Lipid Management Gaps in Mexican Patients at High and Very High Cardiovascular Risk (SANTORINI-MX)

Adults aged 18 years or older classified as having high or very high cardiovascular risk according to the 2019 ESC/EAS guidelines, who are receiving or have a clinical indication for lipid-lowering therapy. Participants will be consecutively enrolled at participating healthcare centers in Mexico and assessed at baseline and after 12 ± 2 months. Lipid levels, cardiovascular risk factors, lipid-lowering treatments, treatment intensification, medication adherence, and barriers to optimal lipid management will be recorded. All treatments will be prescribed according to routine clinical practice, without protocol-assigned interventions.

Lipid-lowering medications prescribed as part of routine clinical care, including statins, ezetimibe, PCSK9 inhibitors, inclisiran, bempedoic acid, fibrates, and omega-3 fatty acids. Medication class, dose, treatment intensity, combinations, and changes during follow-up will be documented. Treatment decisions will be made exclusively by the treating physicians. No medication will be assigned, administered, or modified by the study protocol.

The percentage of participants achieving low-density lipoprotein cholesterol (LDL-C) targets according to their cardiovascular risk category, as defined by the 2019 ESC/EAS guidelines: LDL-C below 70 mg/dL for high-risk participants and below 55 mg/dL for very-high-risk participants. The numerator will be the number of participants achieving their corresponding risk-based LDL-C target, and the denominator will be the number of evaluable participants with baseline LDL-C data. Results will be reported overall and stratified by cardiovascular risk category, with 95% confidence intervals.

Percentage of participants achieving their cardiovascular risk-based LDL-C goals at follow-up, defined according to the 2019 ESC/EAS guidelines as LDL-C below 70 mg/dL for high-risk patients and below 55 mg/dL for very-high-risk patients. The numerator will include participants achieving their respective LDL-C target, and the denominator will include participants with an evaluable follow-up LDL-C measurement. Results will be reported overall and stratified by cardiovascular risk category, with 95% confidence intervals.

Number and percentage of participants receiving each lipid-lowering therapy class, including statins, ezetimibe, PCSK9 inhibitors, inclisiran, bempedoic acid, fibrates, and omega-3 fatty acids. Statin intensity (low, moderate, or high) and use of combination therapies will be described at baseline and follow-up.

Percentage of participants undergoing lipid-lowering treatment intensification during follow-up, defined as an increase in statin intensity, addition of another lipid-lowering agent, initiation of advanced lipid-lowering therapy, or escalation to combination treatment. Types and reasons for intensification will be described.

Clinical inertia will be assessed as a single binary outcome (yes/no) among participants with LDL-C levels above their cardiovascular risk-based treatment targets according to the 2019 ESC/EAS guidelines. It will be defined as the absence of lipid-lowering treatment intensification during follow-up.

Treatment intensification includes an increase in statin intensity, initiation of ezetimibe, or initiation of advanced lipid-lowering therapy. These criteria will be combined to classify each participant as having or not having clinical inertia, rather than being reported separately.

The outcome will be expressed as the percentage of evaluable participants with LDL-C above their treatment targets who do not undergo treatment intensification. The numerator will include participants with clinical inertia, and the denominator will include all evaluable participants with LDL-C above their corresponding targets.

Absolute changes from baseline to follow-up in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), remnant cholesterol, and triglycerides, expressed in mg/dL. Apolipoprotein B (mg/dL) and lipoprotein(a) (mg/dL or nmol/L) will also be evaluated when available. LDL-C and remnant cholesterol will be calculated centrally using standardized methods, including the Sampson equation for LDL-C. Changes will be summarized overall and by cardiovascular risk category.

Percentage of participants with at least one documented barrier to lipid-lowering treatment optimization, assessed through patient interviews and/or treating physician evaluation. Barriers will be classified as patient-related (medication cost, fear of adverse effects, forgetfulness, polypharmacy, and access difficulties), physician-related (perceived lack of need for treatment intensification, uncertainty regarding treatment targets, and limited consultation time), or institutional (medication unavailability, drug shortages, and administrative requirements). The numerator will include participants with at least one reported barrier, and the denominator will include participants with an evaluable barrier assessment. Individual barrier categories will be summarized descriptively.

Percentage of participants classified as having high adherence to prescribed lipid-lowering therapy, based on patient self-report and treating physician assessment. Adherence will be categorized as high, moderate, or low according to medication-taking behavior, missed doses, treatment discontinuation, and understanding of treatment instructions. The denominator will include participants with an evaluable adherence assessment.

Statin intolerance will be evaluated as a single binary outcome (yes/no) using the study questionnaire and available clinical information.

The assessment will consider previous exposure to at least two different statins, muscle-related symptoms or creatine kinase elevation, and available evidence of symptom improvement following statin discontinuation or recurrence after rechallenge.

These clinical and laboratory findings will be used collectively to determine whether each participant meets the study definition of documented statin intolerance; they will not be reported as separate outcome measures under this endpoint.

The outcome will be expressed as the percentage of evaluable participants classified as having documented statin intolerance.

The numerator will be the number of participants meeting the study definition of statin intolerance, and the denominator will be the total number of participants with an evaluable statin intolerance assessment.

Absolute change in glycated hemoglobin (HbA1c), expressed in percentage points, from baseline to 12 months. The change will be calculated as the 12-month value minus the baseline value. Analyses will include participants with available paired HbA1c measurements. This is a continuous laboratory measurement, not a scoring scale.

Absolute change in high-sensitivity C-reactive protein (hs-CRP), expressed in mg/L, from baseline to 12 months. The change will be calculated as the 12-month value minus the baseline value. Analyses will include participants with available paired hs-CRP measurements. This is a continuous laboratory measurement, not a scoring scale.

Absolute change in serum creatinine concentration, expressed in mg/dL, from baseline to 12 months. The change will be calculated as the 12-month value minus the baseline value. Analyses will include participants with available paired serum creatinine measurements. This is a continuous laboratory measurement, not a scoring scale.

Change in health-related quality of life assessed using the EQ-5D-5L questionnaire, including five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five response levels, from no problems to extreme problems or inability to perform the activity. Responses will be analyzed at baseline and follow-up when questionnaires are available.

Change in patient activation from baseline to follow-up, assessed using the 13-item Patient Activation Measure (PAM-13). The instrument evaluates patients' knowledge, skills, and confidence in managing their health. Standardized activation scores range from 0 to 100, with higher scores indicating greater patient activation. Changes will be analyzed among participants with evaluable questionnaires at both time points.

Absolute change in estimated glomerular filtration rate (eGFR), expressed in mL/min/1.73 m², from baseline to 12 months. The change will be calculated as the 12-month value minus the baseline value. Analyses will include participants with available paired eGFR measurements. This is a continuous renal function measurement, not a scoring scale.

Absolute change in urinary albumin-to-creatinine ratio (UACR), expressed in mg/g, from baseline to 12 months. The change will be calculated as the 12-month value minus the baseline value. Analyses will include participants with available paired UACR measurements. This is a continuous laboratory measurement, not a scoring scale.

Number and proportion of participants with documented cardiovascular events during follow-up, based on available clinical records. Events will be summarized descriptively as exploratory outcomes. No formal hypothesis testing for cardiovascular event reduction is planned.

Descriptive assessment of healthcare resource utilization during follow-up, based on available clinical records and patient-reported information when collected. The frequency and types of documented healthcare encounters will be summarized as exploratory outcomes.