SEA 2026 Standards for Global Control of Vascular Risk

Abstract

Vascular diseases are the main cause of mortality in Spain, are associated with a high degree of disability and involve high healthcare costs. The Spanish Society of Arteriosclerosis meets this challenge by trying to improve the knowledge, prevention and management of these disorders. For prevention to be effective, the multifactorial nature of atherosclerosis encourages a global approach that addresses all risk factors. This document updates the clinical evidence, summarizes recent progress in research and covers all phases of the vascular patient’s journey: initial examination and tests, diagnostic criteria, vascular risk assessment, general and pharmacological recommendations and criteria for referral and discharge. Furthermore, guidelines to set up a vascular risk consultation are issued. The aim is to provide healthcare professionals with a reference handbook for the daily practice in the vascular field.

Resumen

Las enfermedades vasculares constituyen la principal causa de mortalidad en España, conllevan un alto grado de discapacidad y acarrean un alto coste sanitario. La Sociedad Española de Arteriosclerosis (SEA) afronta este reto tratando de mejorar el conocimiento, la prevención y el tratamiento de estas patologías. De cara a una prevención eficaz, la naturaleza multifactorial de la arteriosclerosis hace recomendable un abordaje global que atienda a todos sus factores de riesgo. Este documento actualiza la evidencia clínica, recoge los últimos avances en investigación y cubre todas las etapas del recorrido del paciente vascular: exploración y pruebas iniciales, criterios diagnósticos y estimación del riesgo vascular, recomendaciones, generales y farmacológicas, para su control, y criterios de derivación y alta. Asimismo, se propone la organización de una consulta de riesgo vascular. El objetivo es que esta guía constituya una herramienta de referencia que proporcione pautas prácticas para el día a día del profesional de la salud que desempeñe su actividad en este campo.

Introduction, objective and scope of the document

Medicine is a constantly evolving science. In recent years, we have witnessed continuous progress in the diagnosis and treatment of atherosclerotic vascular disease (ASVD) and its risk factors, making ongoing updates to treatment guidelines essential.

The Spanish Society of Arteriosclerosis (SEA for its initials in Spanish) aims to contribute to a better understanding and control of vascular risk factors (VRFs) in Spain, particularly dyslipidaemia, through its network of Lipid Units. As a result, the SEA has developed Standards for the Global Control of Vascular Risk, intended to summarise the scientific evidence and national and international recommendations on the main VRFs. As indicated in the first version of these standards, published in the journal “Clínica e Investigación en Arteriosclerosis” in 2022, the document was created with the intention of being reviewed and updated periodically. This fourth edition therefore includes changes in all sections. The aim of this document is to continue being useful to all clinicians who, in one way or another, care for patients at vascular risk (VR), whether in primary or hospital care, for primary or secondary prevention, and, in general, to all members of the societies that make up the Spanish Interdisciplinary Committee for Vascular Prevention (CEIPV for its initials in Spanish). This document is also intended for professionals in training, not exclusively those in healthcare professions, and in particular for frontline researchers interested in the arteriosclerosis process.

Medical history, examination and complementary tests in the health centre

The conventional medical history and the systematic collection of the patient's symptoms and signs constitute the standard procedure for establishing a clinical diagnosis. Table 1^1–6 summarises the elements that should be performed in a consultation addressing VR.

Table 1.

Medical history, examination, and complementary tests for Vascular Risk (VR) assessment.

	Essential	Recommended
Medical history	FH of early onset ASVD or VRF	Edinburgh questionnaire^1 (Annexes)
	PH of ASVD (territory, presentation, date or age of the episode)	Erectile dysfunction questionnaire (SQUED)^2 (Annexes)
	PH of VRF	Fagerström test in smokers^3,4
	Alcohol and smoking consumption
	Treatments, including treatment of VRFs: DM, HTN, dyslipidaemia
	Symptoms by system (cardiac, neurological, intermittent claudication, erectile dysfunction)
Physical examination	Anthropometry: weight, height, BMI, abdominal circumference	Search for corneal opacity and tonsillar hypertrophy
	Blood pressure measurement	Fundoscopy
	Central and peripheral pulses and vascular bruits	ABI
	Cardiac and neurological examination
	Abdominal examination: hepatomegaly and Splenomegaly
	Xanthomas, xanthelasmas, and corneal arcus
Additional tests	ECG.	ABPM or HBPM
	Lipid profile (TCl, HDL-C, TG, non-HDL-C, and LDL-C)	Abdominal ultrasound
	Apo B	Monofilament test
	Lp(a)	Genetic testing
	Liver profile (bilirubin, ALT, AST, GGT, ALP)	Apo E phenotype
	Glycaemia, Sodium, potassium, calcium, uric acid	Apo A1
	HbA1c	Number and size of lipoproteins
	eGFR and albuminuria
	TSH
	CPK
Diet and physical activity questionnaires;	Generic assessment of diet and exercise adherence	Mediterranean diet score s) MEDAS^5 (Annexes)
		IPAQ^6 exercise questionnaire (Annexes)
Subclinical vascular disease SVD) assessment		ITB
		Carotid and/or femoral ultrasound
		CSC

ABI: ankle-brachial index; ABPM: ambulatory blood pressure monitoring; ALP: alkaline phosphatase; ALT: alanine aminotransferase; Apo A1: apolipoprotein A1; Apo B: apolipoprotein B; Apo E: apolipoprotein E; AST: aspartate aminotransferase; ASVD: atherosclerotic vascular disease; BMI: body mass index; Ca: calcium CPK: creatine phosphokinase CSC: coronary calcium score; DM: diabetes mellitus; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; FH: family history; GGT: gamma-glutamyl transferase; HBPM: home blood pressure monitoring; HDL-C: high-density lipoprotein cholesterol; HbA1c: glycated haemoglobin; HTN: hypertension; IPAQ: International Physical Activity Questionnaire; K: potassium; LDL-C: low-density lipoprotein colesterol; Lp(a): lipoprotein(a); MEDAS: Mediterranean Diet Adherence Screener; Na: sodium; non-HDL-c:non-HDL cholesterol; PA: personal history; SQUED: Screening Questionnaire for Erectile Dysfunction; TC: total cholesterol; TG: triglycerides; TSH: thyroid-stimulating hormone; VRF: vascular risk factors.

Medical history, examination and complementary tests in the health centre: essential

Family history

Knowledge of first-degree relatives' family history is necessary, both regarding prevalent diseases related to atherosclerotic vascular disease (ASVD) and vascular risk factors (VRFs), especially in cases with suspected familial hypercholesterolaemia (FH) or premature ASVD. Family history is more valuable when it appears in first-degree relatives (parents, children, or siblings) and at early ages, below 55 years in men and below 65 years in women.

Personal history

In addition to conventional personal history (allergies, surgical procedures, etc.), specific inquiries should be made regarding the patient's history of adverse vascular events (AVEs) and various major risk factors (diabetes mellitus [DM], hypertension [HTN], dyslipidaemia, smoking, and obesity). If available, the age of onset and any current or past treatments should be noted, regardless of their indication. In the case of lipid-lowering therapy, the type of treatment, its intensity, and the duration of treatment (or the start date) should be indicated. Adverse reactions or intolerances to medications, as well as pregnancy or the possibility of pregnancy, should also be reported. The weight and timing of VRFs should be quantified: number of cigarettes smoked per day and years of smoking; peak levels of low-density lipoprotein cholesterol (LDL-C); glycated haemoglobin (HbA1c); systolic (SBP) and diastolic (DBP) blood pressure; weight; height, and body mass index (BMI). The presence of systemic diseases with a low-grade inflammatory burden, such as psoriasis; human immunodeficiency virus (HIV) disease; rheumatoid arthritis or systemic lupus erythematosus; chronic obstructive pulmonary disease (COPD); obstructive sleep apnoea, and neoplasms, should also be recorded, as these conditions, either on their own or through their treatment, increase VR. In women, the following should also be recorded: cardiometabolic diseases of pregnancy (hypertension, eclampsia/preeclampsia, dyslipidaemia, and gestational diabetes); polycystic ovary syndrome (PCOS); early menarche; the date of menopause onset, and any hormonal treatments received.

Current and systemic history

The reason for the consultation must be defined. In VR clinics this control is usually lacking for one or more VRFs or abnormalities in laboratory and imaging tests occur. It is important to inquire about symptoms associated with ischaemic episodes in the three main vascular territories that may have gone unnoticed or are not yet diagnosed (transient neurological deficits, chest pain with exertion, palpitations, dyspnoea, or intermittent claudication), cardinal symptoms of diabetes mellitus (DM), headache or dizziness associated with elevated blood pressure (BP), and symptoms related to processes that cause secondary hypertension (Table 2).^7–9 If the patient has been instructed, it would be advisable to record ambulatory blood pressure (ABPM) measurements. Additionally, current pharmacological treatment and the response or intolerance to previous VRF treatments should be recorded.

Table 2.

Clinical features suggestive of secondary hypertension.

Criteria based on clinical presentation
Young patients (<40 years) with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, or children with any degree of hypertension
Abrupt onset of hypertension in previously normotensive individuals
Abrupt worsening of previously well-controlled blood pressure
Stage 3 hypertension or malignant hypertension
Hypertensive emergency
Confirmed resistant hypertension
Extensive or severe load on blood flow, especially if disproportionate to the duration or severity of hypertension
Clinical presentation suggestive of secondary HTN	Clinical suspicion
Paroxysmal elevation of blood pressure or established hypertension with additional crises, and the standard triad of headache, sweating, and palpitations	Pheochromocytoma
Paradoxical response to beta-blockers	Pheochromocytoma
Presence of abdominal bruits	Renovascular hypertension
Snoring and hypersomnia	OSAHS
Muscle cramps, weakness (hypokalaemia))	Hyperaldosteronism
Oedemas, asthenia, tenesmus, and pollakiuria	Kidney disease
Central obesity, moon face, ecchymosis, striae	Cushing's syndrome
Drug abuse (alcohol, NSAIDs, cocaine, amphetamine, liquorice, topical corticosteroids, etc.).)	Drug-induced hypertension

BP: blood pressure; DBP: diastolic blood pressure; HTN: hypertension; NSAIDs: nonsteroidal anti-inflammatory drugs; OSAHS: obstructive sleep apnea-hypopnea syndrome; SBP: systolic blood pressure; TOD: target organ damage.

Adapted from Refs.^7–9

Physical examination

Weight, height, and abdominal circumference should be recorded, and BMI calculated. Blood pressure should be measured according to the recommendations in Table 3, both in the health centre and at home.¹⁰ A basic cardiovascular examination is mandatory, especially noting the presence of murmurs and the presence and symmetry of arterial pulses. The interpretation of the findings will depend on the context: an absence of pedal pulses in an elderly patient with claudication may indicate peripheral arterial disease (PAD), while pulse asymmetry in a young hypertensive patient may indicate coarctation of the aorta. The presence of hepatomegaly and/or splenomegaly should be noted. The presence of xanthomas, their morphology, and their location often constitute a primary diagnostic factor.

Table 3.

Basic conditions for an adequate measurement of blood pressure in the health centre.

Basic conditions

• Blood pressure (BP) will be measured using a validated upper arm oscillometric device

• The patient will be comfortably seated in a relaxed environment for 5 min before the BP measurement begins

• Three measurements will be taken and recorded 1–2 min apart. An additional measurement will be taken if there is a difference in systolic blood pressure (SBP) > 10 mmHg between any of the readings. The average of the last two readings will be considered the result

• In patients with arrhythmias, particularly atrial fibrillation, additional measurements will be taken, and the use of the classic auscultatory technique will be considered if a validated oscillometric device is not available

• The standard cuff, suitable for most patients, will measure 12–13 cm wide and 35 cm long. Larger cuff sizes will be available for arms with a circumference > 32 cm and smaller cuff sizes for arms with a circumference < 26 cm

• The arm being measured should be supported, relaxed, and the cuff positioned at heart level

• When using the auscultatory technique, Korotkoff sounds I and V will be used to identify systolic and diastolic blood pressure, respectively

• Blood pressure will be measured in both arms at the first visit to detect any differences; the arm with the higher blood pressure will be used as the reference

• After measurements taken while seated, blood pressure will be measured after 1–3 min of standing to detect orthostatic hypotension (a drop ≥ 20 or 10 mmHg in systolic or diastolic blood pressure, respectively). This manoeuvre will be performed on the first visit to all patients and also on subsequent visits in elderly patients, patients with diabetes mellitus or with other conditions in which orthostatic hypotension is frequent. BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure

As a general example, tendon xanthomas suggest familial hypercholesterolaemia (FH), tuberoeruptive xanthomas suggest chylomicronaemia, and palmar striated xanthomas are characteristic of dysbetalipoproteinaemia. The presence of stony xanthomas adhered to bone surfaces is suggestive of cerebrotendinous xanthomatosis (Fig. 1).¹¹

Figure 1.

Physical examination findings in primary dyslipidaemias. A) Tendon xanthomas in a case of beta-sitosterolaemia (image provided by the author); B) Stony xanthomas in a case of cerebrotendinous xanthomatosis11; C) Corneal arcus in a 25-year-old woman.

Provided by J. Mostaza.

Additional tests

Vascular risk assessment and dyslipidaemia diagnosis necessitate blood and urine tests. The optimal conditions for their collection, processing, and evaluation have been published as a consensus by the European Societies of Arteriosclerosis and Laboratory Medicine¹² and can be found in the Appendices.

According to the consensus document prepared by 15 Spanish scientific societies,¹³ a basic lipid profile should be obtained: total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), LDL-C (estimated by the Friedewald, Sampson-NIH, or Martin Hopkins formula, or analysed by a direct method), and the calculation of non-HDL cholesterol (non-HDL-C), a measure of atherogenic cholesterol not influenced by TG concentration. The latest European guidelines on cardiovascular prevention from 2021¹⁴ and the updated European guidelines for the management of dyslipidaemias from 2025¹⁵ include it for calculating VR.

The determination of apolipoprotein B (Apo B) can contribute to the screening for dysbetalipoproteinaemia.¹⁶ Additionally, it indicates the total number of atherogenic lipoproteins and is an excellent marker of vascular events. Its measurement is recommended by European guidelines, especially in patients with diabetes mellitus (DM), visceral obesity, metabolic syndrome (MetS), or when LDL cholesterol (LDL-C) levels are low. Under these circumstances LDL-C estimation is less reliable and elevations of other atherogenic lipoproteins containing Apo B (very low-density lipoproteins [VLDL] and intermediate-density lipoproteins [IDL]) are more frequent. The quantification of lipoprotein(a) (Lp(a)) concentration should be performed at least once in a lifetime, ideally at the first visit.¹³ Elevated Lp(a) plays a significant role in the increased VR observed in some patients with FH and in subjects with premature or recurrent ischaemic heart disease, even when other VRFs are well controlled.¹⁷ patients with very high Lp(a) (>180 mg/dL or >430 nmol/L) have an RV equivalent to that of patients with heterozygous FH (FHHe).

During the first visit, a complete blood count and blood chemistry tests should also be ordered, including a glycaemic profile (fasting glucose, HbA1c), renal and hepatic function tests, as well as creatine phosphokinase (CPK), sodium (Na), potassium (K), calcium (Ca), uric acid, and thyroid-stimulating hormone (TSH) levels. A urine sample, preferably from the first thing in the morning, should be taken to determine the albumin/creatinine ratio, as its elevation, along with the glomerular filtration rate (GFR), contributes to the definition of chronic kidney disease (CKD)¹⁸ and constitutes an independent risk factor.¹⁹ Urine protein measurement is necessary to rule out nephrotic syndrome. Since the risk of hepatotoxicity from these treatments is exceptional,²⁰ routine transaminase monitoring is not recommended during statin therapy, except when the dose is increased (European Atherosclerosis Society/European Society of Cardiology [EAS/ESC], 2019).²¹ A resting electrocardiogram (ECG) provides valuable information in patients being evaluated for hypertension and may show signs consistent with myocardial ischaemia or necrosis, left ventricular hypertrophy, or rhythm disturbances such as atrial fibrillation (AF).

Medical history,physical examination and additional tests in the health centre

Medical history: Edinburgh postnatal questionnaire and erectile dysfunction questionnaire

A specific history regarding smoking should be taken, including the Fagerström test^3,4 in smokers (see below, in the Smoking Patient section). In cases of suspected intermittent claudication, the Edinburgh questionnaire, validated in Spain (Annexes), helps to strengthen the clinical diagnosis of PAD.¹ The Short Diagnostic Questionnaire for Erectile Dysfunction (SQUED)² is shown in the Appendices.

Physical examination

In patients with very low HDL cholesterol, the presence of corneal opacity (lecithin-cholesterol acyltransferase [LCAT] deficiency) or tonsillar hypertrophy (Tangier disease) should be specifically sought. Fundoscopy provides valuable information in the examination of patients with diabetes mellitus, primary chylomicronaemias (lipaemia retinalis), and target organ damage (TOD) in hypertension, and is essential when systolic blood pressure (SBP) is ≥180 mmHg and/or diastolic blood pressure (DBP) is ≥110 mmHg.

Additional complementary tests

The SEA considers it advisable to measure the size and concentration of lipoparticles when there is:

• •

  Suspected mismatch between lipid concentration and particle number, a common situation in diabetes mellitus, obesity, and metabolic syndrome.

• •

  Early or recurrent ASVD without any underlying VRFs.

• •

  Rare or complex lipid disorders, such as extremely high HDL cholesterol levels.

