Two‐Year Trajectories of DIAL2 ‐Predicted Cardiovascular Risk After Initiation of Semaglutide, Empagliflozin or Their Combination: The DIAL ‐ STEP Study

ABSTRACT Aims To describe observed clinical changes and trajectories of DIAL2‐predicted cardiovascular risk during 24 months of oral semaglutide, empagliflozin or combination treatment. Materials and Methods This retrospective cohort included 332 adults without prior cardiovascular disease (semaglutide, 139; empagliflozin, 106; combination, 87). The primary endpoint was the investigator‐defined HIGH category (calculated 1‐year risk ≥ 3%); continuous risk was secondary. Generalized estimating equations and linear mixed models assessed trajectories. Sensitivity models added baseline age, sex and their time interactions or baseline predicted risk. Age‐fixed and Shapley calculations were exploratory. Results Paired 24‐month changes included HbA1c −1.13 percentage points (95% CI: −1.27 to −1.00), systolic blood pressure −7.64 mmHg (−9.48 to −5.79), total cholesterol −20.28 mg/dL (−23.84 to −16.73) and weight −3.91 kg (−4.40 to −3.41). Standard DIAL2 was valid for 329, 327 and 325 participants across visits. HIGH prevalence was 24.6%, 23.2% and 23.7%, without a time‐by‐treatment interaction ( p = 0.731). The continuous‐risk interaction was significant ( p = 0.002; demographic‐time‐adjusted p = 0.006). In 324 complete cases, standard predicted risk changed from 2.172% to 2.052% (relative change −5.5%); holding age fixed yielded 1.777% at 24 months (−18.2%). These relative changes concern calculated probabilities. Conclusions Glycaemia and several other measured risk factors improved during follow‐up. Categorical DIAL2 status remained broadly stable, while continuous estimates varied with risk‐factor changes and chronological age. Repeated DIAL2 and its explanatory decompositions do not establish fewer cardiovascular events or superiority of a treatment strategy.