Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1) promote weight loss, improve diabetes, and reduce cardiovascular events in obesity. While physical activity (PA) should be integral to weight loss interventions, the effectiveness of GLP-1, with weight loss in the range of 15-20%, may remove incentives to exercise. Cardiorespiratory fitness (fitness), a marker of habitual PA and health outcomes, may increase with weight loss. GLP-1 effects on PA and fitness are not clear. Thus, in a preventive medicine cohort, the question of whether GLP-1 use is associated with changes in fitness was evaluated. Methods: A cohort of 205 generally healthy men and women reported leisure-time PA and completed treadmill exercise testing to estimate fitness before and during GLP-1 use (+GLP-1), 2009-2024. A similar cohort of 10,903 men and women did not report GLP-1 use (-GLP-1) in the same period. A repeated measures growth model provided estimates of the group difference in fitness changes adjusted for sex, age, time between visits, PA, and weight. Results: Before treatment in +GLP-1, 89% were overweight/obese, 19% were diabetic, and 1% had prior cardiovascular events (versus 64%, 2%, and 1% in -GLP-1). The mean (SD) baseline age was 52.0 (8.5) years in +GLP-1 and 52.3 (9.7) in -GLP-1. In +GLP-1, the mean follow-up was 2.6 years (versus 2.5 in -GLP-1). Mean body mass index decreased 2.1 kg/m2 in +GLP-1 versus no significant change in -GLP-1. Mean glucose also decreased in +GLP-1 (from 108.4 mg/dL to 97.5 mg/dL, p<0.001) but no change in -GLP-1. Mean PA was largely unchanged in both groups (+50 versus +30 MET-minutes/week, p=0.8). Mean unadjusted fitness was stable at 9.1 METs in +GLP-1, p=0.5, and decreased from 11.0 to 10.7 METs in -GLP-1, p<0.001 (group difference in changes p<0.001). Results were similar when adjusted for sex, age, time between visits, and PA changes. However, when also adjusted for weight change, mean fitness fell 0.5 METs in +GLP-1 versus 0.2 METs in -GLP-1, p<0.001. Fitness increased less in +GLP-1 than in -GLP-1 whether weight was lost or gained. Conclusions: Fitness changes in +GLP-1 were largely mediated by weight loss. While GLP-1 use was associated with greater weight loss, fitness outcomes were worse in +GLP-1 than in -GLP-1 with similar weight changes. Healthcare providers should prescribe and monitor PA along with GLP-1 receptor agonists, as tolerated by patient’s overall status, to improve weight loss and fitness.

Introduction: Dysfunction of the autonomic nervous system—which regulates involuntary physiological functions throughout the body such as heart rate—increases the risk of cardiovascular disease (CVD) and CVD-related mortality. The health implications of autonomic dysfunction may also extend beyond CVD, including to cancer outcomes, although these associations are less well-understood. Methods: We studied a prospective cohort of healthy adults in the Cooper Center Longitudinal Study who completed a preventive medicine exam, which included assessment of heart rate and blood pressure before, during, and after a maximal treadmill test. We examined the associations between multiple established markers of autonomic dysfunction—resting heart rate, heart rate recovery at 1-, 2- and 5-minutes, heart rate reserve, and systolic blood pressure [SBP] response to exercise—with all-site and site-specific cancer mortality (lung, prostate, pancreas, colorectal) ascertained through the National Death Index. Gompertz mortality models were used to estimate the associations between each marker of autonomic dysfunction and cancer mortality, adjusted for demographic and health-related variables. Analyses were sex-stratified when a significant sex interaction was present. Results: Among 75,222 participants (26.8% women), 3853 cancer deaths (644 among women) were identified during a median follow-up of 21.9 years. Each marker of autonomic dysfunction was related to higher cancer mortality risk, including: higher resting heart among men (hazard ratio [HR] per 10 beats per minute [bpm]: 1.04; 95% CI: 1.01, 1.08), though not women; slower heart rate recovery among men and women combined (e.g., at 5-minutes, HR per 10 bpm slower recovery: 1.06; 95% CI: 1.03, 1.09); lower heart rate reserve among men and women combined (HR per 10% lower reserve: 1.05; 95% CI: 1.02, 1.07); and higher SBP response among men (HR per 10 mmHg: 1.02; 95% CI: 1.00, 1.04) and women (HR per 10 mmHg: 1.06; 95% CI: 1.01, 1.10). Slower heart rate recovery, lower heart rate reserve, and higher SBP response were similarly associated with increased lung cancer mortality (687 deaths). No other site-specific associations were statistically significant. Conclusions: Multiple non-invasive markers of autonomic function routinely obtained during exercise testing were related to the risk of cancer mortality in healthy adults. Autonomic dysfunction may represent an early marker linking cardiovascular health with cancer risk.

