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

BackgroundThe 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. MethodsWe 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. Findings1 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. InterpretationHigher 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. FundingNone. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSType 2 diabetes is a growing public health issue, affecting at least half a billion people globally. Modifiable factors such as physical activity and the closely related trait cardiorespiratory fitness, which are inversely associated with type 2 diabetes, are declining, particularly among youth. Since these traits track from youth into adulthood, early-life interventions might have important implications for prevention. However, previous studies have typically focused on middle-aged individuals, leaving gaps in understanding whether fitness in youth is associated with type 2 diabetes in the long-term. Moreover, they have not been designed to adequately account for unobserved confounders. Triangulating the evidence across different methods, such as using sibling comparison analysis, would be important to obtain more accurate and reliable estimates of the causal relationship. Added value of this studyIn this nationwide sibling-controlled cohort study encompassing more than 1 million young men, of which half a million were full siblings, higher levels of adolescent cardiorespiratory fitness were associated with a substantially lower risk of developing type 2 diabetes up to five decades later. The association was clinically relevant already from low levels of fitness, and it appeared similar in those with overweight as in those without overweight. While the association replicated after adjusting for unobserved familial confounders shared between full siblings, the magnitude of association attenuated by an amount that appeared clinically relevant. For example, the incidence differences between deciles of fitness were about 40% smaller in sibling-comparison analyses as compared to cohort analysis, and the preventable share of type 2 diabetes associated with hypothetical interventions shifting the population-level of fitness was reduced by about one-third. Implications of all the available evidenceAdolescent cardiorespiratory fitness is a strong marker of long-term risk of type 2 diabetes, both in those with and without overweight. These findings render support to large-scale surveillance of fitness from a prevention perspective, and if the findings are confirmed using other lines of causal analysis, they may render support to interventions targeting fitness already from a young age. Yet, these findings also highlight the importance of triangulation for obtaining more reliable evidence of the magnitude of association, and shed light on the pitfalls of conventional observational analysis which may yield biased estimates.