• •

  Clinical situations in which standard analytical techniques cannot be applied, such as when LDL cholesterol levels are very low.²²

Lipoprotein separation by ultracentrifugation could be useful for confirming dysbetalipoproteinemia (very low-density lipoprotein cholesterol [VLDL cholesterol]/TG ratio in mg/dL > .3)²³ and for determining the composition of plasma lipoproteins, but its high cost and complexity limit its use. Apolipoprotein A1 (Apo A1) determination is recommended in the evaluation of childhood hypercholesterolaemia. An Apo B/Apo A1 ratio greater than .82 has shown greater sensitivity and specificity in detecting carriers of a genetic variant associated with FH.²⁴

When FH is suspected, the clinical and biochemical criteria of the Dutch Lipid Clinic Network Diagnostic Criteria for Familial Hypercholesterolaemia (Annexes)²⁵ should be used and confirmed with genetic testing. The availability of high-throughput sequencing and the commercialisation of genetic panels for hypercholesterolaemia allow for its diagnosis and the differentiation between heterozygous, compound heterozygous, double heterozygous, and homozygous forms (the latter three could be grouped as biallelic). Clinical and analytical overlap may exist among all these forms,²⁶ or the finding of other diseases with which it may share a phenotype (lysosomal acid lipase deficiency or beta-sitosterolaemia).²⁷ The apolipoprotein E (Apo E) genotype or phenotype should be requested when dysbetalipoproteinaemia is suspected. Genetic testing should only be ordered when a monogenic dyslipidaemia is suspected.²⁸ Currently, genetic studies that assess the risk of severe polygenic hypercholesterolaemia have little impact on the diagnosis and treatment of patients with primary dyslipidaemias and should not be routinely ordered for clinical purposes.²⁹

Among the additional complementary tests, 24 -h ambulatory blood pressure monitoring (ABPM) should be ordered for all patients with hypertension or suspected hypertension. It is especially indicated when there is a discrepancy between office and ambulatory blood pressure readings, when there is high variability in measurement, when nocturnal hypertension is suspected (e.g., sleep apnoea), and in cases of resistant hypertension.¹⁴ HBPM for five to seven days can replace ABPM, especially during follow-up, if good concordance between the two is demonstrated.

Imaging-based vascular risk modifiers in arteriosclerosis

The tests discussed in this section are performed with the intention of re-stratifying risk factors, as they concern a patient without an established ASVD or symptoms suggestive of hypertension. They refer to a period in the natural history of the atherosclerotic process during which, in the absence of symptoms and signs, demonstrable vascular structural abnormalities exist. By definition, their existence can only be determined through specific diagnostic tests. Both VRFs and atherosclerotic disease are systemic, so the finding of vascular involvement in one area also provides information about the disease status in other areas. The available diagnostic techniques must be non-invasive, and their use is intended to obtain complementary information for estimating cardiovascular risk, to redefine lipid targets, and to guide therapeutic decisions.¹⁵ The use of some of these tests for systematic screening has also been proposed

The most relevant risk modifiers in current clinical guidelines are those that directly assess atherosclerosis through imaging.¹⁴ These tests improve the prediction of VR and are the only markers that enable both escalation and de-escalation of risk, avoiding unnecessary treatments if no atherosclerosis is detectable. Beyond the presence of plaques, the prognostic value improves with parameters such as atherosclerotic burden, plaque vulnerability, and the presence of significant stenosis (≥50%). Recent documents suggest their use to decide not only the initiation of statins, but also lipid and blood pressure control targets, and even secondary prevention therapies, based on the fact that they confer a risk similar to that of a patient who has already experienced a clinical event.^30,31

The choice of tests to assess atherosclerosis should be based on scientific evidence, accessibility, and patient characteristics, prioritising the most effective tests according to the stage of the disease's natural history, determined by age, sex, and VRFs.

The incidental detection of atherosclerosis in imaging studies ordered for another reason should be considered a relevant finding, requiring a detailed patient history. If the patient is asymptomatic, their VRFs should be managed and optimised similarly to how we would proceed if atherosclerosis were found in a test specifically designed for risk assessment.

Coronary calcium score

The coronary calcium score (CCS) is the most robust marker for predicting cardiovascular events and is supported by numerous clinical guidelines as a tool to guide prevention.^14,15,32,33 It is expressed in Agatston units associated with short-term risk (five to 10 years) and in percentiles adjusted for age, sex, and race (MESA study), which are useful for estimating long-term risk (10–30 years), especially in young people.³⁴ There is consensus among scientific societies regarding the cut-off values that determine the atherosclerotic burden and, therefore, guide prevention strategies³¹:

• •

  1−99: mild plaque burden.

• •

  100−299 or ≥75th percentile: moderate plaque burden.

• •

  300-999: severe plaque burden, equivalent to secondary prevention.

• •

  ≥1,000: very severe plaque burden.

A CCS between 100 and 299 or ≥75th percentile is the cut-off point used to reclassify an individual into a higher risk category. A CCS > 300 would classify a person directly into the very high-risk category, comparable to that of a patient with established ASVD, given the high event rate (≈ 20% at five years) observed in large population-based cohort studies.^15,35–37 A CCS of 0 in individuals without diabetes mellitus, a family history of early cardiovascular disease (CVD), or heavy smoking would indicate a very low 10-year risk, which would be even lower if repeated at five years and still 0. Therefore, initiating preventive pharmacological treatment would not be justified in any of the aforementioned situations.³⁵ Recent studies confirm that using the CCS after clinical assessment (Systematic Coronary Risk Estimation 2 [SCORE2]/Systematic Coronary Risk Evaluation 2-Older Persons [SCORE-OP]) would be efficient (NNT at 10 years = 12 in men and 25 in women).³⁸

Among its limitations, the CCS detects atherosclerosis in advanced stages of the disease (it does not detect soft plaques), so its use would be restricted to men >40 years and women >50 with VRFS,³⁹ Furthermore, CCS monitoring may not be useful in patients treated with statins, since their plaque-stabilising effect is associated with increased coronary calcification.

Incidental quantification of coronary calcium on a non-cardiac-gated chest computed tomography (CT) scan shows good agreement (correlation coefficient ≥ .81) with the CCS.⁴⁰ Coronary calcium can also be visually assessed in a standardised manner according to the CCS categories.⁴¹ The presence of severe coronary calcification does not, in itself, justify catheterisation. Clearly asymptomatic patients would generally only require preventive treatment. If symptoms are present, given the high pretest risk of significant coronary artery disease (CAD), chronic coronary syndrome guidelines recommend performing an ischaemia test rather than a CT angiogram to determine the need for revascularisation. The use of coronary CT angiography in the presence of severe calcification is controversial, as calcium can limit its usefulness. Its indication will depend on the centre's experience, the expected quality of the study, and the suspicion of high-risk coronary anatomy.⁴²

Coronary computed tomography angiography

Coronary CT angiography is the test of choice for evaluating chest pain in low- or intermediate-risk individuals.⁴² The presence of significant stenosis (>50%) on invasive coronary imaging or CT angiography places the patient at very high risk, equivalent to an established ASVD.¹⁴ Studies such as PROMISE, SCOT-HEART, and ISCHAEMIA have demonstrated the prognostic value of CT angiography, even in the absence of stenosis, by allowing optimisation of medical treatment guided by parameters such as the presence, extent, and characterisation of atherosclerosis when it is not obstructive.^43,44 In the absence of coronary obstruction, a high global plaque burden predicts a 10-year risk >15%.⁴⁵ If plaques with adverse characteristics are present, the risk increases 3⁴⁶-fold, and 6-fold if a high burden of soft plaques predominates.⁴⁷ Given its impact on patient management according to CAD-RADS (Table 4) and supported by the recent 2019 ESC/EAS guidelines update,¹⁵ all this information should be included in clinical reports along with the assessment of the degree of stenosis.⁴⁸ Outside of the study of chest pain, coronary CT angiography has been proposed for asymptomatic individuals with increased clinical risk but a low probability of coronary calcifications for coronary artery disease (young people with familial hypercholesterolaemia, family history of early cardiovascular disease, diabetes mellitus, HIV infection, inflammatory conditions, etc.). However, its use in the general asymptomatic population is not justified. Ongoing studies, such as SCOT-HEART-2 and RESPECT-2, will evaluate its usefulness in the context of primary prevention.

Table 4.

CAD-RADS adapted from the original document.⁴⁸

l CAD-RADS categories
Score	Stenosis		Interpretation		Further studies
0	0%		Absence of HD		None
1	1−24%		Minimal non obstructive HD		None
2	25−49%		Mild non obstructive HD		None
3	50−69%		Moderate stenosis		Consider further study of its functional impact
4A	70−99%		Severe stenosis		Consider invasive angiography
4B	Trunk > 50% or 3 vessels 70−99%
5	100%		Total chronic occlusion		Consider invasive angiography and viability study
N	Non diagnostic test		Obstructive HD cannot be excluded		Needs additional assessment

Coronary plaque burden
	Quantity	CCS		SIS	Visual
P1	Mild	1−100		≤ 2	1−2 Vessels with mild plaque burden
P2	Moderate	101−300		3−4	1−2 vessels with moderate plaque burden. 3 vessels with mild plaque burden
P3	Severe	301−999		5−7	3 vessels with moderate plaque burden.; 1 vessel with severe burden
P4	Extensive	≥ 1,000		≥ 8	2−3 vessels with severe burden
Modifiers
HRP (high risk plaques)	Plaques with low attenuation, positive remodelling, punctate calcification, or presence of the napkin-ring sign
Risk management
CAD-RADS 1	P1: consider modifying risk factors with or without preventive treatment P2: modification of risk factors and preventative therapy P3/P4: intensive management of risk factors with preventative therapy
CAD-RADS 2	P1/P2: Modification of risk factors and preventive therapy P3/P4: Intensive management of risk factors with preventive therapy
CAD-RADS 3	P1/P2/P3/P4: Intensive management of risk factors with preventive therapy, considering antiplatelet therapy, including symptomatic antianginal treatment
CAD-RADS 4A/4B	P1/P2/P3/P4: Management of secondary prevention
CAD-RADS 5	P1/P2/P3/P4: Management of secondary prevention

CAD-RADS: Coronary Artery Disease Reporting and Data System; CCS: coronary calcium score; SIS: segment involvement score derived from the assessment of the 16 coronary segments (17 if there is an intermediate branch) and the presence of atherosclerotic plaques.

Vascular scan

Carotid intima-media thickness (CIT) measurement currently has a class III recommendation⁴⁹ after ultrasound has shown that plaque detection has greater prognostic value. A plaque is defined as a protrusion into the lumen ≥50% of the adjacent CIT or a diffuse increase in CIT ≥ 1.5 mm.⁵⁰ Guidelines consider those with significant carotid stenosis (>50%) to be at very high risk, as a review of 17 studies (11,391 patients) showed an annual cardiovascular mortality rate of 2.9%.⁵¹ Furthermore, guidelines support plaque detection to improve risk stratification in subjects for whom carotid intima-media thickness (CIT) is not feasible.¹⁴ Quantifying the carotid atherosclerosis burden, beyond simple plaque detection, predicts cardiovascular risk with similar efficacy to CIT^52–54 and allows for targeted statin therapy, reducing cardiovascular events^53,55 A 2020 consensus statement⁵⁶ recommends, due to its simplicity, reproducibility, and prognostic value, measuring the maximum plaque thickness, although this choice has been questioned.⁵⁷ A thickness ≥2.5 mm allows for the reclassification of individuals with a low or intermediate risk according to conventional scales as high risk. Plaques <1.5 mm would not modify the risk, and their absence could decrease it.

Including femoral ultrasound alongside carotid ultrasound improves the detection of subclinical atherosclerosis in young and middle-aged adults, surpassing carotid ultrasound alone and CCS.^58,59 It also offers a more comprehensive view of vascular status and prognosis.⁶⁰ For all these reasons, femoral ultrasound is mentioned in current guidelines,^15,61 although the literature is still limited for providing specific recommendations.

Characteristics of plaques, such as their echolucency measured by the Grey Scale Mean (GSM) and the presence of ulcerations or neovascularisation with microbubble contrast, have also demonstrated prognostic value, but their systematic assessment is not recommended.

Functional parameters, such as arterial stiffness (e.g., pulse wave velocity [PWV]), predict cardiovascular events and improve risk stratification.⁶² Arterial stiffness thresholds associated with higher risk include a carotid-femoral PWV > 10 m/s and a brachial-ankle PWV > 14 m/s. However, the 2021 European guidelines do not recommend their routine use due to their complexity, low reproducibility, and evidence that is not free from bias.

Ankle brachial index

The ankle-brachial index (ABI) is the ratio of systolic blood pressure (SBP) at the ankle to that at the arm for each lower limb. A value below .9 indicates a stenosis greater than 50% between the aorta and the distal arteries of the leg, with high specificity (96%) and acceptable sensitivity (69%), allowing for the identification of significant PAD, which may be asymptomatic or present with poorly defined symptoms. An ABI ≤.9 doubles the risk of major cardiovascular events and 10-year mortality.⁶³ Values ≥1.4 usually indicate the presence of arterial calcification, a condition also associated with an increased risk of vascular complications, especially common in patients with diabetes mellitus. Due to its simplicity, the ABI can be used in the assessment of a patient's vascular status. Its measurement is recommended by the 2024 European guidelines as a screening tool for PAD.⁶⁴ However, its systematic use for assessing cardiovascular risk has lost support, as its cost-effectiveness is low in the general population (prevalence of low ankle-brachial index between .1 and 3.1%) and even in high-risk groups (diabetics, smokers, or the elderly) its prevalence varies between 7% and 29%, according to different studies.⁶⁵

Diet and physical activity questionnaires: recommended scales

Beyond finding out about general dietary data, such as whether it is rich in carbohydrates or saturated fats, or about alterations in the eating pattern, diet can be evaluated with a simple 14-question questionnaire: Mediterranean Diet Adherence Screener (MEDAS) on adherence to the Mediterranean diet (Annexes), which has been validated in the Prevention with Mediterranean Diet trial (PREDIMED) and is associated with the presence of VRFs and with VRs.⁶⁶ In addition, alcohol consumption must be quantified, which can be done by noting the number (volume in mL) of beers, wine, and/or liquor per week or by quantifying the grams of alcohol ingested per week, estimating a proof of 6, 12, and 40 degrees, respectively, using the formula (volume in mL × proof × .8) / 100. Physical activity can be assessed semi-quantitatively during work (1 = does not work or sedentary; 2 = walks regularly during work; 3 = walks regularly and lifts weights; and 4 = significant physical activity) as well as during leisure time (1 = does not exercise; 2 = walks at least 4 h per week; 3 = walks >4 h per week; and 4 = vigorous training).⁶⁷ Finally, physical activity can also be easily quantified using the International Physical Activity Questionnaire (IPAQ), which has also been validated⁶ and is available online⁶⁸ (Annexes).

Specific testing indications

Some biomarkers have been extensively investigated as predictors of VR (homocysteine, lipoprotein-associated phospholipase A2, thrombogenic and fibrinolytic factors) but have not been incorporated into routine clinical practice because they do not provide relevant additional information about VR. Overall, these biomarkers lack clinical justification, as they do not increase the predictive capacity of events compared to the European SCORE.¹⁴ Even more controversial is the role of the most studied of these, high-sensitivity C-reactive protein (hs-CRP), which has shown an ability to predict cardiovascular risk in several studies. Its determination in epidemiological studies allows for the identification of patients who may have a residual risk independent of lipid parameters, although it has the drawback of high intra-individual variability, which hinders its use in clinical practice.⁶⁹ The latest update of the European guidelines for the management of dyslipidaemia¹⁵ considers a persistently elevated CRP > 2 mg/dL as a risk-modifying factor, so its determination could be useful in patients close to the treatment decision thresholds.

In the presence of suggestive symptoms or signs, or when disease is suspected, the relevant complementary tests should be requested, including non-invasive coronary imaging or ischaemia detection tests in cases of chest pain, or imaging tests if secondary hypertension is suspected, hormonal tests, etc.

Vascular risk diagnosis

Medical history diagnoses collection: diagnostic criteria

Every patient seen in a vascular risk (VR) clinic should have a standardised list of diagnoses in their medical record, including those listed in Table 5. In addition, all diagnoses derived from any other cardiovascular or non-cardiovascular diseases should be included.^7,70–77

Table 5.

Diagnostic criteria.