Introduction: Cardiorespiratory fitness (CRF) and coronary artery calcium (CAC) score, both established cardiovascular risk markers, may be interrelated; however, their individual and joint associations with dementia risk remain unclear. We examined midlife CRF and CAC in relation to later-life dementia in a large prospective cohort. Methods: Individual participant data from the Cooper Center Longitudinal Study (CCLS; 1998–2018) were linked to Medicare claims records (1999–2019). CAC was measured by cardiac computed tomography and dichotomized as <100 or ≥100 Agatston units (AU). CRF was estimated using a maximal treadmill exercise test following a modified Balke protocol. Participants were categorized into low, moderate, or high CRF based on age- and sex-specific cutoffs. Incident all-cause dementia was identified via Medicare surveillance using the Chronic Condition Warehouse. Pertinent participant characteristics were assessed at the baseline clinic visit, and stroke or transient ischemic attack (TIA) during follow-up was recorded as an interim event. Illness-death models with semi-competing risks were used to estimate hazard ratios for dementia associated with CAC and CRF categories, adjusting for demographic and clinical covariates. Results: Participants free of cardiovascular disease and dementia with complete exposure and outcome data were analyzed [n=11,259; mean (SD) baseline age, 56.8 (7.0) years; 3,400 (30.2%) women]. The prevalence of clinically-meaningful CAC (≥100 AU) decreased across CRF categories, from 34.4% in the low CRF group to 29.6% in the moderate group and 26.8% in the high CRF group. The mean (SD) time between the clinic visit and the start of Medicare surveillance was 8.6 (5.6) years. During a mean (SD) Medicare follow-up of 6.7 (5.0) years, 923 cases of dementia were identified. Higher CRF was associated with a lower risk of dementia, whereas higher CAC was associated with a higher risk. These associations persisted across models with hierarchical adjustment for demographics, cardiovascular risk factors, interim stroke/TIA, and the other primary exposure (CAC or CRF; see Table). Conclusions: In this cohort of generally healthy adults, higher CRF and lower CAC in midlife were associated with a reduced risk of later-life dementia. These associations were independent of traditional cardiovascular risk factors and interim cerebrovascular events, highlighting the potential importance of fitness and vascular health in dementia prevention.

Introduction: Delaying the onset of disease so that morbidity is compressed into a shorter period before death can improve quality of life and lower healthcare costs. Cardiorespiratory fitness (CRF) is one of the strongest known predictors of health, but its association with morbidity compression is unclear. Methods: We examined whether higher CRF in midlife is associated with morbidity compression and life extension (i.e., living a longer, healthier life) among older adults. The sample included 26,237 Cooper Center Longitudinal Study participants (n=19,569 men; n=6,668 women) who had CRF estimated via maximal treadmill test at a mean age of 48.5 (SD: 9.7) years and were later enrolled in Medicare. Participants were healthy through age 66.5 years. Morbidity was defined as incidence of any of the following 11 chronic conditions identified from the Chronic Condition Warehouse: heart failure, ischemic heart disease, stroke, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, dementia, or colorectal, lung, breast, or prostate cancer. Illness-death models were used to estimate the likelihood of transitioning between states of health, morbidity, and death by relative CRF, categorized as low (quintile 1), moderate (quintiles 2-3), or high (quintiles 4-5) based on age- and sex-specific distributions. Sex-stratified models adjusted for year of birth, age, smoking, BMI, fasting glucose, cholesterol, and blood pressure. Model parameters were used to estimate Aalen-Johansen state probabilities, and simulated Markov chains were used to calculate expected occupancy times in each state up to age 100. Results: Among men, high (vs. low) CRF was associated with postponement of morbidity (HR: 0.78, 95% CI: 0.72, 0.84) and death after morbidity (HR: 0.61, 95% CI: 0.54, 0.69). Among women, high (vs. low) CRF was similarly associated with postponement of morbidity (HR: 0.83, 95% CI: 0.73, 0.94) but not death after morbidity (HR: 0.85, 95% CI: 0.67, 1.09). On average, participants with high (vs. low) CRF developed morbidity 1.0 (women) – 1.1 (men) years later and had longer life expectancies (women: age 89.5 vs. 88.1; men: age 87.0 vs. 84.6) ( Figure ). Conclusions: High CRF at midlife was associated with a roughly 1-year extension of healthy life and a 1.4-2.4-year extension of total life expectancy. Interventions that improve CRF through lifestyle behaviors may contribute to meeting AHA’s 2030 Impact Goal of increasing healthy life expectancy by two years.

Background: While physical activity (PA) is associated with a lower risk of atrial fibrillation (AF), prior studies have observed a higher prevalence of AF among athletes. Therefore, we sought to characterize the association between PA and the risk for AF in a large cohort of healthy adults with relatively high levels of self-reported leisure time PA levels. Methods: Individual participant data from the Cooper Center Longitudinal Study were linked to Medicare administrative claims files. PA volume (MET-min/wk), duration of moderate (< 6 METs), and duration of vigorous PA (≥ 6 METs) PA were measured by self-report at study entry. Other risk factors such as age, current smoking status, weekly alcohol consumption, BMI, blood glucose, systolic blood pressure, and cholesterol were measured using a standard approach. AF was identified using Medicare claims. A proportional hazards illness-death model was used to estimate hazard ratios for incident atrial fibrillation and multivariable-adjusted for all measured baseline covariates.PA was evaluated as an ordinal variable (< 500, 500-1499, 1500-3000, and ≥ 3,000 MET-min/week). In analyses for subtype of activity, moderate and vigorous activity were mutually adjusted and evaluated as a continuous covariate (per hour). Results: We included 26,549 participants (71.9% men, mean age 54 years at baseline), who received Medicare coverage from 1999 to 2019. After 195,343 person-years of Medicare follow-up time, we observed 3,939 cases of AF. Higher PA was associated with a modest increase in the risk for AF above 1,500 MET-min/week, but with less precision at PA above 3,000 MET-min/week (Figure 1). We also observed vigorous activity, but not moderate activity, was associated with higher risk of AF (Figure 2). Conclusion: After accounting for covariates, higher PA volume was associated with increased risk of AF at doses more than 3x the guideline-recommended amount. These associations appear to be more apparent for vigorous exercise intensity.