Citations

Introduction: Seasonal, geographic, and socioeconomic factors all influence cardiovascular (CV) mortality. Long-term seasonal trends across United States regions remain insufficiently characterized. Research Question: We evaluated longitudinal trends in CV mortality across seasons in the U.S., stratified by geographic region and degree of urbanisation, from 1999 through 2020. Methods: Data on CV mortality (ICD-10: I00-I99) were extracted from the CDC WONDER database and stratified by season (Winter, Spring, Summer, Fall), U.S. Census region (Northeast, Midwest, South, West), and degree of urbanisation (6-level National Center for Health Statistics classification). Age-adjusted mortality rates (AAMRs) were calculated, and Joinpoint regression was used to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals. Results: From 1999 to 2020, 18.8 million CV deaths were recorded (Table 1). Winter accounted for the highest mortality burden across all regions and urban settings but also showed the greatest improvement of the the 20-year study period, with AAPC reductions most pronounced in the Northeast (–2.83%) and Large Central Metro areas (–2.79%; p < 0.000001 for all trends; Figure 1). Summer and Fall, while associated with fewer deaths, showed slower progress, particularly in the Midwest (Fall AAPC: –1.81%; Summer: –1.77%) and rural areas (NonMetro Fall AAPC: –1.56%). Notably, Midwest Fall mortality demonstrated a statistically significant reversal, with an APC increase of +3.87% from 2018 to 2020 (p = 0.02)(Figure 1). Conclusion: CV mortality in the U.S. follows a distinct and evolving seasonal pattern. Although winter remains the deadliest season, it has seen the most substantial mortality reductions, likely tied to improved awareness, continuity of care, and cold-weather adaptations. However, slower progress during summer and fall, particularly in the Midwest and rural areas, reveals growing seasonal and geographic disparities. Most notably, the recent and statistically significant rise in Midwest fall mortality signals an urgent concern. This reversal may reflect emerging climate stressors such as prolonged heat, air pollution, and environmental volatility during transitional months compounded by reduced healthcare access or changing behavioral risk factors. These findings call for year-round, seasonally tailored public health strategies especially for underserved and climate-vulnerable populations.

Cardiovascular–Kidney–Metabolic (CKM) syndrome symbolizes a single pathophysiologic entity including obesity, type 2 diabetes, chronic kidney disease, and cardiovascular disease. These conditions altogether accelerate adverse outcomes when they coexist. Recent evidence has shown that the function of glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter-2 inhibitors (SGLT2i) alleviate stress on multiple organs. SGLT2i has been demonstrated to benefit heart failure, hemodynamic regulation, and renal protection while GLP-1RA on the other hand has been shown to demonstrate a strong impact on glycemic management, weight loss, and atherosclerotic cardiovascular disease. This review will aim to understand and evaluate the mechanistic rationalization, clinical evidence, and the potential therapeutic treatment of SGLT2 inhibitors and GLP-1 receptor agonists to treat individuals who have CKM syndrome. This analysis also assesses whether combination therapy can be a synergistic approach that may benefit patients but is still underutilized because of the lack of clear guidelines, the associated costs, and disparities in accessibility. Therefore, in this review, we will be discussing the combination therapy’s additive and synergistic effects, current recommendations and clinical evidence, and mechanistic insights of these GLT2 inhibitors and GLP-1 receptor agonists in CKM syndrome patients. Overall, early and combination usage of GLP-1RA and SGLT2i may be essential to demonstrating a significant shift in modern cardiometabolic therapy toward patient-centered care.