Diagnosis	Definition
Hypercholesterolaemia	In secondary prevention (coronary, cerebrovascular, or peripheral arterial disease) or if obstructive plaques are present in the carotid or coronary arteries: LDL-C > 55 mg/dL or non-HDL-C > 85 mg/dL
There is no optimal total cholesterol (TC) or LDL cholesterol level, since the lower the concentration, the better	In T2DM, with TOD, SVD, or with 3 or more VRFs: LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL
High cholesterol is considered to be any level above which lipid-lowering treatment is recommended, which depends on each person's baseline risk	In T2DM, without TOD, without SVD, and with fewer than 3 VRFs: LDL-C > 100 mg/dL or non-HDL-C > 130 mg/dL
	In patients with stage 3 CKD, without TOD or SVD: LDL-C > 100 mg/dL or non-HDL-C > 130 mg/dL
	In patients with stage 3 CKD, with TOD or SVD: LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL
	In patients with stage 4 or 5 CKD: LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL
	In patients without cardiovascular disease, DM, or CKD, LDL-C > 116 mg/dL depending on whether the risk is low or moderate according to SCORE2
Hypertriglyceridaemia	TG desirables < 150 mg/dL
	Hypertriglyceridaemia:
	Mild: 150−499 mg/dL
	Moderate: 500−1,000 mg/dL
	Severe: > 1,000 mg/dL
Mixed hyperlipaemiaa	Raised levels of both LDL-C or Non HDL-C and of TG
Familial hypercholesterolaemia	According to the Dutch Lipid Clinic Network Diagnostic Criteria for Familial Hypercholesterol tables (Annexes)
Atherogenic dyslipaemia	-Hypertriglyceridaemia (TG > 150 mg/dL) and low HDL-C (<40 mg/dL in men or <45 mg/dL in women). Increased number of small, dense LDL particles
Abeta/hypobetalipoproteinaemia	Apo B below the 10th percentile for age, race, and sex
Hypoalfalipoproteinaemia	HDL cholesterol below the 10th percentile for age, race, and sex
Hyperlipoproteinaemia(a)	Lp(a) ≥50 mg/dL or ≥105 nmol/L^15
HTN (measurements in health centre)	Optimal BP: SBP < 120 and DBP < 80 mmHg
	Normal: SBP 120−129 and DBP 80−84 mmHg
	High-normal: SBP 130−139 or DBP 85−89 mmHg
	Stage I hypertension: SBP 140−159 and/or DBP 90−99 mmHg
	Stage II hypertension: SBP 160−179 and/or DBP 100−109 mmHg
	Stage III hypertension: SBP ≥ 180 and/or DBP ≥ 110 mmHg
	Isolated systolic hypertension: SBP ≥ 140 and DBP < 90 mmHg
	A diagnosis is established after verifying BP values in at least 2 measurements on 2 or more visits separated by several weeks
	When SBP and DBP are within Different categories will be assigned to the higher category
	Isolated systolic hypertension is classified into grades (1, 2, or 3) according to the systolic blood pressure (SBP) value
DM	Fasting glycaemia for at least 8 h ≥126 mg/dL (7.0 mmol/L)* or
	Glycaemia 2 h after a 75 g oral glucose tolerance test (OGTT) ≥200 mg/dL (11.1 mmol/L)* or
	HbA1c ≥6.5% (48 mmol/mol) or
	Patient with classic symptoms of hyperglycaemia with a blood glucose value ≥200 mg/dL regardless of fasting status (11.1 mmol/L)*
Prediabetes	Presence of:
	Impaired fasting glycaemia: fasting glycaemia between 100 mg/dL (5.6 mmol/L) and 125 mg/dL (6.9 mmol/L) or
	Glucose intolerance: glycaemia 2 -hs after a 75 g oral glucose tolerance test, between 140 mg/dL (7.8 mmol/L) and 199 mg/dL (11.0 mmol/L) or
	HbA1c between 5.7 and 6.4% (39−47 mmol/mol)
Obesity	BMI ≥ 30.0 kg/m^2:
	Grade I Obesity: 30.0−34.9 kg/m^2
	Grade II Obesity: 35.0−39.9 kg/m^2
	Grade III Obesity: ≥ 40 kg/m^2
Overweight	BMI ≥ 25.0 kg/m^2 and <30.0 kg/m^2:
	Grade I: 25.0−27.5 kg/m^2
	Grade II: 27.6−30.0 kg/m^2
Normal weight	BMI 18.50−24.9 kg/m^2
Low weight	BMI <18.5 kg/m^2:
	Extreme thinness: < 16.0 kg/m^2
	Moderate thinness: 16.0−16.9 kg/m^2
	Slight thinness: 17.0−18.4 kg/m^2
Metabolic syndrome	Three of the following five criteria are required:
	Large abdominal circumference (≥ 94 cm in men and ≥ 80 cm in women of European descent)
	Triglycerides (TG) ≥ 150 mg/dL (1.7 mmol/L) or on treatment with TG-lowering drugs
	HDL cholesterol (HDL-C) < 40 mg/dL (1.0 mmol/L) in men or < 50 mg/dL (1.3 mmol/L) in women or on treatment with HDL-high-C-high drugs
	Blood pressure (BP) ≥ 130/85 mmHg or on treatment with BP-lowering drugs
	Fasting blood glucose ≥ 100 mg/dL or on treatment with antidiabetic drugs
Current smoker	This refers to someone who has smoked at least one cigarette in the last 6 months. Within this group, we can differentiate as follows:
	Daily smoker: someone who has smoked at least one cigarette per day for the last 6 months
	Occasional smoker: someone who has smoked less than one cigarette per day
	Quantification of tobacco consumption (pack-year index): (number of cigarettes smoked per day × number of years of smoking) / 20l
Ex smoker	This is a person who, having been a smoker, has remained completely abstinent for at least the last 6 months.:
Never a smoker	This is a person who has never smoked or has smoked fewer than 100 cigarettes in their entire life.
Passive smoker	A person who does not smoke but is regularly exposed to second-hand smoke.
Target organ damage	Arterial stiffness: pulse pressure (in the elderly) ≥ 60 mmHg or carotid-femoral pulse wave velocity > 10 m/s
	Left ventricular hypertrophy:
	On ECG (Sokolow-Lyon index > 3.5 mV; RaVL > 1.1 mV; Cornell voltage-duration product > 2,440 mV*ms) or
	Echocardiographic (left ventricular mass > 115 g/m² in men or > 95 g/m² in women per body surface area)
	Albuminuria/creatinine ratio > 30 mg/g or albuminuria > 30 mg/24 h
SVD	Presence of:
	ABI < 0.9 (for some authors a value > 1.4 is also pathological) or
	At least one plaque in an epicardial coronary, carotid, or femoral artery or
	Quantification of CCS: Agatston ≥ 100 units or > 75th percentile
GFR (mL/min/1,73m^2) in the CKD	Grade	GF	Definition
	G1	≥90	Normal
	G2	60–89	Slight decrease in GFR
	G3a	45–59	Slight-to-moderate decrease in GFR
	G3b	30–44	Moderate decrease in GFR
	G4	15−29	Severe decrease in GFR
	G5	<15	Kidney failure (predialysis)
Albiminuria category (albuminuria/creatinina ratio in mg/g) in the CKD	A1	<30	Normal
	A2	30−300	Moderately high
	A3	>300	Very high

ABI: ankle-brachial index; Apo B: apolipoprotein B; ASVD: atherosclerotic vascular disease; BMI: body mass index; BP: blood pressure; CCS: coronary calcium score; CKD: chronic kidney disease; DBP: diastolic blood pressure; DM: diabetes mellitus; ECG: electrocardiogram; GFR: glomerular filtration rate; HbA1c: glycated haemoglobin; HDL-C: high-density lipoprotein cholesterol; HTN: hypertension; IMT: intima-media thickness; LDL: low-density lipoproteins; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); non-HDL-c: non-HDL cholesterol; OGTT: oral glucose tolerance test; PWV: pulse wave velocity; RaVL: R-wave voltage in the lead; SBP: systolic blood pressure; SCORE2: Systematic Coronary Risk Estimation 2; SVD: subclinical vascular disease; TC: total cholesterol; T2DM: type 2 diabetes mellitus; TG: triglycerides; TOD: target organ damage; VRF: vascular risk factors.

Definition adapted from the European Societies of Hypertension and Cardiology societies.

*

In the absence of unequivocal hyperglycaemia, the results should be repeated with a second test.

Overall estimation of vascular risk

Concept of vascular risk

One of the first steps when evaluating patients without an ASVD but with VRFs is calculating their overall vascular risk, since certain decisions will be made based on the level or value of the VR, such as when to initiate lipid-lowering treatment and its therapeutic objective.

The (absolute) risk is the probability of a specific vascular event occurring within a defined period, based on the patient's VRFs and belonging to a specific population group. Therefore, there is no universal system for calculating VR. The European guidelines for cardiovascular prevention¹⁴ and dyslipidaemia management,¹⁵ to which the SEA adheres through the CEIPV, recommend the use of the SCORE2 and SCORE2-OP^78,79 systems to assess vascular risk in their low-risk country versions for primary prevention, that is, for individuals who have not yet experienced vascular events.

Calculation of vascular risk: SCORE2 and SCORE2-OP projects

The SCORE2^78,79 system calculates the combined risk of experiencing a vascular complication or vascular mortality within the next 10 years. To obtain the SCORE2 system tables, an analysis was performed on 45 cohorts from 43 countries, including 677,684 individuals and 30,121 cardiovascular events. The variables that predicted the risk of fatal and non-fatal complications were sex, age, smoking (dichotomous), systolic blood pressure (SBP), and non-HDL-C (non-HDL cholesterol). Diabetes mellitus (DM) is was included because it was not intitially considered a high-risk condition. However, specific risk tables for patients with DM have recently been published.⁸⁰ The risk equation is modulated by the incidence of vascular events in each country, resulting in the final indices being distributed into four zones: low risk (which includes Spain), moderate, high, and very high risk, showing a clear east-west gradient. The values are applicable up to age 70, and separate tables have been developed for older individuals up to age 89 (SCORE2-OP)⁷⁹ based on other cohorts, but with the same mathematical analysis as SCORE2 (Fig. 2).¹⁴

Figure 2.

Tables from the Systematic Coronary Risk Estimation 2 (SCORE2) and the Systematic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) for countries with low cardiovascular risk.¹⁵

CV: cardiovascular; HDL: high-density lipoprotein.

Reproduced with permission of Oxford University Press.

Based on these new SCORE2 and SCORE2-OP indices, the 10-year risk is distributed into three categories across three age groups (Table 6).

Table 6.

Vascular risk at 10 years.

Age	Low to moderate	High	Very high
<50 years	<2.5%	2.5% to <7.5%	≥7.5%
50−69 years	<5%	5% to <10%	≥10%
≥70 years	<7.5%	7.5% a <15%	≥15%

Recently, an update to the European guidelines for the management of dyslipidaemia from the European Societies of Cardiology and Arteriosclerosis¹⁵ was published, recommending the use of SCORE2 and SCORE2-OP. However, unlike the 2021 European Guidelines on Cardiovascular Prevention, they consider the same risk cut-off points at any age, but differentiate between low and intermediate risk values, defining low risk as <2%, moderate risk as >2% and <10%, high risk as >10% and <20%, and very high risk as >20%. They also consider other situations that define moderate, high, and very high risk in accordance with Table 7, as well as a new class called extreme risk, which is defined by the recurrence of new vascular events in patients on maximum tolerated doses of statins or by the presence of vascular disease in multiple territories.

Table 7.

Estimation of overall vascular risk.

Criteria
	Without TOD,^a SVD^a or other modulating risk factors^b	With TOD,^a SVD^a or other modulating risk factors^b	Blood pressure 180/110 mmHg or LD-CL ≥ 190 mg/dL (particularly FH)
N0 ASVD, DM or CKD	Estimated according to SCORE2	Increase by one step the category obtained in the SCORE2	High
Moderate CKD^cT1DMor T2DM^d	High	Very high	Very high
Clinical or equivalent vascular disease^eSevere CKD, DM with 3 or more VRFs. Type 1 DM of over 20 years onset.	Very high	Very high	Very high

ACS: acute coronary syndrome; AF: family history; Apo B: apolipoprotein; ASVD: atherosclerotic vascular disease; CCS: coronary calcium score; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CT scan: computed tomography; CV: cardiovascular; DM: diabetes mellitus; FH: familial hypercholesterolaemia; HF: heart failure; HIV: human immunodeficiency virus; HTN: hypertension; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); MetS: metabolic syndrome; OSAHS: obstructive sleep apnoea-hypopnoea syndrome; PAD: peripheral arterial disease; RA: rheumatoid arthritis; SCORE2: Systematic Coronary Risk Estimation 2; SVD: subclinical vascular disease; TIA: transient ischaemic attack; B; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; TOD: target organ damage; TG: triglycerides; VR: vascular risk; VRF: vascular risk factors.-.

a

See Table 5.

b

The increased risk depends on the number and intensity of modulating factors. Generally, several factors or their extreme severity are required to raise the risk category to the same level as the presence of SVD or TOD. Modulating factors include:

Obesity or sedentary lifestyle.

Individual metabolic syndrome in social exclusion setting.

Intolerance to glucose or impaired fasting glycaemia.

Persistent elevation of TG, Apo B, Lp(a), or CRP.

Early onset of FH of ASVD (in men < 55 years or women < 60 years).

Diseases that increase inflammatory-metabolic stress: autoimmune diseases, COPD, RA, MetS, systemic lupus erythematosus, psoriasis, cancer, HIV.

Severe psychiatric disorders (anxiety and depression).

Non-alcoholic fatty liver disease.

Hypertensive disorders of pregnancy.

Premature menopause.

OSAHS.

c

Advanced chronic kidney disease confers per se a very high vascular risk and is defined as the presence of renal failure in stages 4 and 5 of eGFR (<30 mL/min 1.73 m²) or stages 3 b (30−45 mL/min) + albuminuria of any degree, or stage 3 a (45−60 mL/min) with severe albuminuria (>300 mg/g creatinine). Moderate chronic kidney disease confers a high vascular risk and is defined by stage 3b chronic kidney failure (eGFR 30−60 mL/min) without albuminuria, stage 3a (eGFR 45−60 mL/min) with moderate albuminuria (30−300 mg/g creatinine), or by the presence of severe albuminuria (>300 mg/g creatinine) with eGFR >60 mL/min.

d

Patients with type 1 diabetes under 35 years of age or type 2 diabetes under 50 years of age with less than 10 years of disease duration may have a moderate cardiovascular risk.

e

ASVD or its equivalent are considered in the following conditions:

Established clinical ASVD:

• Coronary event (ACS, stable angina, revascularization procedure).

• Cerebrovascular event: stroke or TIA.

• Symptomatic PAD.

• Abdominal aortic aneurysm.

CCS > 300.

ASVD evident by imaging techniques, i.e., presence of significant atherosclerotic plaque:

• By invasive coronary angiography or coronary CT angiography (obstruction > 50% in at least one epicardial artery).

• By carotid or femoral ultrasound (stenosis >50%).

Global vascular risk calculation

Overall VR assessment should be performed using a comprehensive patient evaluation that includes not only the risk value calculated with SCORE2, but also risk-modifying factors, data on cardiovascular disease (LOD), and the presence of a high-risk ASVD (Table 7).^7,14,21

It is recommended that the strategy of the European guidelines for cardiovascular prevention and dyslipidaemia management be followed, as well as those for hypertension (HTN), which classify subjects into four risk categories: low, moderate, high, and very high.

There are situations that directly qualify as high or very high risk: stage 3 hypertension, hypercholesterolaemia with LDL-C >190 mg/dL, stage three or above DM, TOD, CKD, or established ASVD. In all other situations, we will use the SCORE2 system with the cut-off points indicated in the previous section. The presence of several risk modifiers implies moving up a risk category if the values are closer to a higher category. The increased risk depends on the number and intensity of modulating factors. In general, several of these factors, or their extreme severity, are required to elevate the risk category to the same level as the presence of subclinical vascular disease (SVD) or TOD (Table 7).⁸¹

Vascular age and speed of ageing

In young adults with a significant number of multiple VRFs, vascular age can be calculated (Fig. 3)⁸² Communicating this information to the patient is a way to convey their VR status, which can be better understood than the mathematical value of the absolute risk. Individuals should be aware of their risk status so they can adopt appropriate lifestyle and, if necessary, pharmacological therapeutic measures.

Figure 3.

Vascular age table according to Systematic Coronary Risk Estimation 2 (SCORE2) for low cardiovascular risk countries.⁸²

Reproduced with permission of Oxford University Press.

Using the vascular age table derived from SCORE2, absolute risk and vascular age can be reported. Calculating the latter does not require calibration, so it can be applied to any general population, without territorial differences.

Vascular age can be used at any age and is most clinically useful for individuals with a low short-term absolute risk, especially younger adults. Focusing solely on absolute risk can lead to underestimating controllable cardiovascular risk factors with significant effects on lifetime risk.

Derived from the concept of vascular age is the velocity of vascular aging,⁸³ which relates vascular age to chronological age.

Vascular risk in patients with familial hypercholesterolaemia

For patients with FH, who do not qualify for standard vascular risk (VR) calculation tables, several specific tools have been developed. One of these is based on follow-up data from the Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART).⁸⁴ This equation takes into account various factors such as age, smoking, LDL-C levels on treatment, BMI, blood pressure, and Lp(a) levels, and provides a more detailed risk assessment in this population. The SEA registry provides another tool for stratifying VR in FH patients treated with statins, based on the presence of other cardiovascular risk factors (male sex, obesity, hypertension, diabetes mellitus), peak LDL-C levels, and a positive genetic test for FH.⁸⁵ Finally, in patients with a FH phenotype, a risk calculation tool has been developed: the Catalan Primary Care System Database-Familial Hypercholesterolaemia Phenotype (SIDIAP-FHP), with improved predictive capacity in both primary and secondary prevention.⁸⁶

Vascular risk according to lipoprotein(a) levels

Lp(a) is an LDL particle bound to apolipoprotein(a), which confers increased atherogenicity. Several studies have demonstrated a positive and continuous relationship between Lp(a) levels and the risk of vascular complications and aortic stenosis. According to the SEA Consensus on lipoprotein(a),¹⁷Table 8 shows the cardiovascular risk correction based on Lp(a) levels, multiplying the risk obtained from the SCORE2 tables by this coefficient.

Table 8.

Vascular risk (VR) correction coefficient based on lipoprotein concentration(a).¹⁷ Calculated from estimated VR changes in the UK Biobank for Caucasians using British lifetime risk VR scales.

Estimated VR adjusted for Lp(a) levels
Lp(a)		Estimated VR correction factor	Excess risk due to Lp(a) levels
mg/dL	nmol/L
25	50	1.16	None or mild
37.5	75	1.24
50	100	1.34	Moderate
75	150	1.54
100	200	1.78	High
125	250	2.05
150	300	2.36
175	350	2.73
>200	>400	>3	Very high

Lp(a): lipoprotein (a).

General recommendations for vascular risk control

General recommendations for the population to reduce their VR

The Spanish Society of Arteriosclerosis's (SEA) Nutrition and Lifestyle Working Group has a consensus document,⁸⁷ updated from the 2018 version, which provides useful, structured evidence. This serves as a tool for healthcare professionals to help their patients, based on the concept that healthy recommendations should be the same for managing any cardiovascular risk factor and for the primary and secondary prevention of ASVD. It summarises the accumulated evidence on lifestyle components such as diet.⁸⁷ Furthermore, it places special emphasis not on the consumption of isolated nutrients, but on the consumption of foods and, above all, on the most important dietary patterns for vascul

ar prevention. This concept of dietary patterns has become established in recent years as a model for examining the relationship between nutrition and health, and as an educational tool for the population. It modifies the traditional paradigm that the basic nutritional unit of the diet is not nutrients (e.g., fatty

acids), but rather the foods that contain them (oils, nuts, red meat, dairy products, etc.), since their matrices contain a multitude of components capable of interacting synergistically or antagonistically on metabolic pathways that are crucial for vascular health.

