Editorial: Residual cardiovascular risk in diabetes: current state and future perspectives

million annual deaths attributable to diabetes, identifying novel biomarkers for broader risk stratification and the pursuit of agents with pleiotropic properties capable of addressing pathways untouched by conventional risk-factor control have emerged as a critical priority. 3 This research topic includes clinical evidence and mechanistic insights to advance understanding and clarify translational opportunities relevant to cardiometabolic care. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have reshaped the landscape of diabetes care in recent years. 4 Though initially designed for glucose-lowering, robust randomized trials have demonstrated one-third consistent risk reductions in major cardiovascular events including cardiovascular death, all-cause mortality and hospitalization for heart failure. 4 Gliflozins have also prevented kidney function decline and the progression of proteinuria in chronic kidney disease populations, thereby mitigating the burden of diabetic kidney disease and kidney failure. 4 With population-level projections of 5-year rescue of life expectancy, the clinical benefit of this class beyond glycemic control includes weight loss and improvements in myocardial function and fluid balance. 5 As a valuable addition to this remarkable cardiorenal benefit, gliflozins promote sustained blood pressure reduction that, though modest compared with antihypertensive agents, has been recognized as a potential adjunct therapy for management of hypertension. 6 Blood pressure lowering in this context emerges from intricate mechanisms encompassing neurohormonal effects, insulin resistance, osmotic diuresis, and gene polymorphisms. 7 These mechanisms and the role of gliflozins in reducing residual risk through blood pressure lowering are reviewed in this issue. Timely identification of high-risk patients using standardized cardiovascular risk equations based on traditional predictors has been a cornerstone strategy of preventive cardiology. 8 Incorporating novel residual risk biomarkers permits discriminatory power and reclassification capacity refinements through broader assessment of systemic vulnerability to cardiovascular disease. 8,9 Glycated hemoglobin has been the most utilized metabolic stress biomarker in type 2 diabetes showing a graded association with diabetes-related complications. 10 This metric has nonetheless limited capacity to capture glycemic variability, which has incremental prognostic value compared to glycated hemoglobin by reflecting patients physiologic response to acute metabolic stress beyond chronic glycemic control. 11 In this issue, Lian et al contribute to this evolving concept by demonstrating an independent association of stress hyperglycemia ratio, hereby calculated diving post-cardiac arrest glycemia by glycated hemoglobin, with 1-year mortality rates using data from 535 intensive care unit patients enrolled in the MIMIC-IV database. This research topic also presents the results of Kong et al retrospective single-cohort of 201 adults with type 2 diabetes who completed flow-mediated dilation (FMD) and serum soluble TREM-1 (sTREM-1) levels assessments. sTREM-1, a myeloid innate immunity receptor linked to lowgrade lasting vascular inflammation, was independently associated with lower FMD, thereby suggesting the interplay between this reliable marker of residual inflammatory risk and endothelial dysfunction.Diabetes care guidelines endorse structured interdisciplinary lifestyle programs for broad metabolic risk lowering beyond goal-directed pharmacotherapy. 8 This recommendation is grounded by randomized clinical trial (eg., Look-AHEAD study) evidence of sustained improvements in glycemic control, lipid profile, body weight, and overall quality of life and fitness with healthier diets, diabetes education, and physicial activity. 12,13 Emerging evidence supports that replacing saturated fats with dietary polyunsaturated fats (PUFA) could improve residual cardiometabolic risk attributable to nutritional factors with established effects on cholesterol levels, gut microbiota, and liver steatosis.