Search

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for the treatment of type 2 diabetes but have recently been approved for chronic weight management and reducing cardiovascular risk in individuals with overweight and obesity. Despite this approval, significant heterogeneity in the cardioprotective benefits and less desirable increases in resting heart rate (RHR) with GLP-1 RAs have been reported. To better understand cardiovascular responses to GLP-1 RAs and the potential role of health behaviors in influencing these responses, we leveraged wearable technology and causal inference analysis. We tracked RHR, heart rate variability (HRV), physical activity, and sleep in 66 individuals (42 ± 9 yr, body mass index: 30.0 ± 7 kg/m 2 ) from the week before to 12 wk following the initiation of GLP-1 RA medication. Propensity score matching on a larger sample of wearable users identified a control group with similar anthropometric and cardiovascular characteristics ( P s > 0.26). After the 12-wk study period, GLP-1 users showed significant ( P s < 0.05) weight loss (-10.0%, 95% CI: -11.2% to -8.5%) and changes in RHR (3.2 ± 0.8 beats/min) that were mediated ( P < 0.01) by changes in HRV (-6.2 ± 1.4 ms) compared with control. Trends ( P s < 0.10) suggested that increases in weekly physical activity were associated with GLP-1 RA medication (31.5 ± 13.2 min) and that higher physical activity levels accompanied an attenuation of RHR increases. Our real-world findings align with clinical trial data in showing rapid and significant weight loss with GLP-1 RAs, coinciding with increases in RHR that are mediated by changes in autonomic function (i.e., HRV). Physical activity may help to offset RHR increases, but further research is needed to confirm these effects. NEW & NOTEWORTHY These findings are among the first to provide daily insights into cardiovascular and behavioral responses following GLP-1 RA initiation. Substantial weight loss and significant increases in resting heart rate mediated by reductions in heart rate variability during the initial 12 wk of GLP-1 RA therapy were observed. In addition, trends suggest an increase in physical activity with GLP-1 therapy, and that physical activity may help to temper GLP-1 RA-associated increases in resting heart rate.

Viral infections are characterized by dispersal from an initial site to secondary locations within the host. How the resultant spatial heterogeneity shapes within-host genetic diversity and viral evolutionary pathways is poorly understood. Here, we show that virus dispersal within and between the nasal cavity and trachea maintains diversity and is therefore conducive to adaptive evolution, whereas dispersal to the lungs gives rise to population heterogeneity. We infected ferrets either intranasally or by aerosol with a barcoded influenza A/California/07/2009 (H1N1) virus. At 1, 2, or 4 days postinfection, dispersal was assessed by collecting 52 samples from throughout the respiratory tract of each animal. Irrespective of inoculation route, barcode compositions across the nasal turbinates and trachea were similar and highly diverse, revealing little constraint on the establishment of infection in the nasal cavity and descent through the trachea. Conversely, infection of the lungs produced genetically distinct viral populations. Lung populations were pauci-clonal, suggesting that each seeded location received relatively few viral genotypes. While aerosol inoculation gave distinct populations at every lung site sampled, within-host dispersal after intranasal inoculation produced larger patches, indicative of local expansion following seeding of the lungs. Throughout the respiratory tract, barcode diversity declined over time, but new diversity was generated through mutation. De novo variants were often unique to a given location, indicating that localized replication following dispersal resulted in population divergence. In summary, dispersal within the respiratory tract operates differently between regions and contributes to the potential for viral evolution to proceed independently in multiple within-host subpopulations., Competing Interests: Competing interests statement:The authors declare no competing interest.