This guide compiles the main recommendations from the aforementioned documents.^87,88 Different healthy diets have many components in common, some of which are recommended, such as fruits, vegetables, nuts, legumes, and fish, while others should be restricted, such as certain foods high in saturated fat, those with added sugar, high salt content, or that have been processed. There is strong evidence that plant-based dietary patterns, low in saturated fatty acids, cholesterol, and sodium, and high in fibre, potassium, and unsaturated fatty acids, are beneficial and reduce the expression of cardiovascular risk factors (CVRFs). In this context, the Mediterranean diet; the Dietary Approaches to Stop Hypertension (DASH) diet; the vegan-vegetarian diet, and the MIND diet are salient. All of them are plant-based and rich in complex carbohydrates. Data from large cohort studies and, in the case of the Mediterranean diet, the PREDIMED randomised clinical trial, indicate that adherence to these dietary patterns confers a clear vascular benefit.⁸⁹ Conversely, the low-fat diet is currently under scrutiny due to its limited vascular protective potential. Regarding edible fats, virgin olive oil is the most effective cooking fat in preventingASVD.⁹⁰ Nutritional intervention over approximately five years in the PREDIMED study showed that participants assigned to the Mediterranean diet supplemented with extra virgin olive oil or nuts experienced an average reduction of 30% in major vascular events⁸⁹ in addition to other beneficial effects, including a reduction in the risk of T2DM and AF.⁹¹

In 2022, the results of the CordioPrev⁹² study were published. This randomised clinical trial included 1,002 patients with established heart disease (HD) who received a dietary intervention consisting of a Mediterranean diet rich in virgin olive oil versus a low-fat diet rich in complex carbohydrates for seven years. The study's major adverse cardiovascular event occurred in 198 participants, 87 in the Mediterranean diet branch (17.3%) and 111 in the low-fat diet branch (22.2%), representing a 26% reduction in the event rate among participants following the Mediterranean diet (Hazard Ratio [HR] for the different models ranged from .719 to 95% confidence interval: .541–.957– to .753 –.568–.998–). These effects were more pronounced in men, where the difference between diets was 33% in favour of the Mediterranean diet. The results are relevant to clinical practice, supporting the benefit of the Mediterranean diet in preventing the recurrence of ASVD and complementing the results of the PREDIMED study, conducted in patients undergoing primary prevention.

Regarding the consumption of major food groups, it is of note that consuming fish or seafood at least three times a week, two of those times in the form of oily fish, reduces VRs. Therefore, encouraging its consumption is an important component of lifestyle modifications for the prevention of ASVD and is especially beneficial when it replaces meat as the main course. However, due to their high levels of marine pollutants, children and women of childbearing age should not consume large, oily fish (bluefin tuna, swordfish, shark) or mackerel, as these contain more pollutants than smaller species. Evidence regarding meat indicates that consuming white or lean meat (without visible fat), three to four servings per week, does not increase cardiovascular risk (CVR), unlike the consumption of processed meats (bacon, sausages, cold cuts), which contain harmful additives such as salt and nitrates, increasing overall mortality and the risk of developing T2DM and ASVD. However, in recent years, awareness of the need to transform the food system has been raised, with the adoption of a new model that is healthy for the humans and also for the planet. Red meat and its derivatives are a highly significant source of global warming, land overuse, and water consumption. Similarly, ultra-processed foods, whether meat or not, and the vast majority of ready-made meals contain products such as added sugars or trans fats which our diet should not contain. They should therefore be avoided, and the consumption of foods rich in plant protein should be increased, compared to those rich in animal protein.⁹³

Regarding dairy products, it is advisable to consume at least two servings daily (milk, fermented milk, cheese, yogurt, etc.) due to their important nutritional role in calcium metabolism and their richness in high-quality protein. Regular consumption of dairy products with added sugars is discouraged, and in cases of excess weight or obesity, skimmed dairy products are preferable to reduce caloric intake. For vascular prevention, it is recommended to reduce the consumption of concentrated dairy fats, such as butter and cream. Eggs contain ovalbumin (a high-biological-value protein), minerals, vitamins, and antioxidants such as lutein and zeaxanthin. Although they are a food rich in cholesterol, current scientific evidence suggests that their consumption is not harmful within the context of a healthy diet.⁹⁴ Both the general healthy population and individuals with VRFs AND ASVD can consume up to one egg per day without concern for their cardiometabolic health.⁸⁷ In individuals with T2DM, observational studies show an increased VR with egg consumption, but clinical trials have not demonstrated any adverse effects. An aggregated analysis of North American cohorts demonstrated a direct relationship between egg consumption and the risk of T2D, an association not found in other European and Asian cohorts,⁹⁵ suggesting the possible influence of dietary patterns and cooking methods for eggs or accompanying foods.

Legumes and whole grains are seeds that contain multiple healthy nutrients, and their frequent consumption is associated with a reduction in VRFs and ASVD. To promote vascular health and lower cholesterol, a minimum of two servings (200 g) of legumes per week is recommended, and ideally, four servings per week.⁸⁷ The recommended intake of grains is about four servings per day, including bread at every meal, pasta two to three times per week, and rice two to three times per week. Whole-grain bread is recommended, but the Mediterranean diet typically includes white bread, and whole-grain rice and pasta are rarely consumed. However, refined grains are not eaten in isolation, but rather with other foods (bread), in vegetable dishes, or mixed with stir-fry vegetables, which improves their palatability and reduces their glycaemic index.⁸⁷

Regarding fruit and vegetable consumption, existing evidence recommends four to five servings of fruits and vegetables daily, as this reduces overall and vascular mortality. Consumption of tubers (especially potatoes) is not associated with an increased cardiovascular risk unless they are fried in unhealthy oils and salted. Frequent consumption of nuts is associated with a reduction in ASVD, particularly HD, and all-cause mortality.⁸⁹ Consuming a handful of nuts (equivalent to a 30 g serving) frequently (daily or at least three times a week) is highly recommended for cholesterol control and overall health. It is advisable to consume them raw and unpeeled (not roasted or salted) if possible, since most of the antioxidants are in the skin. To maintain a feeling of fullness and avoid weight gain, they should be consumed throughout the day, not as a dessert. Recommended nuts include hazelnuts, walnuts, almonds, pistachios, cashews, macadamia nuts, pine nuts, etc. While peanuts are not actually tree fruits, but legumes, their overall composition and high content of unsaturated fatty acids alikens them to nuts both nutritionally and in terms of their biological effects.

Cocoa is a seed rich in nutrients, and consuming its main derivative, chocolate, improves VRF and is associated with a reduction in ASVD and T2DM. There is evidence that it has cholesterol-lowering and antihypertensive effects, reducing insulin resistance. Therefore, dark chocolate (≥70%) without added sugar can be consumed as part of a healthy diet. Furthermore, it is advisable to consume it during the day and not at night after dinner, when the feeling of satiety cannot be offset by eating less at the next meal.

Sugary drinks are part of the regular diet of many people and can account for up to 20% of daily caloric intake, contributing to an increase in ASVD, obesity, and T2DM. Replacing these types of drinks with water greatly reduces sugar consumption and the risk of these conditions and their complications. Recent evidence also suggests an increase in cardiovascular and all-cause mortality, as well as the risk of stroke, ASVD and T2DM with the increased consumption of artificially sweetened soft drinks. Their recommendation as substitutes for sugary beverages is therefore inappropriate.⁹⁶

Alcohol consumption and VR is a controversial issue, and consumption should not be promoted among people who do not usually drink alcohol. Moderate consumption is acceptable with meals and as part of a healthy diet, such as the Mediterranean diet. Recommendations differ for men and women, as women are more sensitive to the effects of alcohol. Coffee (both regular and decaffeinated) and tea are rich in polyphenols, and there is strong evidence that their regular consumption is associated with VR and a lower risk of developing T2DM. Numerous functional foods and nutraceuticals are designed to reduce cardiovascular risk, primarily by lowering cholesterol levels. The SEA has prepared a position paper on the usefulness of these products, identifying the following clinical scenarios in which they could be used⁹⁷:

• •

  Lipid-lowering treatment in patients with statin intolerance.

• •

  Customised lipid-lowering treatment in individuals undergoing primary prevention.

• •

  Long-term vascular prevention in individuals without an indication for lipid-lowering treatment.

• •

  Patients on optimised lipid-lowering therapy who are not achieving therapeutic targets.

The SEA emphasizes that there are no studies on vascular morbidity and mortality with nutraceuticals or functional foods, and that long-term safety data are scarce or limited. Both aspects should be discussed with the patient before recommending their use. It should be noted that the European Commission, through Regulation (EU) 2024/2041 of July 29, 2024, recently removed monacolin K from red yeast rice from the list of health claims for safety reasons.

Excessive salt consumption is associated with ASVD and cardiometabolic mortality. A low-salt diet (<5 g/day) should be recommended for the general population and even more strongly promoted for hypertensive patients and their families, remembering that to calculate total salt intake, the sodium content of foods must be multiplied by 2.5. Particularly effective measures for this purpose include limiting the consumption of foods high in salt, such as precooked meals, canned goods, salted meats, processed meats, and carbonated beverages. An alternative to salt is using lemon juice, garlic, or aromatic herbs.

It is reasonable to think, and recent evidence shows, that there is no standard model of a healthy diet, but rather that the biological response varies among individuals, especially due to individual differences in the genome and microbiome. In upcoming years, personalised and precision nutrition, along with other sciences such as chronobiology, in which each person adopts the diet that is personally most beneficial to them, will be a challenge for the scientific community. Finally, one of the most complex problems in the relationship between people and their diet is adherence, which depends on very different factors, such as those of the patient, their family, the healthcare team supporting them, and the healthcare system itself. Therefore, it is essential to implement strategies to achieve it.

Table 9, taken from the SEA’s 2024,⁸⁷ update document on diet and cardiovascular prevention, provides a practical overview of the frequency, form, and quantity of food consumption. One way to assess adherence to the Mediterranean diet is by using the MEDAS questionnaire (Annexes).

Table 9.

Desirable frequency in the form and quantity of food consumption.⁸⁷

Consumption frequency	Daily	3 times per week maximum	Not recommended or occasional
Edible fats	Extra virgin olive oil	Margarine for spreading	Frying with seed oils, margarine, or butter
Cereals	Bread, preferably wholemeal. Pasta, rice, corn, other grains		Pastries, cakes, cookies, etc.
Fruits and vegetables	5 servings combining different types of fruits and vegetables, including natural juices (without added sugar)		Commercial fruit juices Canned fruit in syrup
Legumes	Cooked beans, chickpeas, lentils, etc.		Cooked with fats such as chorizo, bacon, etc.
Tubers	Cooked potatoes and sweet potatoes with vegetables		Commercial potato crisps
Nuts and peanuts	Raw or toasted (30 to 45 g)
Eggs	Whole eggs are not discouraged
Fish and seafood^a	Blue or White Seafood (crustaceans and molluscs) Canned goods in water or olive oil	Preserves in vegetable oils.	Commercially fried, salted, and smoked foods
Meat^b	Poultry and rabbit)	Lean red meats.	Processed meats, cold cuts
Dairy products	Whole milk and yoghurts or skimmed milk (sugar free Any type of cheese)l	Butter, cream	Cured cheeses in hypertensive patients
Chocolate	Dark with ≥ 70% cocoa	Dark with <70% cocoa	Milk and White Chocolate
Coffee and tea	Unlimited tea and up to 5 cups of coffee per day, without sugar or artificial sweeteners
Sugary drinks or drinks with artificial sweeteners			Avoid
Alcoholic beverages	Limit to 30 g of alcohol in male drinkers and 15 g in female drinkers. Preferable fermented drinks (beer, wine) with meals		Non drinkers
Salt	Between 2.5 and4 g daily		Salted fish
Food preparation^c	Preferably cooked, grilled or sauteed	Fried in virgin olive oil	Avoid smoked, processed and fried in seed oils

a

Recommended consumption is at least twice a week.

b

Meats, an important source of animal protein, should be alternated with fish, consuming one of these options per day. White meat is preferable to red meat.

c

Dishes seasoned with tomato, garlic, onion, or leek sauce, slowly cooked in extra virgin olive oil (stir fried), can be consumed daily.

Physical activity, according to the World Health Organization (WHO), is any bodily movement produced by skeletal muscles that requires energy expenditure. When performed regularly and consistently, it protects against VRs and improves VRFs. Its practice should be adapted to the individual characteristics of each person, based on the principle that any is better than none, and considering that it encompasses activities such as those performed during work, active transportation, household chores, or recreational activities. Physical exercise, however, is a type of physical activity that is planned, structured, repetitive, and has the objective of improving or maintaining physical fitness. Both should be done slowly and moderately, rather than intensely and with concentration.

General pharmacological recommendations in patients undergoing primary prevention

Clinical management recommendations for VRs in patients without ASVD, DM OR CKD are summarised in Fig. 4.

Figure 4.

Clinical management recommendations for vascular risk in patients without established vascular disease, diabetes mellitus (DM), or chronic kidney disease (CKD).

AF: atrial fibrillation; BP: blood pressure; CVD: cardiovascular disease; HTN: hypertension; MS: metabolic syndrome; RV: vascular risk.

Antiplatelet agents

Treatment with low-dose acetylsalicylic acid (ASA) has been shown to reduce the risk of vascular complications, primarily in middle-aged individuals, mainly by reducing non-fatal myocardial infarctions, without affecting the risk of stroke or mortality. However, some of the benefit of ASA is offset by its adverse effects, especially those related to its bleeding potential. Therefore, the balance of risks and benefits of low-dose ASA is not clearly established in primary prevention. The U.S. guidelines - The U.S. Preventive Services Task Force (USPSTF)⁹⁸ - recommends initiating low-dose aspirin (≤100 mg/day) for primary prevention of ASVD in adults aged 50–59 years who have a 10-year vascular risk of morbidity and mortality greater than or equal to 10%; who do not have an increased risk of bleeding; who have a life expectancy of at least 10 years, and are willing to take this treatment daily for at least 10 years. The decision to initiate treatment in adults aged 60–69 years with a 10-year vascular risk greater than or equal to 10% should be individualised.⁹⁸

However, the 2021 European guidelines for cardiovascular prevention do not routinely recommend antiplatelet therapy for patients without ASVD due to the increased risk of bleeding.¹⁴ In this regard, several clinical trials using ASA for primary prevention in patients with and without DM have recently been published, finding no benefit in its use for the primary prevention of ASVD^99–101 especially when existing VRFs are adequately controlled.

Lipid-lowering therapy

In numerous clinical trials and meta-analyses,¹⁰² statins have been shown to reduce vascular events in patients without ASVD, even with non-elevated cholesterol levels. The reduction in the relative risk of ASVD is independent of baseline vascular risk (VR), being approximately 22% for each mmol/L reduction in LDL-C. However, for treatment to be effective, it is important to select patients with a high baseline VR so that the absolute reduction in VR is greater. Other drugs such as ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, and bempedoic acid have been shown to reduce vascular events equivalently to statins in proportion to their lipid-lowering potency.

The indications for lipid-lowering therapy in primary prevention are discussed in the corresponding chapter (Therapeutic Recommendations in Patients with Dyslipidaemia, Chapter 5).

Vitamin supplements

Many prospective observational case-control studies have described inverse associations between the intake or serum concentrations of vitamins (A, B complex, C, D, and E) and the risk of ASVD. However, data from prospective studies and interventional clinical trials with vitamin and mineral supplements have not demonstrated any vascular benefit.¹⁰³ The use of vitamin supplements for the prevention of ASVD is not indicated.

General recommendations for patients with subclinical vascular disease and in secondary prevention

Primary prevention with in patients with atherosclerosis detected by imaging techniques

Imaging in atherosclerosis has shown that vascular risk is a continuum and that we should not only be guided by the presence or absence of events. Some atherosclerotic lesions carry a risk similar to that of established vascular disease. Therefore, LDL-C and blood pressure targets should be adapted to individual risk, defined by clinical and imaging parameters (when available), as described in the section on imaging risk modifiers in atherosclerosis. To sum up, there are imaging markers that may risk re-stratify risk in patients at intermediate risk or even directly increase risk to very high, recommending management with lipid-lowering agents with targets similar to those for secondary prevention.

A CCS between 100 and 299, or above the 75th percentile, as well as a high plaque burden on CT angiography or vascular ultrasound, could increase the risk estimated by SCORE2. Similarly, a CCS > 300, the presence of significant epicardial artery stenosis on invasive imaging or CT angiography, or carotid stenosis > 50% would classify these individuals as very high risk. In all these situations, LDL-C targets should be achieved in accordance with their risk level.

The CCS would also help identify patients who would benefit from initiating antihypertensive treatment, even at levels of "elevated blood pressure" without hypertension, if their overall VR were reclassified as high.⁸ Even patients with a CCS > 220 would potentially benefit from intensifying blood pressure control targets, up to 120/70 mmHg according to the SPRINT strategy.¹⁰⁴

Regarding the indication for antiplatelet therapy, finding a high or very high plaque burden (CCS > 300), lesions with adverse characteristics, or significant stenosis (coronary or peripheral vascular) could lead to recommending ASA, as these are very high-risk equivalents. The indication for ASA outside of these scenarios has been evaluated primarily for CCS, finding a potential benefit against the risk of bleeding when indicated at a CCS > 100, but especially when it is >300.¹⁰⁵ Interest has been raised in identifying the coronary calcium threshold at which the benefit of antiplatelet therapy outweighs the risks of bleeding, and it is therefore likely that clinical trials will be conducted in this regard.^106,107

The use of antiplatelet agents in patients with SVD has little supporting evidence. In subjects with a low ABI but without intermittent claudication, antiplatelet treatment has not been shown to be effective.¹⁰⁸

Evidence is also very limited in subjects with asymptomatic carotid stenosis >50%, although the European Society of Vascular Surgery (ESVS) recommends the use of ASA at doses of 75–325 mg or, in case of intolerance, clopidogrel, with the aim of reducing the rate of coronary complications or complications in other vascular beds.¹⁰⁹

Some clinical trials with different preventive treatments have included asymptomatic subjects with imaging-confirmed arteriosclerosis, which opens the door to the possible usefulness of other therapies in these circumstances, such as the LoDoCo2 study with colchicine¹¹⁰ or the REDUCE-IT study with eicosapentaenoic acid (EPA).¹¹¹

It is important to emphasize that the detection of any degree of atherosclerosis, even if mild, should always be accompanied by recommendations on lifestyle habits, including a review of smoking, diet, physical activity, and sleep quality, among others.

Of note is the fact that the progression of atherosclerosis, as evidenced by imaging, implies a very high risk of vascular complications¹¹² and, if these occur despite optimal treatment or if there is significant vascular involvement in several areas extreme risk is indicated. Although evidence is still limited for these definitions, these are cases in which more stringent LDL-C targets (<40 mg/dL) could be considered, and, in addition, an effort should be made to identify other potential non-conventional VRFs in that individual that require specific intervention.

