Changes in Cardiovascular Risk Factors After Protocolized Adherence Reinforcement and Treatment Optimization: Results...

Background: Despite evidence-based guidelines for cardiovascular risk management, many patients fail to achieve therapeutic targets. The relative contribution of medication non-adherence versus suboptimal treatment optimization to poor cardiovascular outcomes remains unclear in real-world primary care settings. The aim of this study was to describe changes in cardiovascular risk factor control following protocolized adherence reinforcement combined with physician-driven treatment optimization in high-risk patients. Methods: This multicenter, real-world longitudinal study included 789 participants with high or very high cardiovascular risk enrolled from primary care settings across 9 Spanish regions between 2023 and 2025. All participants received a protocolized intervention combining adherence reinforcement and physician-driven treatment optimization. This was a single-arm, pre-post study without a concurrent control group; observed changes therefore cannot be attributed to the intervention alone. Of 789 participants screened, all completed the baseline assessment, and 628 (79.6%) completed the 90-day follow-up. A total of 161 participants (20.4%) were lost to follow-up. Primary outcomes included changes in systolic and diastolic blood pressure, lipid parameters (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], triglycerides [TG]), glucose, glycated hemoglobin (HbA1c), and body mass index (BMI) from baseline to 90-day follow-up. Changes were assessed using linear mixed models. Results: Among participants with complete paired data (n = 453-615 depending on the outcome), significant improvements were observed in most cardiovascular risk factors (HDL-c and HbA1c did not change significantly). Mean changes (95% confidence interval [CI]) were: systolic blood pressure, -9.24 mmHg (-10.41 to -8.06; p < 0.001); diastolic blood pressure, -4.75 mmHg (-5.49 to -4.01; p < 0.001); LDL-c, -22.29 mg/dL (-25.59 to -19.00; p < 0.001); TC, -23.24 mg/dL (-26.73 to -19.74; p < 0.001); TG, -16.75 mg/dL (-23.03 to -10.46; p < 0.001); fasting plasma glucose, -10.03 mg/dL (-12.61 to -7.46; p < 0.001); and BMI, -0.46 kg/m² (-0.58 to -0.35; p < 0.001). Linear mixed models including all available data (n = 628 at 90-day follow-up) confirmed these findings. No significant interactions were observed between assessment timepoint and sex, age, or overweight/obesity status for most outcomes, except for age-related differences in lipid responses. Conclusions: Protocolized adherence reinforcement combined with physician-driven treatment optimization was associated with clinically meaningful improvements in multiple cardiovascular risk factors in high-risk primary care patients. Given the single-arm pre-post design, the observed improvements are associative and cannot establish causality. Residual uncontrolled risk, particularly in lipid management and among older adults, persisted despite active treatment optimization (treatment was modified in 82.0% of participants), consistent with residual suboptimal treatment intensification even after adherence had been reinforced. These findings suggest that achieving optimal cardiovascular risk factor control requires addressing both medication adherence and treatment intensification, particularly in patients with multimorbidity.