.4 years. Compared to the first decile of fitness, higher fitness levels were associated with a progressively lower risk of T2D. In cohort analysis, the hazard ratio (HR) in the second decile was 0.83 (95% CI, 0.81 to 0.85), with a difference in the standardized cumulative incidence at age 65 of 4.3 (3.8 to 4.8) percentage points, dropping to a HR of 0.38 (0.36 to 0.39; incidence difference 17.8 [17.3 to 18.3] percentage points) in the tenth decile. When comparing full siblings, and thus controlling for all unobserved behavioral, environmental, and genetic confounders that they share, the association replicated, although with attenuation in magnitude. The HR in the second decile was 0.89 (0.85 to 0.94; incidence difference 2.3 [1.3 to 3.3] percentage points), and in the tenth decile it was 0.53 (0.50 to 0.57; incidence difference 10.9 [9.7 to 12.1] percentage points). Hypothetically shifting everyone in the first decile of fitness to the second decile was estimated to prevent 7.2% (6.4 to 8.0) of cases at age 65 in cohort vs. 4.6% (2.6 to 6.5) in full-sibling analysis. The association was similar in those with overweight as in those without. Interpretation: Higher levels of adolescent cardiorespiratory fitness are associated with lower risk of T2D in late adulthood, with clinically relevant associations starting already from very low levels of fitness, and similarly in those with overweight compared to those without. The association replicates, but becomes weaker, after adjusting for unobserved familial confounders shared between full siblings. This suggests that adolescent cardiorespiratory fitness is a robust marker of long-term T2D risk, but that conventional observational analysis may yield biased estimates.