Most current recommendations, supported by guidelines, are based primarily on observational population cohort studies that demonstrate the clinical risk associated with atherosclerosis. Several clinical trials are underway to demonstrate the efficacy and cost-effectiveness of imaging-based strategies, which would enable identification of the population with the greatest potential benefit, increasing the efficiency and cost of the studies. Using image-guided retraction strategies would help demonstrate the potential reduction of events with a smaller number of patients and in a shorter time, overcoming one of the main barriers that has limited the performance of randomised trials in population-based prevention strategies.^113,114

Secondary prevention

In patients undergoing secondary prevention, in addition to the previously discussed lifestyle modifications (see Chapter 4.1) and the treatments indicated for the control of VRFs, there are a number of treatments that have been shown to reduce the risk of new vascular events (Table 10).^115–117

Table 10.

Pharmacological measures that have been shown to reduce the rate of atherosclerotic vascular complications in subjects in secondary prevention.

Treatment	Potential indications
Antiaggregates	Low-dose aspirin or clopidogrel in patients with symptomatic coronary, cerebrovascular, or peripheral arterial disease
	Aspirin plus clopidogrel after a TIA or minor stroke^115,116
	Aspirin and dipyridamole in subjects with previous stroke or TIA
	Aspirin plus a P2Y12 inhibitor in subjects with ACS or stent placement, maintained for at least 12 months
Hypolipaemiants	Statins, with or without ezetimibe or bempedoic acid, to reduce LDL cholesterol by at least 50% and below 55 mg/dL. PCSK9 inhibitors if adequate reductions are not achieved with prior lipid-lowering therapy and according to the criteria in Table 13 (see below)
	Ezetimibe and bempedoic acid in patients with statin intolerance and in those in whom targets are not achieved with other cholesterol-lowering therapies
	Purified IPE 4 g/day in hypertriglyceridaemia >150 mg/dL that persists despite statin therapy in high-RV^117. patients. Its protective effect is independent of its effect on TG

ACS: acute coronary syndrome; ASA: acetylsalicylic acid; EPA: ethyl eicospentaenoic acid; LDL-C: low-density lipoprotein cholesterol; P2Y12 inhibitor: adenosine diphosphate chemoreceptor trigger zone inhibitor; PCSK9 inhibitor: protein subtilisin/kexin 9 convertase inhibitor; TG: triglycerides; TIA: transient ischaemic attack; VR: vascular risk;

Antiplatelet agents

Aspirin (ASA) is the most studied antiplatelet agent for long-term vascular prevention in patients with acute myocardial infarction, ischaemic stroke, or symptomatic PAD. In a meta-analysis of 16 clinical trials with more than 17,000 patients, ASA treatment significantly reduced major vascular events (coronary and cerebrovascular) and all-cause mortality.¹¹⁸ ASA treatment was also associated with a significant excess of major bleeding and the development of anaemia, even in the absence of apparent bleeding. However, the vascular benefits of ASA clearly outweighed the bleeding risk.

Clopidogrel has a similar effect to ASA in patients with myocardial infarction or ischaemic stroke, but may be superior in patients with symptomatic PAD. The combination of ASA and clopidogrel in secondary prevention significantly reduces major cardiovascular events compared to ASA monotherapy, but with a significantly increased risk of bleeding.

In patients with non-cardioembolic ischaemic stroke or transient ischaemic attack (TIA), ASA can be used as monotherapy or in combination with dipyridamole, and clopidogrel can also be used as monotherapy. In patients with a TIA or minor stroke, the benefit of dual antiplatelet therapy for up to 90 days outweighs the increased risk of bleeding.^115,116 Protection occurs during the first 21 days, making this the most recommended interval for dual therapy.¹¹⁹

The standard treatment for a patient who has suffered an acute coronary syndrome (ACS), with or without stent placement, is dual antiplatelet therapy (ASA with an adenosine diphosphate chemoreceptor trigger [A2Y12] inhibitor) for 12 months. In patients at high risk of bleeding, the duration of dual antiplatelet therapy can be shortened to one to three months.

Lipid-lowering agents

Numerous clinical trials and meta-analyses¹⁰² have demonstrated that treatment with lipid-lowering drugs (resins, statins, ezetimibe, PCSK9 inhibitors, bempedoic acid, eicosapentaenoic acid) in patients with established ASVD reduces major vascular events and mortality (see chapter on the treatment of dyslipidaemia).

Patients with multi-vessel HD (especially if it is not revascularisable) or with involvement of multiple arterial beds have a particularly high risk of vascular complications, and therefore more intensive lipid-lowering therapy may be considered (e.g., target LDL-C <40 mg/dL).120.¹²⁰

Other drugs

While various drugs have been shown to reduce the rate of vascular complications in patients undergoing secondary prevention, this review focuses on those that intend to reduce it through actions on atherosclerotic plaque. In patients undergoing secondary prevention or with high-risk DM treated with statins (mean LDL cholesterol 75 mg/dL and triglycerides between 150 and 499 mg/dL), treatment with 4 g of EPA reduced the risk of major vascular events by 25%,¹¹⁷ likely independently of its triglyceride-lowering effect. This drug has also been shown to reduce the progression of atherosclerotic plaque in patients with hypertriglyceridaemia treated with statins.¹²¹

The use of aspirin, a statin, and an angiotensin-converting enzyme (ACE) inhibitor in a single tablet facilitates treatment adherence in patients undergoing secondary prevention¹²² and has been shown to reduce the rate of vascular complications compared to standard treatment for the disease.¹²³

Finally, targeted interventions targeting inflammation have also been shown to reduce the number of vascular complications. The use of the anti-interleukin-1β (anti-IL-1β) monoclonal antibody, canakinumab, significantly reduced the recurrence rate of ASVD, demonstrating a benefit despite an increase in serious and fatal infections.¹²⁴

Several clinical trials and meta-analyses have shown that low-dose colchicine (.5 mg daily) significantly reduces the incidence of major cardiovascular events, without reducing cardiovascular or all-cause mortality.¹²⁵ Its use in the secondary prevention of heart disease can therefore be considered to prevent new events.¹²⁶

Specific treatment recommendations

Patients with dyslipidaemia

Patients with hypercholesterolaemia

The Mediterranean-type diet, rich in plant-based products and low in animal fats, is recommended for cardiovascular prevention in the general population and especially for preventing it in patients with hypercholesterolaemia, as outlined in the SEA's dietary recommendations (see the section on dietary recommendations).

In addition to diet, the indication for initiating lipid-lowering therapy is based on both LDL-C concentration and baseline VR.¹⁵ This treatment should be aimed at achieving the LDL-C targets indicated in the following sections. To reach these targets, combinations of drugs are often necessary; therefore, emphasis is placed on the use of high-intensity lipid-lowering therapies, which should include statins as shown in Table 11.¹²⁷

Table 11.

Hypolipidemic therapies, in monotherapy or combination, according to their cholesterol-lowering intensity.

Lipid-lowering treatments
	LOW INTENSITY Lipid-Lowering treatment LDL-C reduction ≤30%		MODERATE INTENSITY Lipid-Lowering treatment LDL-C reduction >30% and ≤50%		HIGH INTENSITY lipid-lowering treatment LDL-C reduction >50% and ≤60%		VERY HIGH INTENSITY lipid-lowering treatment LDL-C reduction >60% and ≤80%		MAXIMUM INTENSITY lipid-lowering treatment LDL-C reduction >80%
	% LDL-C reduction^a: Monotherapy	baseline LDL-C with which ≤55 mg/dL (1.4 mmol/L) can be achieved^c	% LDL-C reduction: When combined with a moderate-intensity statin	baseline LDL c with which ≤55 mg/dL (1.4 mmol/L) can be achieved	% LDL-C reduction: When combined with a high-intensity statin,	baseline LDL-C that can be achieved at ≤55 mg/dL (1.4 mmol/L)	% LDL-C reduction: Combined with high-intensity statin + ezetimiba^d	Baseline LDL-C can be reduced to ≤55 mg/dL (1.4 mmol/L)^c	% LDL-C reduction: Combined with high-intensity statin + ezetimib + bempedoic acid,	baseline LDL-C can be reduced to ≤55 mg/dL (1.4 mmol/L).
Moderate intensity statin^e	40	92 (2.4)
High intensity statin^f	50	110 (2.8)
Ezetimibe	25	73 (1.9)	55	122 (3.1)	63	149 (3.8)
Bempedoic acid	23 (18.0)^b	71 (1.8)	51	112 (2.9)	59	134 (3.5)	69	183 (4.7)
Bempedoic acid + ezetimibe	42 (38.0)^b	89 (2.3)	63	149 (3.8)	69	177 (4.6)
Evolocumab 140 (every 14 days)	65	157 (4.1)	79	262 (6.8)	83	324 (8.4)	87	423 (10.9)	89	500 (13.0)
Alirocumab 150 (every 14 days) or 300 (once a month)	62	145 (3.7)	77	239 (6.2)	81	289 (7.5)	85	367 (9.5)	88	458 (12.0)
Alirocumab 75 (every 14 days)	53	117 (3.0)	72	196 (5.1)	77	239 (6.2)	82	305 (7.8)	85	367 (9.5)
Inclisiran (twice a year)	50	110 (2.8)	70	183 (4.7)	75	220 (5.7)	81	289 (7.5)	85	367 (9.5)

Theoretical efficacy of lipid-lowering treatment with monotherapy and combination therapy. Average reduction of low-density lipoprotein cholesterol (LDL-C) by lipid-lowering monotherapy and combination therapies and baseline LDL-C suitable to be reduced to the LDL-C target of 55 mg/dL (1.4 mmol/L) by different therapies.¹²⁷

Low-intensity statins with a lipid-lowering effect of less than 30–40 %: simvastatin 10 mg; pravastatin 10−20 mg; lovastatin 10−20 mg; fluvastatin 40 mg; pitavastatin 1 mg (not included in the table).

a

Average % reduction of LDL-C with moderate- and high-intensity statins as defined. The % reduction in LDL-C by other drugs was taken from Toth P, et al.¹²⁷

b

% Mean % reduction in LDL-C with bempedoic acid without and in combination with a statin.

c

Maximum LDL-C concentration at which lipid-lowering therapy can achieve a mean LDL-C reduction of up to 55 mg/dL (1.4 mmol/L).

d

The efficacy of combination therapies was calculated according to the following formula: %A + %B (1 − %A) + %C [1 − (%A + %B (1 − %A))]; where %A is the theoretical LDL-C reduction induced by drug A, %B by drug B, and %C by drug C.¹²⁸

e

Atorvastatin 10−20-40; rosuvastatin 5–10; simvastatin 20–40; pravastatin 40; lovastatin 40; fluvastatin 80; pitavastatin 2−4.

f

Atorvastatin 80; rosuvastatin.20−40

Low-to-moderate vascular risk patient

This refers to patients in primary prevention, without DM, with preserved renal function, without FH, and a VR of under 10% according to the SCORE2 tables without coexisting risk modulating, SVD or TOD (Table 7). In this clinical situation, an LDL-C level of less than 115 mg/dL would be considered ideal, and no specific action would be required. Conversely, if LDL cholesterol (LDL-C) were above 190 mg/dL, the patient would be considered high-risk by definition, and familial hypercholesterolaemia (FH) should be ruled out, and lipid-lowering treatment initiated. The recommended LDL-C concentration in these circumstances would be <70 mg/dL (Table 12).

Table 12.

Indications for lipid-lowering treatment according to vascular risk and low-density lipoprotein cholesterol concentration.

VR	LDL-C
	55−70 mg/dL	< 70 mg/dL	70−115 mg/dL	116−190 mg/dL	>190 mg/dL
low or moderate		No treatment required Lifestyle recommendations	No treatment required Lifestyle recommendations	Lifestyle modifications Consider functional foods or lipid-lowering therapy Target: LDL-C <100 mg/dL	High risk by definition. Lifestyle modifications Start high intensity lipid-lowering treatment Target: LDL-C <70 mg/dL
High		No treatment required Lifestyle recommendations	Lifestyle modification Start lipid-lowering treatment if targets not met	Lifestyle modification.Start high-intensity lipid-lowering treatment	Lifestyle modification.Start high-intensity lipid-lowering treatment
			Target: LDL-C <70 mg/dL	Target: LDL-C <70 mg/dL	Target: LDL-C <70 mg/dL
Very high	Lifestyle modification Assess lipid-lowering treatment	Lifestyle modification Start lipid-lowering treatment	Lifestyle modification Start high/very high intensity lipid-lowering treatment	Lifestyle modification Start high/very high intensity lipid-lowering treatment	Lifestyle modification Start high/very high intensity lipid-lowering treatment
	Target: LDL-C <55 mg/dL	Target: Target: LDL-C <55 mg/dL	Target: LDL-C <55 mg/dL	Target: LDL-C <55 mg/dL	Target: LDL-C < 55 mg/dL

LDL-C: low-density lipoprotein cholesterol; VR: vascular risk.

If LDL-C was between 115 and 190 mg/dL, treatment would be based on therapeutic lifestyle changes (TLSC), which would include a diet based on Mediterranean dietary guidelines, along with increased physical activity, smoking cessation, and weight loss if necessary. The use of functional foods enriched with phytosterols and fibre to lower cholesterol may also be indicated. The prescription of lipid-lowering drugs is not universally accepted in this population group and should be considered on an individual basis if a patient presents with two of the following VRFs: age (men >45 years; women >50 years), BMI > 30 kg/m², smoking, hypertension, early-onset FH of ASVD, atherogenic dyslipidaemia, metabolic syndrome, Lp(a) >50 mg/dL, or FH with a milder phenotype. Lipid-lowering treatment should be discussed with the patient.

High-risk vascular patient

The therapeutic target is to reduce LDL cholesterol to <70 mg/dL and achieve at least a 50% reduction from baseline LDL cholesterol levels.

Initial treatment will be based on the application of TLSC. If LDL-C levels remain >70 mg/dL, high-intensity cholesterol-lowering therapy is recommended to ensure an LDL-C reduction of at least 50% (Table 12). Initial treatment should be with statins and, if the target is not achieved, with ezetimibe or bempedoic acid. This combination should be considered initially in patients with baseline LDL-C levels >140 mg/dL.

Very high vascular risk patient

The therapeutic target is an LDL-C <55 mg/dL and a reduction of at least 50% from baseline values.

Initial treatment will be based on the application of TLSC and simultaneous high/very high-intensity cholesterol-lowering therapy to ensure an LDL-C reduction of at least 50% and allow the therapeutic target to be reached (Table 12). The common practice of initiating treatment with statins and subsequently adding other lipid-lowering agents in a second phase has proven insufficient for several reasons: a significant proportion of patients do not achieve reductions of >50%, which, combined with therapeutic inertia and poor adherence, means that most patients will not reach their therapeutic goals in the future. For this reason, it is reasonable to consider the use of combination oral therapy (statins + ezetimibe/bempedoic acid) from the outset. This will facilitate achieving therapeutic goals in less time, promote adherence, and reduce the risk of side effects associated with the maximum statin dose. Combination therapy is mandatory from the outset during hospitalisation for an acute coronary syndrome (ACS) if it is estimated that goals will not be achieved with statin monotherapy.

The use of PCSK9 inhibitors is recommended according to the indications listed in Table 13, particularly in patients requiring LDL-C reductions greater than 60%. It is important to note that achieving LDL-C concentrations below the target range is beneficial for patients. No adverse effects have been detected associated with extremely low LDL-C levels. Furthermore, significant reductions in LDL-C have been shown to decrease the size of atherosclerotic lesions and make plaques more stable. In Spain, this treatment should be considered in patients with LDL-C >100 mg/dL who are on high-dose, high-potency statins and in whom the addition of ezetimibe/bempedoic acid is not expected to achieve therapeutic goals.

Table 13.

Criteria of the Spanish Society of Arteriosclerosis (SEA) for the use of iPCSK9.

Clinical situations	Further conditioning factors	LDL-C
Homozygous familial hypercholesterolaemia (HoFH)	–	>100
Heterozygous familial hypercholesterolaemia (HeFH) (HFHe)	<4 associated VRFs	>160
	≥4 associated VRFs	>130
	With DM	>100
	With ASDV	>70
Secondary prevention	Stable	>130
	ACS (<1 year)	>100
	DM + additional VRF	>100
	More than 2 additional uncontrolled VRFs	>100
	Lp(a) >50 mg/dL (100 nmol/L)	>70
	Recurrent or non-revascularisable multivessel coronary artery disease	>70
	Isolated symptomatic PAD or polyvascular disease	>70
	ACS <1 year + DM	>70
	CKD stage ≥ 3 + 1 VRF	>70
Primary prevention with very high risk	CKD ≥3 b (not in dialysis) + DM	>130

ACS: acute coronary syndrome; CKD: chronic kidney disease; DM: diabetes mellitus; LDL-c: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); PAD: peripheral arterial disease; PCSK9i: protein subtilisin/kexin 9 convertase inhibitor; VAS: atherosclerotic vascular disease; VRF: vascular risk factors.

Adapted from Ref.¹²⁹

Treatment of hypercholesterolaemia in special situations

Patients infected with HIV have a high risk of vascular complications. In primary prevention, the REPRIEVE study¹²⁸ demonstrated that pitavastatin treatment reduces major vascular complications. For this reason, the EAS/ESC¹⁵ recommendations state that any HIV-infected patient over 40 years of age should receive lipid-lowering therapy, regardless of their estimated risk and LDL-C concentration. They also recommend evaluating the statin to be used based on potential drug interactions. It is important to consider that the net benefit is greater in subjects with an estimated 10-year risk of vascular complications >5%, since lower risks represent a very high number needed to treat (NNT).

Patients with atherogenic dyslipidaemia

In patients with atherogenic dyslipidaemia, the main goal is to achieve LDL-C and non-HDL-C within therapeutic targets according to the risk level, using, in addition to a healthy diet, ⁸⁷ statin therapy or high-intensity combination therapies. Once this target is achieved, in patients undergoing primary prevention with diabetes mellitus (DM) or secondary prevention who, despite optimal lipid-lowering therapy, maintain a triglyceride (TG) concentration >150 mg/dL, the use 4 g/day EPA should be considered (Class IIa recommendation in the recent 2025 guidelines).¹⁵

Patients with hypertriglyceridaemia

Except in severe hypertriglyceridaemia, the therapeutic approach consists of reducing the VR by controlling LDL-C, with particular attention in these cases to controlling non-HDL-C).

Triglycerides between 200 and 500 mg/dL

In these patients, the approach should be as described above for their VR level and their LDL-C and non-HDL-C levels. According to EAS recommendations, in very high-risk patients in whom TG levels remain >150 mg/dL after LDL-C control with statins plus ezetimibe/bempedoic acid/PCSK9 inhibitors, the use o EPA should be considered. Results from various clinical trials, including the PROMINENT¹³⁰ study, question the use of fibrates for reducing cardiovascular risk. However, the EAS/ESC¹⁵ recommendations indicate that if TG levels remain above 200 mg/dL after achieving LDL-C targets with statins and EPA cannot be used, the use of fenofibrate/bezafibrate could be considered (level IIb recommendation).

Triglycerides between 500 and 1,000 mg/dL

In these circumstances, the above guidelines should be followed, using cholesterol-lowering treatment according to the VR and non-HDL cholesterol levels (applying the same criteria as for LDL-C plus 30 mg/dL).

If, after implementing these measures, triglyceride levels remain >500 mg/dL, the combination of fenofibrate and/or omega-3 fatty acids (at doses ≥3 g per day)¹³¹ should be considered to reduce the risk of pancreatitis.

Triglycerides >1,000 mg/dL

Lowering triglycerides (TG) through diet is a priority to prevent pancreatitis. This involves reducing alcohol and carbohydrate intake, and in resistant forms, limiting total fat intake to less than 30 g per day. Weight loss, physical activity, and glycaemic control should also be recommended for patients with diabetes. In severe and persistent cases, generally associated with multifactorial chylomicronaemia syndrome (MCS), treatment with fenofibrate and/or omega-3 fatty acids (3–6 g daily) should be initiated, and their combination should be considered if glycaemic control is inadequate. Additionally, the introduction of medium-chain triglyceride (MCT) oil should be considered if TG levels remain very high. Specific treatments for patients with familial chylomicronaemia syndrome (FCS) are explained in the corresponding section. Volanesorsen (an antisense oligonucleotide anti-apoC3) is indicated and approved for use in patients with FCS and episodes of pancreatitis.

Patients with genetic dyslipidaemias

Familial hypercholesterolaemia

Patients with FH are considered high-risk by definition and should achieve an LDL-C <70 mg/dL or <55 mg/dL if VRFs or ASVD are associated. In addition to diet and a healthy lifestyle, most patients should receive a combination of high-potency statins with ezetimibe,¹³² also considering triple therapy with bempedoic acid. Based on their baseline risk (which, as previously mentioned, should be stratified), these patients may be treated with PCSK9 inhibitors (Table 13). Early treatment is necessary to prevent the development of future vascular complications. Patients with the homozygous form of the disease should receive, in addition to conventional lipid-lowering therapy (high-dose statins and ezetimibe), a PCSK9 inhibitor if they have at least one defective (non-null) allele. While LDL apheresis has been considered the gold standard in these patients, the2023¹³³ EAS guidelines and the 2025¹⁵ update recommend considering cholesterol-lowering therapies that act on pathways independent of the LDL receptor, such as lomitapide, indicated and approved in adults and with positive clinical data in children from five years of age, or evinacumab, which is approved for use from six months of age.

Lomitapide is a small molecule administered orally that inhibits microsomal triglyceride transfer protein (MTP), limiting VLDL formation. It reduces LDL cholesterol by more than 50%. Fat intake should be monitored, the diet supplemented with vitamin E and fatty acids, and hepatic fat accumulation should be controlled. Evinacumab is a monoclonal antibody against angiopoietin-like 3 (ANGPTL3), a protein that inhibits lipoprotein lipase (LPL) and endothelial lipase, a deficiency of which is associated with generalised hypolipidaemia. It is administered by intravenous infusion once a month and allows for VLDL remodelling, enabling its removal from plasma via pathways independent of the LDL receptor. The recommended LDL cholesterol target in children is <115 mg/dL and in adults <70 or 55 mg/dL, depending on the presence of ASVD.

Dysbetalipoproteinaemia

This is a rare hyperlipidaemia characterised by elevated IDL levels, resulting in severe mixed hyperlipidaemia, the occasional presence of palmar striated xanthomas, and a high risk of early ASVD, with a particular predilection for PAD. It is usually caused by the combination of an E2/E2 genotype in the Apo E gene and one or more environmental factors (hypothyroidism, obesity, etc.). It should be suspected in any mixed hyperlipidaemia with low Apo B levels (<120 mg/dL).¹³⁴ Treatment is aimed at controlling the coexisting environmental factor, especially obesity, and using statins, with or without ezetimibe and/or fibrates. Given the characteristics of the dyslipidaemia, the main goal is to control non-HDL cholesterol.¹³⁵

Chylomicronaemia syndrome

This syndrome involves the accumulation of chylomicrons in the bloodstream due to a lack of LPL activity, leading to insufficient TG catabolism and a severe increase in their concentration in the blood.¹³⁶ There is a group of chylomicronaemias with a severe genetic basis, FCS^137,138 and another, much more frequent one, due to the association of less pathogenic genetic variants with aggravating factors, MCS.¹³⁹ FCS is a rare disease, affecting 1 in 1,000,000 people. It is due to recessive loss-of-function variants, which are homozygous or compound heterozygous, of the LPL, apolipoprotein C2 (Apo C2), apolipoprotein A5 (Apo A5), lipase maturation factor 1 (LMF1), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), or glycerol 3-phosphate dehydrogenase 1 (G3PDH1) genes.^140,141 Chylomicronaemia occurs even without aggravating factors, and TG concentrations remain chronically very high, generally >10 mmol/L (885 mg/dL).¹⁴² The most serious complication of this disease is acute pancreatitis, which is more frequent and recurrent the higher the TG concentration and can appear in the first years of life.¹⁴³ Pancreatitis can progress to chronic pancreatitis with pancreatic insufficiency and pancreatic DM. Eruptive xanthomas affecting the extensor surfaces of the limbs and trunk, hepatosplenomegaly, and lipaemia retinalis may also appear.¹⁴⁴

MCS is due to the association of various genetic factors of lower pathogenicity, linked to conditions responsible for secondary hypertriglyceridaemia.¹⁴⁵ There is a risk of pancreatitis, but it is lower than in FCS due to the lesser severity and persistence of the hypertriglyceridaemia.¹⁴⁶ The response to diet, physical activity, and hypotriglyceride-lowering drugs is usually good. MCS typically appears in adulthood or midlife.

In both conditions, treatment is based on a diet with significant restriction of total fat intake (<30 g per day), the use of oil rich in medium-chain triglycerides (MCTs), fibrates, and omega-3 fatty acids at doses greater than 3 g per day. However, in FCS, the response to fibrates and omega-3 s may be very poor or absent because LPL activity cannot be stimulated. Currently available is volanesorsen, an antisense oligonucleotide that blocks the synthesis of apolipoprotein C3 (Apo C3), a protein involved in the metabolism of triglyceride-rich lipoproteins, hindering, among other effects, their clearance from the plasma. It produces a reduction in triglycerides of more than 50%. Platelet counts should be monitored, as it can cause thrombocytopenia. Other drugs in development for the treatment of this disease include olezarsen and plozasiran.

Hypoalphalipoproteinaemia

The most common causes of hypoalphalipoproteinaemia are those related to hypertriglyceridaemia and atherogenic dyslipidaemia. Primary forms are rare and include Tangier disease, LCAT deficiency, and genetic variants of the Apo A1¹⁴⁷ gene. There are no specific treatments for these conditions, and the management of these patients should focus on the strict control of other VRFs and associated organ dysfunction, such as renal involvement in some of the pathologies.¹⁴⁸

Hypobetalipoproteinaemia

These are patients with very low levels of lipoproteins containing Apo B. They present clinically with very low LDL-C levels (below the 10th percentile). They include conditions such as abetalipoproteinaemia (MTP deficiency), hypobetalipoproteinaemia (homozygous or heterozygous Apo B gene alteration), PCSK9 and angiopoietin-like protein 4 (ANGPTL4) deficiencies, and chylomicron retention disease (deficiency of Ras-associated secretion-related GTPase 1β [SAR1B]). In cases of total Apo B deficiency, severe clinical manifestations occur, including intestinal malabsorption, fatty liver, hemolytic anaemia, and neurological disorders due to vitamin and essential fatty acid deficiencies. These are treated with supplements of the deficient elements. Moderate forms of hypobetalipoproteinaemia do not usually cause complications and are generally considered benign and associated with a lower vascular resistance. In cases due to reduced Apo B synthesis, an increased risk of fatty liver has been reported.¹⁴⁹

Hyperlipoproteinaemia(a)

The presence of an elevated Lp(a) concentration is considered a modulating risk factor for the development of vascular complications and aortic stenosis.¹⁷ However, the relationship between Lp(a) and vascular risk is continuous; the higher its level, the greater the risk. Therefore, its concentration should be considered when estimating an individual's overall risk, multiplying the risk calculated from the tables by the increased risk attributable to the Lp(a) concentration¹⁷ (Table 8). Effective treatments for its clinical management will soon be available. We refer the reader to the SEA document on this topic.¹⁷

Patients with high blood pressure

An appropriate blood pressure measurement is recommended to confirm the diagnosis of hypertension (Table 3) A blood pressure difference between both arms, measured simultaneously, >10–15 mmHg is associated with an increased risk of ASVD.

During the first visit, blood pressure (BP) should be measured in the supine position after 5 min of rest, and subsequently in the standing position after 1–3 min. Orthostatic hypotension is defined as a reduction in systolic blood pressure (SBP) in the standing position of >20 mmHg and should be considered at the beginning of, or after initiating or intensifying, antihypertensive treatment, especially in elderly patients or those with long-standing diabetes mellitus.

ABPM and HBPM correlate more closely with prognosis and TOD than clinical measurement, making their use highly recommended.^10,150 It should be noted that the blood pressure thresholds that define hypertension vary depending on the technique used: clinical blood pressure, ABPM, or 24-h HBPM.

ABPM is not only useful for diagnosis in untreated patients and the detection of white coat hypertension (elevated blood pressure in the office setting, but normal values in ABPM), but it is also a valuable tool for therapeutic monitoring, evaluating treatment adherence, and identifying masked hypertension, characterised by normal blood pressure readings in the office setting, but elevated readings outside of it.

Table 14 shows the blood pressure (BP) categories according to the values obtained through clinical BP measurement, and Table 15 defines hypertension (HTN) according to the threshold values for clinical, ambulatory, or home-measured BP.

Table 14.

Blood pressure classification in adults.

Category	SBP (mmHg)	DBP (mmHg)
Optimal	<120	<80
Normal	120−129	80−84
Normal high	130−139	85−89
Grade 1 hypertension	140−159	90−99
Grade 2 hypertension	160−179	100−109
Grade 3 hypertension	≥180	≥110
Isolated systolic hypertension	≥140	<90

A diagnosis of hypertension (HTN) is established after verifying blood pressure (BP) values in two or more measurements taken during each of two or more visits.

When systolic BP (SBP) and diastolic BP (DBP) fall into different categories, the higher category will be applied.

Isolated systolic hypertension is classified into stages (1, 2, or 3) according to the SBP value.

Table 15.

Definitions of hypertension according to clinical, outpatient or home measurement values.

Category	SBP (mmHg)	DBP (mmHg)
BP in clinic	≥140	≥90
Outpatient BP
Daytime (or under surveillance)	≥135	≥85
Night time (or sleeping)	≥120	≥70
24 h	≥130	≥80
BP at home	≥135	≥85

BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure.

Adapted from Ref.⁷

BP values obtained through ambulatory blood pressure monitoring (ABPM) distinguish four phenotypes:

• •

  Normotension: normal BP values in the clinic and in ABPM.

• •

  White coat hypertension: elevated BP values in the clinic, but normal BP levels in ABPM.

• •

  Masked hypertension: normal BP levels in the clinic, but elevated values in ABPM.

• •

  Established hypertension: elevated BP values in the clinic and in ABPM.

Blood pressure (BP) values obtained by HBPM also correlate better with TOD and the incidence of ASVD, but ABPM provides information on nocturnal BP, which has a strong correlation with prognosis. Elevated nocturnal BP is especially prevalent in certain clinical situations, such as resistant hypertension, hypertension associated with DM or advanced CKD, and hypertension associated with obstructive sleep apnea-hypopnea syndrome (OSAHS).

Initiation of antihypertensive treatment

The decision to initiate pharmacological treatment will depend not only on the BP level, but also on overall VR based on other associated VRFs, the presence of TOD, which predicts cardiovascular mortality independently of the SCORE2/SCORE2-OP score,^7,14,78,79 especially in the moderate-risk group, and the presence of ASVD or established kidney disease.

Initial treatment will be determined based on blood pressure levels (stages 1–3) (Table 14) and the hypertension (1–3) stage:

• •

  Stage 1: Uncomplicated hypertension, without TOD, DM, ASVD and with an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m².

• •

  Stage 2: Hypertension in the presence of TOD, DM, or stage 3 CKD.

• •

  Stage 3: Presence of ASVD or stage 4 CKD (eGFR <15−29 mL/min/1.73 m²) or stage 5 (eGFR <15 mL/min/1.73 m²) CKD.

Hypertension treatment should always include lifestyle modifications. In cases of stage 1 hypertension with low or moderate cardiovascular risk, it is recommended to begin with non-pharmacological measures only. If the risk is high or if there is a presence of TOD (stage 2 hypertension), pharmacological treatment should be added once the diagnosis is confirmed.

In patients with stage 2 hypertension (systolic blood pressure 160–179 mmHg and/or diastolic blood pressure 100–109 mmHg) or stage 3 hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg), pharmacological treatment should be added from the outset, and most of them will require combination antihypertensive therapy with at least two antihypertensive agents. Approximately 10%–12% of treated hypertensive patients will require more than three antihypertensive agents.¹⁵¹

The main benefit of antihypertensive treatment stems from the reduction in blood pressure (BP),¹⁵² regardless of the drug used. Treatment can be initiated with thiazide diuretics or similar agents (indapamide, chlorthalidone), ACE inhibitors or angiotensin II receptor blockers (ARBs), calcium channel blockers, or beta-blockers. The position of the latter as first-line drugs has been questioned due to their lower effectiveness in stroke prevention or their potential adverse metabolic effects (although this may not apply to all beta-blockers), except in clinical situations with a specific indication for these agents (HD, heart failure with reduced left ventricular ejection fraction, [LVEF] etc.). They may also be indicated as initial treatment in young hypertensive patients with a hyperkinetic pattern and a tendency toward tachycardia, or in women of childbearing age, in whom the use of renin-angiotensin system (RAS) inhibitors is contraindicated from the early stages of pregnancy.

A 5 mmHg reduction in SBP decreases serious cardiovascular events by approximately 10%, in both primary and secondary prevention.¹⁵³

Therapeutic target of anti-hypertensive treatment

The new 2023 ESH guidelines recommend therapeutic goals based on age,⁷ although current evidence suggests a therapeutic goal (if tolerated) of less than 130 mmHg systolic blood pressure (SBP) and a diastolic blood pressure (DBP) between 70 and 79 mmHg.

In elderly patients with isolated systolic hypertension, treatment intensification is usually necessary if SBP is >160 mmHg, even if DBP is <70 mmHg.

SBP < 120 mmHg or DBP < 70 mmHg is not recommended.

Treatment of hypertension in patients with comorbidities

Hypertension and diabetes mellitus

The prevalence of hypertension in patients with diabetes mellitus is up to 80%, twice that observed in the non-diabetic population of the same age and characteristics. The co-existence of hypertension and diabetes mellitus increases the risk of developing ASVD, with a higher incidence of ischaemic heart disease, heart failure, peripheral artery disease, stroke, and cardiovascular mortality.

It is recommended to initiate treatment with a combination of a renin-angiotensin-aldosterone system (RAS) inhibitor plus a calcium channel blocker or a thiazide or thiazide-like diuretic, except when the eGFR is <30 mL/min/1.73 m², in which case a loop diuretic would be indicated. The combination of two RAS inhibitors is not recommended.

Pharmacological treatment should be initiated whenSBP is ≥140 mmHg or DBP is ≥90 mmHg, and the therapeutic goal is an SBP < 130 mmHg, but not less than 120 mmHg, with a DBP < 80 mmHg, but not <70 mmHg.

Hypertension and chronic kidney disease

The prevalence of hypertension in these patients is 67%–92%, and it represents their most frequent comorbidity. Furthermore, the presence of hypertension can accelerate kidney damage, in addition to increasing VR. As in all patients with hypertension, pharmacological treatment should be accompanied by lifestyle changes, with particular emphasis on reducing sodium intake. Loop diuretics should replace thiazide or thiazide-like diuretics when the eGFR is <30 mL/min/1.73 m².

A clinical trial published in 2021 showed that in subjects with advanced CKD (eGFR of 23 ± 4.2 mL/min/1.73 m²), chlorthalidone at doses of 12.5–50 mg/day improves blood pressure control in poorly controlled patients compared to placebo at 12 weeks of follow-up.¹⁵⁴

Because lowering blood pressure reduces perfusion pressure, a 10%–20% reduction in eGFR at the start of treatment is not uncommon. Careful electrolyte monitoring is required.

The therapeutic target is a SBP <130 mmHg, but not below 120 mmHg, and a DBP <80 mmHg, but not <70 mmHg.

An RAS inhibitor plus a calcium channel blocker or a diuretic is recommended as initial treatment. The concurrent use of ACE inhibitors and angiotensin II receptor blockers (ARBs) is not recommended.

Hypertension and stable coronary artery disease

HTN is a major VRF for IHD. Numerous clinical trials have demonstrated the benefits of antihypertensive treatment in reducing the incidence of IHD, both in primary and secondary prevention.

Except in some cases, such as frail elderly patients or those over 80 years of age, dual therapy with an RAAS inhibitor (ACE inhibitor or ARB) plus a beta-blocker or calcium channel blocker is generally recommended as initial treatment, although other combinations such as a dihydropyridine calcium channel blocker plus a beta-blocker may be used. As a second step, if hypertension is not controlled, the patient should be treated with triple therapy, generally adding a diuretic to one of the aforementioned combinations.

If symptomatic angina is present, a combination of beta-blockers and dihydropyridine calcium channel blockers is recommended.

Pharmacological treatment is recommended when blood pressure (BP) is ≥130/80 mmHg, and the therapeutic target is a SBP of 130 mmHg or lower if tolerated, but not <120 mmHg, and aDBP <80 mmHg, but not < 70 mmHg.

Hypertension and heart failure

A history of hypertension is present in 75% of patients with chronic heart failure. Antihypertensive treatment is recommended when clinical BP is ≥130/80 mmHg, both in patients with HF with reduced LVEF and in those with HF with preserved LVEF. In patients with HF and reduced LVEF, treatment with an renin-angiotensin-aldosterone system (RAAS) inhibitor (ACE inhibitor or ARB) or sacubitril/valsartan, a beta-blocker, and a diuretic is recommended, along with an SGLT2 inhibitor and a mineralocorticoid receptor antagonist, provided there are no contraindications. If hypertension is not controlled despite the above treatment, a dihydropyridine calcium channel blocker may be added.

In patients with HF and preserved LVEF, the use of ACE inhibitors or ARBs, beta-blockers, calcium channel blockers, and thiazide or thiazide-like diuretics in combination with SGLT2 inhibitors is recommended for the control of hypertension.

Hypertension and atrial fibrillation

Hypertension is the most common modifiable VRF for preventing the development of atrial fibrillation (AF). The coexistence of hypertension and AF significantly increases the risk of ischaemic and haemorrhagic stroke. All first-line antihypertensive drugs would be indicated for the control of hypertension, but the use of RAS inhibitors and beta-blockers could be considered in AF to prevent its recurrence. The threshold for initiating antihypertensive treatment and the therapeutic goal would be the same as for the general population.

In patients with AF and SBP >160 mmHg, it is necessary to improve hypertension control before initiating anticoagulant therapy.

Hypertension and stroke

Stroke is a major cause of mortality, disability, and dementia, and is independently associated with an increased risk of major vascular events in both sexes.¹⁵⁵ Because stroke is a heterogeneous group in terms of aetiology and underlying haemodynamics, managing hypertension in these patients is complex and truly challenging. The therapeutic target is a blood pressure <130/80 mmHg.¹⁵⁶ This BP target of <130/80 mmHg is also recommended in TIAs, as advised by a recent American Heart Association (AHA) document, since it reduces the risk of stroke recurrence by 22%.¹⁵⁷

Resistant and refractory hypertension

There are several causes of poor hypertension control in clinical practice, which should be considered before labelling a patient with resistant hypertension (Fig. 5).¹⁵⁸

Figure 5.

Factors Associated with Difficult-to-Control Hypertension.

Resistant hypertension accounts for approximately 10%–12% of treated hypertensive patients.¹⁵¹ Hypertension is considered resistant when blood pressure (BP) cannot be reduced to <140/90 mmHg despite optimal (or maximum tolerated) doses of three medications and a treatment plan that includes a diuretic (typically an ACE inhibitor or ARB plus a calcium channel blocker and a diuretic).

Poor control should be confirmed by ABPM (preferred) or HBPM, and causes of pseudo resistance (e.g., poor adherence) and secondary hypertension must be ruled out.

In recent years, a new phenotype of refractory hypertension has been described in which BP is not achieved to <140/90 mmHg despite the use of ≥5 antihypertensive medications.^159,160 It is uncommon (1.4% of treated hypertensive patients) and also requires 24 -h ambulatory blood pressure monitoring (ABPM) for confirmation, as well as ruling out the causes of pseudo resistance, as mentioned previously in resistant hypertension. A prospective cohort study¹⁶¹ demonstrated that patients with refractory hypertension, confirmed by 24-h ABPM, have a higher risk of major cardiovascular events and mortality.

Fig. 6 presents a practical algorithm for the diagnosis and monitoring of resistant and refractory hypertension.

Figure 6.

Clinical management of resistant and refractory hypertension.

ABPM: ambulatory blood pressure monitoring; DBP: diastolic blood pressure; SBP: systolic blood pressure.

Monitoring the patient with hypertension

After initiating antihypertensive drug treatment, it is important to monitor adherence at least once within the first two months to assess its effect on blood pressure (BP), detect any adverse effects, and identify potential poor adherence. A follow-up visit is then recommended at three months to verify BP control and evaluate adherence.

Poor adherence is a frequent cause of uncontrolled BP. Nurses, community pharmacists, and other healthcare professionals play a fundamental role in its detection and assessment. They are also invaluable in educating, supporting, and providing long-term follow-up for hypertensive patients and should therefore be part of the overall strategy for improving BP control. Simplifying treatment and reducing the number of tablets would undoubtedly contribute to better adherence and improved BP control in the medium and long term.

In individuals with normal to high blood pressure, even without pharmacological treatment, lifestyle changes and regular follow-up (at least one annual visit) are recommended to measure clinical and ambulatory blood pressure, as well as to reassess their cardiovascular risk.

Patients with hyperglycaemia (prediabetes and diabetes mellitus)

Classification and diagnostic tests

Hyperglycaemia is defined as at least two fasting plasma glucose values≥ 100 mg/dL, and diabetes mellitus as two fasting plasma glucose values ≥ 126 mg/dL. In addition to the fasting glucose criterion, prediabetes and DM can be diagnosed if at least one of the following criteria is met: HbA1c, random blood glucose values, or plasma glucose values​at 2 h from the oral glucose tolerance test (OGTT), as described in Table 16.¹⁶²

Table 16.

Diagnostic criteria of prediabetes and diabetes mellitus from the American Diabetes Association (ADA).¹⁶²

Prediabetes and diabetes diagnosis criteria*	Normal	Prediabetes	DM
HbA1c (%) or	<5.7	5.7−6.4	≥6.5
Fasting plasma glycaemia (mg/dL) or	<100	100−125	≥126
2-h OGTT glycaemia with 75 g (mg/dL) or	<140	140−199	≥200
Random glycaemia with hyperglycaemic symptoms (mg/dL)			≥200

DM: diabetes mellitus; HbA1c: glycated haemoglobin; OGTT: oral glucose tolerance test.

*

Two abnormal tests are required for the diagnosis of DM.

The OGTT is performed by administering 75 g of glucose to an adult or 1.75 g/kg of body weight (maximum 75 g) to children under standardised conditions. It is a very useful test for confirming the diagnosis of DM in patients who are not diagnosed based on fasting glucose or HbA1c values alone, but who have a high probability of being diagnosed: obese individuals, those with metabolic syndrome, gestational DM, and individuals meeting the criteria for prediabetes.^74,162 HbA1c measurements should be performed using a standardised, reference method.¹⁶²

We recommend screening for diabetes mellitus (DM) in asymptomatic individuals to facilitate early diagnosis (Table 17). In this case, to aid diagnosis, we will use fasting glucose and HbA1c levels. An oral glucose tolerance test (OGTT) is not necessary for screening. Furthermore, screening protocols based on new information technologies and artificial intelligence should be implemented to detect DM early using biochemical analyses performed in a health department.

Table 17.

Subjects to be screened for diabetes mellitus.⁷⁴

Age ≥ 35 years	Age < 35 years
In all cases	With a diagnosis of prediabetes or
	With a history of gestational diabetes or
	HIV or
	If they have a BMI ≥ 25 kg/m^2, or ≥ 23 kg/m^2 in Asians, with at least one of the following:
	Diabetes in first-degree relatives
	Belonging to an ethnic group at high risk for diabetes (African Americans, Latinos, etc.)
	History oafs
	HTN (≥ 140/90 mmHg or under treatment)
	HDL -C < 35 mg/dL, TG > 250 mg/dL, or both
	PCOS
	Sedentary lifestyle
	Other conditions associated with insulin resistance (acanthosis nigricans, non-alcoholic fatty liver disease, familial combined hyperlipidaemia, etc.)

ASVD: atherosclerotic vascular disease; BMI: body mass index; DM: diabetes mellitus; HD-C: high-density lipoprotein cholesterol; HIV: human immunodeficiency virus; HTN: hypertension;PCOS: polycystic ovary syndrome.

Newly diagnosed DM patients have high VR without necessarily having TOD of ASVD. The SCORE-2 DM⁸⁰ can be used to assess VR in this patient group.

Control targets in prediabetes and diabetes mellitus

The general control targets are presented in Table 18.

Table 18.

General targets for prediabetes and diabetes control.

Targets
Establish, achieve, and maintain good metabolic controls
Prevent complications of diabetes mellitus (DM)
Preserve the patient's life and alleviate the symptoms of hyperglycaaemia
Empower the patient to achieve a good quality of life (personal, family, work, and social)
Individualise HbA1c levels

DM: diabetes mellitus; HbA1c: glycated haemoglobin.

To achieve good glycaemic control, the first step is to individualise the HbA1c target.¹⁶² To determine the HbA1c value, we consider: the patient's level of motivation, the presence of chronic complications or serious comorbidities, the patient's age, estimated survival, and disease duration (Fig. 7). In young patients without chronic complications or comorbidities, with short disease duration and long estimated survival, we will aim to intensify treatment to achieve an HbA1c between 6% and 7%¹⁶² and if possible ≤ 6%.

Figure 7.

Therapeutic scheme in type 2 diabetes mellitus (DM).

BMI: body mass index; HbA1c: glycated haemoglobin.

To accurately treat patients with DM, it is necessary not only to control glycaemia and aim for an individualised HbA1c value, but also to monitor blood pressure, lipid levels, weight, and smoking. This is known as comprehensive DM management. This treatment will always be individualised and initiated early. The specific BMI, smoking, blood pressure, and biochemical targets for diabetes mellitus (DM) treatment are listed in Table 19.

Table 19.

Specific clinical and biochemical targets for treatment in diabetic adults.

Targets	Optimal	Acceptable	Undesirable
Baseline glycaemia (mg/dL)	80−130	130−179	≥180
Postprandial glycaemia 2 h (mg/dL)	<180	180−199	≥200
HbA1c (%)	<7.0	7.0−7.9	≥8.0
LDL-C (mg/dL)*	Variable	Variable	Variable
PA (mmHg)	<130/< 80	130−139/80−89	≥140/≥90
Tobacco	DO NOT SMOKE
BMI (kg/m^2)	Ideal <25; in obese patients, <30

BP: blood pressure; BMI: body mass index; DM: diabetes mellitus; HbA1c: glycated haemoglobin; LDL-C: low-density lipoprotein cholesterol.

*

LDL-C according to cardiovascular risk: Very high-risk DM LDL-C <55 mg/dL, High-risk DM LDL-C <70 mg/dL, Moderate-risk DM LDL-C <100 mg/dL.

Treatment of prediabetes and diabetes mellitus

The treatment of prediabetes and diabetes is based on lifestyle changes, diet, and medication to achieve the therapeutic goals discussed.

Diet and lifestyle changes

Treatment should be geared toward meeting all the overall goals outlined. The cornerstone of prediabetes and type 2 diabetes treatment is diet, lifestyle changes, and physical activity.^14,162,163 Since most affected individuals are obese, the dietary treatment is similar to that described in the section on obese patients.

Lifestyle modification in DM is an essential intervention to improve not only glycaemic control but also associated comorbidities, such as dyslipidaemia, obesity, and hypertension. Changes towards a healthy lifestyle should include the following: smoking cessation and moderation of alcohol intake, weight loss (>5%) in cases of overweight or obesity, personalised nutritional counselling, and activity with continuous supervision. Carbohydrate intake from vegetables, fruits, whole grains, legumes, and dairy products is recommended over other sources.^14,163 Processed foods containing added fats, sugars, or sodium should be especially limited. Consumption of omega-3 polyunsaturated fatty acids found in fish, especially oily fish (sardines, salmon, tuna, mackerel, horse mackerel, etc.), is recommended. In summary, a Mediterranean-type diet rich in monounsaturated fatty acids (virgin olive oil and nuts) can be useful for the overall management of cardiovascular risk in these patients.^14,163

Several studies included in meta-analyses have evaluated the effects of lifestyle interventions in people with prediabetes and have found that they effectively prevent the development of DM.¹⁶² These studies support the use of a Mediterranean-type diet in individuals with prediabetes.¹⁶³

General recommendations for physical activity in people with prediabetes or DM are summarised in Table 20. It is necessary to implement a progressive physical activity programme.

Table 20.

General physical exercise recommendations for people with prediabetes and diabetes mellitus.

General recommendations
Engage in at least 150 min of moderate-to-vigorous aerobic activity per week, spread over at least 3 days. Avoid going more than 2 days without physical activity.
Perform 2–3 resistance training sessions per week on non-consecutive days.
Reduce daily time spent on sedentary activities.
For older adults, perform flexibility and balance exercises 2–3 times per week.

Pharmacological intervention

In individuals with prediabetes, the ADA recommends metformin treatment in those with a BMI > 35 kg/m², a history of gestational diabetes, fasting plasma glucose ≥110 mg/dL and HbA1c ≥6.1%, and in obese individuals with visceral fat deposits.¹⁶²

The goals of treatment for patients with DM are to prevent and delay macrovascular and microvascular complications and to reduce the high rate of vascular morbidity and mortality. The greatest benefit in cardiovascular prevention for patients with DM is achieved by simultaneously addressing all cardiovascular risk factors: smoking, dyslipidaemia, hypertension, and hyperglycaemia.^14,162

Focusing on the pharmacological treatment of hyperglycaemia, once the target HbA1c value has been established, the choice of medications will depend on age, the degree and type of obesity, the efficacy and tolerability of the drugs, cost, and comorbidities (secondary prevention, heart failure, or diabetic kidney disease).

Table 21 presents the main medications used to treat hyperglycaemia in diabetes mellitus and their indications.

Table 21.

main drugs used in diabetes mellitus treatment.

Drug	Dose	Indication
Metformin	850 mg × 3	T2DM
	Titrate gradually	T1DM obese
		DM gestational
Pioglitazone	30−45 mg/day	T2DM
	Authorisation required	T2DM and fatty liver
DPP-4 inhibitor	Sitagliptin 100 mg/day	T2DM
	Vildagliptin 50 mg × 2
	Saxagliptin 5 mg/day
	Linagliptin 5 mg/day
	Alogliptin 25 mg/day
GLP-1 receptor	Exenatide 5 μg s.c. × 2 for 1st month, 10 μg s.c. × 2 for 2nd month	T2DM obese in secondary prevention
	Liraglutida .6 mg/day, 1.2 mg/day for 2nd week and if necessary 1.8 mg/day	T2DM with obesity
	Exenatide long acting (LAR), 2 mg/week
	Lixisenatide, 10 μg/day for 2 weeks, increase to 20 μg/day
	Dulaglutide .75 mg/week, increase to 1.5 mg/week
	Semaglutide .25 mg/week for 4 weeks and increase to .5 mg/week.
	Maximum 1 mg/week
GLP-1 and GIP (dual) RAs	Tirzepatide 2.5 mg/week up to a maximum of 15 mg/week	T2DM with obesity
iSGLT2	Empagliflozin 10 and 25 mg/day	T2DM
	Canagliflozin 100 and 300 mg/day	T2DM with HF
	Dapagliflozin 10 mg/day	T2DM in secondary prevention
	Ertugliflozin 5 and 15 mg/day	T2DM with nephropathy
Meglitinides	Repaglinide .5−4 mg before the three main meals.	T2DM with CKD
	Nateglinide 120 mg with the three main meals. Authorisation required.
3rd generation sulfonylureas	Start with low doses and gradually increase the dose.	T2DM
Alpha-glucosidase inhibitors:	Acarbose or miglitol 50 mg 3 times daily, at the start of meals. Maximum 100 mg 3 times daily.	T2DM

BMI: body mass index; CKD: chronic kidney disease; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; DM: diabetes mellitus; GLP-1 receptor agonists: GLP-1 receptor agonists; DDP-4 inhibitors: dipeptidyl peptidase-4 inhibitors; HF: heart failure; s.c.: subcutaneous; SGLT2 inhibitors: sodium-glucose cotransporter 2 inhibitors.

Table 22^{162,164–171} summarises the main benefits, contraindications, adverse effects, and cardiovascular prevention capacity independent of their hypoglycemic effect.

Table 22.

Benefits, contraindications, main adverse effects and vascular prevention capacity of the main hypoglycaemic drugs used in the treatment of diabetes mellitus.

Drug	Benefits	Contraindication	Disadvantages/adverse effects	CV prevention
Metformin	↓ HbA1c 1%	eGFR <30 mL/min/1,73 m^2	Nausea, vomiting, abdominal pain	Yes^162
	↓ weight (1.5−2 kg)	Severe liver failure	Exceptional: vitamin B12 deficiency and lactic acidosis
	↓ cost	24 h prior to surgery
	No hypoglycaemia
Pioglitazone	↓ HbA1c 0.5−1%	Heart failure	↑ weight	Yes, in primary prevention Stroke^162
	↓ TG and ↑ HDL-C		↑ cost
			Oedemas
			HF
			Fracture
			In post menopausal women
IDPP-4	↓ HbA1c 0,8%	FG <60 mL/min/1.73 m^2 adjust dose sitagliptin 25 and 50 mg/day, alogliptin 6.25 and 12.5 mg/day	↑ cost	No
	Weight =  No hypoglycaemias	Does not require linagliptin	Skin lesions (bullous pemphigoid)	Saxagliptin ↑ HF admissions
			Do not combine with GLP-1 receptor agonists
			Rare pancreatitis
GLP-1RA	↓ HbA1c 1%	Pregnancy	Nausea, vomiting, diarrhoea	Yes
	↓↓ weight	Caution in patients with kidney failure (see section on obese patients)	↑ cost	Liraglutide and semaglutide in secondary prevention.^164,165
	No hypoglycaemias		Rarely pancreatitis	Dulaglutide in primary and secondary prevention^166
				Liraglutide, semaglutide, and dulaglutide ↓ progression of diabetic kidney disease
GLP-1 and GIP (dual)RAs	↓ HbA1c 1%	Pregnancy	Nausea, vomiting, diarrhoea, constipation	Under study
	↓↓↓ weight	Caution in patients with kidney failure (see section on obese patients)	↑ cost
	No hypoglycaemias		Rarely pancreatitis
SGLT2i	↓ HbA1c 1%	Pregnancy	Urinary infections	Yes
	↓ weight		Genital mycosis	Empagliflozin and canagliflozin in secondary prevention^167,168
	↓ BP		Rare orthostatic hypotension, necrotising fasciitis, dehydration, and euglycemic ketoacidosis	Empagliflozin mortality^167
	No hypoglycaemias			Dapagliflozin CV mortality^169
				Empagliflozin, canagliflozin, dapagliflozin, ertugliflozin HF admissions^167–169
				Canagliflozin and dapagliflozin preservation kidney function and ↓ progression of diabetic kidney disease^170,171
Meglitinides	↓ HbA1c 0.8%	Pregnancy and breastfeeding	Hipoglucaemias	No
	↑ Weight
	Use in CKD
Third-generation sulfonylureas	↓ HbA1c 1%	Pregnancy and breastfeeding	Hypoglycaemias	No
	↑ Weight (2−4 kg)	Hospitalised patient	Do not use if CKD, liver failure and HF
Alpha-glucosidase inhibitors	↓ HbA1c 0.5%	T1DM	Gastrointestinal: flatulence, swelling, pain	No
	Weight =	Pregnancy and breastfeeding
		Gastrointestinal diseases

BP: blood pressure; CKD: chronic kidney disease; CV: cardiovascular; DDP-4 inhibitors: dipeptidyl peptidase-4 inhibitors; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; GFR: glomerular filtration rate; GLP-1RAs: GLP-1 receptor agonists; HbA1c: glycated haemoglobin; HDL-C: high-density lipoprotein cholesterol; HF: heart failure; SGLT2i: sodium-glucose cotransporter 2 inhibitors; TG: triglycerides; T1DM: type 1 diabetes mellitus.

Therapeutic guidelines

Fig. 8 presents the different therapeutic guidelines based on the presence or absence of ASVD, diabetic kidney disease, HF, and BMI. In patients with ASVD or a very high VR, SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are the preferred choice, provided studies demonstrate their effectiveness in preventing vascular events. In cases of severe or morbid obesity, we recommend using GLP-1 receptor agonists (Fig. 8A).¹⁶²

Figure 8.

(A) Therapeutic regimen in patients with type 2 diabetes mellitus; established atherosclerotic vascular disease; very high vascular risk; heart failure, or with diabetic kidney disease; (B) Therapeutic regimen in patients with type 2 diabetes mellitus and moderate/low vascular risk, without established atherosclerotic vascular disease, without heart failure, or without diabetic kidney disease.

BMI: body mass index; CVD: cardiovascular disease; DM: diabetes mellitus; DPP-4i: dipeptidyl peptidase-4 inhibitors; GLP-1r: glucagon-like peptide-1 receptor agonists; HbA1c: glycated haemoglobin; HF: heart failure; SGLT2i: sodium-glucose cotransporter 2 inhibitors; SU: sulfonylureas.

Numerous interventional studies have demonstrated the effectiveness of SGLT2 inhibitors^167–169 or GLP-1 receptor agonists in vascular prevention^164–166 and in preventing the progression of diabetic kidney disease.^170,171 They should therefore be the firstline drugs for the treatment of T2DM.

In individuals with DM and severe or morbid obesity, semaglutide or tirzepatide should be used preferentially due to their high efficacy in weight loss (Fig. 8B).

Depending on the HbA1c value, the initial treatment for hyperglycaemia will vary. If HbA1c is less than 7.5%, monotherapy will be used. If it is between 7.5% and 9%, dual therapy, and in cases of HbA1c >9% with cardinal symptoms, insulin therapy will be chosen.

Insulin therapy in T2DM with a long-acting or basal insulin will be indicated if triple therapy fails (third step in treatment, Fig. 8), always after having tried a GLP-1 receptor agonist. In cases where there is clear clinical evidence of hyperglycaemia with elevated HbA1c, insulin therapy will also be necessary, as previously mentioned. The total daily dose to start insulin therapy is .1–.3 U/kg of body weight, with dose adjustments every three days until the target is achieved. The actual need to increase the dose should be assessed on a case-by-case basis, since in subjects with obesity and insulin resistance, high doses can increase weight and, consequently, insulin resistance, without improving glycemica control.¹⁶²

Cardiovascular prevention in diabetes mellitus

Treatment and prevention of atherosclerotic vascular disease in people with diabetes mellitus

Cardiovascular prevention in DM requires early, intensive, and sustained intervention of all VRFs: dyslipidaemia, blood pressure, smoking, and abdominal obesity (Table 23).^14,162,172

Table 23.

Treatment and prevention of atherosclerotic cardiovascular disease in people with diabetes mellitus.

VRF	Target	Treatment
Hyperglycaemia control	HbA1c <7%	Hypoglycaemic diet
		Hypoglycaemic medications
HTN	Systolic blood pressure (SBP) <130 mmHg, but not less than 120 mmHg, with diastolic blood pressure (DBP) <80 mmHg, but not <70 mmHg	Reduce salt intake to <3 g/24 h If macroalbuminuria or renal insufficiency is present, restrict protein intake to .6–.8 g/kg/24 h
		Reduce alcohol consumption (maximum tolerated 30 g/day)
		Reduce alcohol consumption (maximum tolerated 30 g/day)
		Moderate coffee consumption (2 cups/24 h)
		ACEI or ARB
Tobacco	Do not smoke actively or passively
Obesity	BMI <30 kg/m^2	Dietary therapy and drug strategy
Dyslipidaemia	Primary: LDL-C reduction depending on patient risk Secondary TG <200 mg/dL	Statins, with or without ezetimibe/bempedoic acid, PCSK9 inhibitors in secondary prevention according to SEA recommendations (Table 13)
	Secondary TG <200 mg/dL	EPA for risk reduction in selected patients

ARB: angiotensin II AT1 receptor antagonists; ACEI: angiotensin-converting enzyme inhibitor; ASVD: atherosclerotic cardiovascular disease; BP: blood pressure; BMI: body mass index; DM: diabetes mellitus; EPA: Eicosapentaenoic acid; GLP-1 RA: glucagon-like peptide-1 receptor agonists; HbA1c: glycated haemoglobin; LDL-C: low-density lipoprotein cholesterol; PCSK9 inhibitor: protein subtilisin/kexin 9 convertase inhibitor; SEA: Spanish Society of Arteriosclerosis; SGLT2 inhibitor: sodium-glucose cotransporter 2 inhibitor; TG: triglycerides; VRF: vascular risk factors.

Dyslipidaemia in diabetes mellitus

In general, people with T2DM are considered of high VR.^14,173 People with T2DM and multiple VRFs (dyslipidaemia, hypertension, smoking), SVD, or TOD, or those undergoing secondary prevention, are considered to have a very high VR,¹⁴ The primary goal for prevention is to achieve a target LDL-C) or non-HDL-C level, as listed in Table 7, according to the patient's risk.¹⁴

To achieve these targets, high-intensity statins will be necessary, in most cases combined with ezetimibe or bempedoic acid. Once the LDL-C or non-HDL-C target is reached, we should consider achieving a secondary target of triglyceride (TG) concentration.^14,71

Patients with obesity and metabolic syndrome

Patients with metabolic syndrome

Table 24 defines the criteria that comprise metabolic syndrome (MetS).⁷⁴

Table 24.

Metabolic syndrome diagnostic criteria.

Diagnostic criteria*	Description
Abdominal obesity: Fasting blood glycaemia (mg/dL)	Waist circumference (above the iliac crests) elevated according to sex and ethnicity (≥94 cm in men and ≥80 cm in Caucasian women)
Plasma triglycerides (mg/dL)	≥150 or prior specific treatment
HDL-C(mg/dL) BP (mmHg):	<40 in men or <50 in women or on specific treatment Systolic ≥130 or diastolic ≥85 or on antihypertensive treatment

BP: blood pressure; H: men; HDL-C: high-density lipoprotein cholesterol; M: women; TG: triglycerides.

*

Three criteria are required for diagnosis.

Among the metabolic alterations associated with MetS, the following stand out⁷⁴:

• •

  Dyslipidaemia, primarily hypertriglyceridaemia, decreased HDL cholesterol, and the presence of small, dense LDL cholesterol particles, with increased plasma levels of free fatty acids. This set of alterations is known as atherogenic dyslipidaemia.

• •

  Hyperglycaemia or DM.

• •

  Elevated BP.

These alterations, along with abdominal obesity, are the established parameters for the diagnosis of MetS. In addition, many other alterations not used for diagnosis are common in these patients, such as hyperuricaaemia, gout, hypercoagulability, and fibrinolysis defects, which frequently present with elevated plasminogen activator inhibitor-1 (PAI-1), non-alcoholic fatty liver disease, and hyperandrogenism. The clinical relevance of MetS is related to its prevalence: 20%–40% of the general population and 80%–85% of individuals with type 2 diabetes mellitus (T2DM). Patients with metabolic syndrome (MetS) have an elevated risk of developing ADV and T2D.

Data from various meta-analyses indicate that individuals with MetS double their risk of vascular events and increase their all-cause mortality by 1.5 times compared to those without MetS.⁷⁴ Recent studies have found a five- to ten-fold increase in the relative risk of developing T2D. Other complications related to MetS include fatty liver disease associated with metabolic dysfunction, obstructive sleep apnoea (OSA), respiratory failure or idiopathic alveolar hypoventilation syndrome, and various forms of cancer (breast, uterus, colon, oesophagus, pancreas, kidney, prostate, etc.).

Treatment is aimed at controlling all components of the syndrome (Table 25, Table 26). The cornerstone of treatment is lifestyle modification, aiming for weight loss and control of atherogenic dyslipidaemia^74,172,174 and pharmacological management, if necessary, of the individual components of the syndrome (Table 26).

Table 25.

Metabolic syndrome treatment.

Treatments
Diet	Mediterranean-style diet (saturated fats <7% of total caloric intake. cholesterol <200 mg/day, avoid trans fats)
	Rich in fibre
	Limit salt intake (5−6 g/day)
	Foods with a low glycaemic index.
	Avoid simple sugars
	Increase fruits, vegetables, and whole grains
	Olive oil as the main cooking fat
	Avoid processed foods
Physical activity	Moderate-to-vigorous physical activity 30 min/day (preferably 45−60 minutes)
	Continuous/intermittent
	At least 5 days/week
	Adapted to the patient's age and cardiovascular status

MetS: metabolic syndrome; min: minutes; Na: sodium.

Table 26.

Treatment of other metabolic syndrome components.

Components	Target	Secondary targets	Treatment
Dyslipidaemia	LDL cholesterol based on associated cardiovascular risk factors*	HDL-C mg/dL >40 M and >50 W	Personal hygiene and dietary measures
	If hypertriglyceridemia → non-HDL c (30 mg/dL above the LDL target) or Apo B	TG <150 mg/dL	Statins, Ezetimibe and/or fibrates if required
Hypertension and microalbuminuria	SBP <130 and DBP <80 mmHg		Hygienic and dietary measures
			ACE inhibitors or ARBs ± other medications
Other VRFs	Give up smoking
	Consider antiplatelet therapy in selected very high-risk cases (ASA)

ACEI: angiotensin-converting enzyme inhibitor; Apo B: apolipoprotein B; ARB: angiotensin II AT1 receptor antagonists; ASA: acetylsalicylic acid; BP: blood pressure; HDL-c: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; M: men; MetS: metabolic syndrome; non-HDL-C: non-HDL cholesterol; TG: triglycerides; VRF: vascular risk factors; W: women.

*

Metabolic syndrome (MetS) is not a coronary equivalent, but it is a modulator of vascular risk (Table 7).

Obese patients

Obesity is a chronic disease caused by adipose tissue dysfunction resulting from excessive and/or abnormal fat accumulation. Currently, the concept of obesity based solely on BMI may be considered imprecise, but due to the difficulty of quantifying fat mass, this parameter continues to be used in its diagnosis and classification. Obesity is defined as a BMI ≥ 30 kg/m².¹⁷⁵ Patient classification based on BMI is shown in Table 27. Waist circumference allows for the diagnosis of the type of obesity (abdominal obesity) and cardiometabolic risk. Waist circumference values vary among ethnic groups.⁷⁵ We must add to BMI the presence or absence of comorbidities, which better define the patient's risk and allow for the individualisation of their treatment.

Table 27.

Classification of individuals according to body mass index. Definition of thinness and obesity.

Classification	BMI
Underweight	<18.5 kg/m^2
Normal weight	18.5−24.9 kg/m^2
Overweight (Grade 1)	25−26.9 kg/m^2
Overweight (Grade 2)	27−29.9 kg/m^2
Obesity (Grade 1)	30−34.9 kg/m^2
Obesity (Grade 2)	35−39.9 kg/m^2
Obesity (Grade 3 or Morbid)	40−49.9 kg/m^2
Obesity (Grade 4 or Extreme)	≥50 kg/m^2

Obesity is highly prevalent in Spain. According to the European Health Survey in Spain (EESE for its initials in Spanish), in 2020, 16.5% of men and 15.5% of women were obese, and 44.9% of men and 30.6% of women were overweight. Obesity is the main risk factor for developing type 2 diabetes abdominal obesity in particular is associated, with a high VR.¹⁷⁵

The treatment of obesity is complex and must be individualised. ¹⁷⁵ It is based on dietary therapy strategies (Table 28 and Fig. 9),¹⁷⁶ lifestyle changes, psychotherapy, and medications (Table 29).¹⁷⁵

Table 28.

Indications for very low calorie diets.

Indications	Contraindications
Patients with BMI > 35 kg/m^2 in whom conventional treatment has failed and who also present with:	BMI < 30 kg/m^2
Need for rapid weight loss, e.g., severe respiratory failure or orthopaedic surgery	Pregnancy and breastfeeding
Serious obesity-related pathology that responds to weight reduction, such as T2DM, HTN, dyslipidaemia, OSAHS	Severe systemic or organ pathology, except in situations clearly aggravated by overweight, in which individual risk-benefit assessment is recommended
	T1 DM
	Psychiatric disorders: eating disorder, severe depression, psychosis, drug or alcohol addiction
	Electrolyte imbalances and orthostatic hypotension
	Diseases with protein loss: Cushing's disease, systemic lupus erythematosus, proteinuria, neoplasms, malabsorption, inflammatory bowel disease, etc.
	Acute cardiovascular diseases, cardiac arrhythmias, stroke
	Major surgery or trauma within the last 3 months

BMI: Body mass index; HTN: Hypertension; OSAHS: Obstructive sleep apnoea-hypopnoea syndrome; T1DM: Type 1 diabetes mellitus.

Figure 9.

Dietary strategies in obesity treatment.

Table 29.

Pharmacological treatment of obesity.

Liraglutide (Saxenda®)
Dosage
1st week .6 mg/day; 2nd week 1,2 mg/day; 3rd week 1,8 mg/day; 4th week 2,4 mg/day
Maintenance 3 mg/day
Clinical effects
Weight loss of 8% maintained over 3 years
Progressive prediabetes to DM reduction
Adverse effects
Nausea and vomiting
Contraindications
Pregnancy and breastfeeding
Multiple endocrine neoplasm (MEN-2)
Medular thyroid carcinoma
Not recommended in:
• Severe kidney failure (creatinine clearing < 30 mL/min)or terminal
• Severe kidney failure
• Patients with acute personal history of pancreatitis
Use with caution in patients with mild or moderate liver failure
Semaglutide (Wegovy®)
Dosage
Dose scaling	Weekly dose
Week 1 to 4	.25 mg
Week 5 to 8	.5 mg
Week 9 to 12	1 mg
Week 13 to 16	1.7 mg
Maintenance dose	2.4 mg
Clinical effects
Weight loss of 14.9% at 68 weeks
Adverse effects
Nausea and vomiting
Diarrhoea
Contraindications
Pregnancy and breastfeeding
Multiple endocrine neoplasm (MEN2) or Medular thyroid carcinoma
Not recommended in:
• Severe kidney failure (eGFR < 30 mL/min/1.73 m^2)
• Severe liver failure and should be used with caution in patients with mild or moderate liver failure
• Class IV congestive heart failure
• T1DM
• Patients with a personal history of acute pancreatitis
There is limited experience in patients (use with caution) ≥ 75 years old, with inflammatory bowel disease and with diabetic gastroparesia
Tirzepatida (Mounjaro®)
Dosage
Dose scaling	Weekly dose
Week 1 to 4	2.5 mg
Week 5 to 8	5 mg
Week 9 to 12	7.5 mg
Week 13 to 16	10 mg
Week 17to 20	12.5 mg
Maximum dose	15 mg
Maintenance: 10−15 mg/week
Clinical effects
↓ 20% weight at 68 weeks
↓ 2% HbA1c
Adverse effects
Nausea, vomiting, diarrhoea or constipation
Contraindications
Multiple endocrine neoplasia (MEN-2) or medullary thyroid carcinoma
Not recommended in:
• Pregnancy or women of childbearing potential not using contraception
• Breastfeeding
• Patients with a personal history of acute pancreatitis
Limited experience exists in patients (use with caution): ≥ 85 years, with severe or end-stage renal disease, with severe hepatic impairment
Orlistat
Dosage
Orlistat 120 mg/2−3 times per day with main meals (requires a prescription)
Orlistat 60 mg/2−3 times per day with main meals (requires a prescription)
Clinical effects
↓ 37% progression to T2DM
Dose 120 mg/3 times per day ↓ 3.1% initial weight at one year
↓ SBP, DBP, TC, LDL-C
Adverse effects
15−25% gastrointestinal
May ↓ absorption of fat-soluble vitamins
Oxalate nephrolithiasis (orlistat increases urinary oxalate levels and should be used with caution in patients with a history of oxalate nephrolithiasis)
Contraindications
Chronic malabsorption syndrome
Cholestasis
Pregnancy
Breastfeeding
Naltrexone/Bupropion (not marketed in Spain)
Dosage
When starting treatment, the dose should be increased over 4 weeks:
• Week 1: one tablet in the morning
• Week 2: one tablet in the morning and another at night
• Week 3: two tablets in the morning and one at night
• Week 4 and after: two tablets in the morning and two at night
It is recommended that the last dose be taken in the evening to avoid insomnia if taken at dinner time.
Clinical effects
50% of patients lose ≥ 5% weight
Adverse effects
Nausea
Raised heart rate
Contraindications
Pregnancy and breastfeeding
Uncontrolled hypertension
Patients currently suffering from seizure disorders or with a history of seizures
Known neoplasm of the central nervous system
Alcohol or benzodiazepine withdrawal syndrome
History of bipolar disorder
Any concomitant treatment containing bupropion or naltrexone
Current or previous diagnosis of bulimia or anorexia nervosa
Dependence on long-acting opioids or opioid agonists (e.g., methadone) or acute opioid withdrawal syndrome
Concomitant treatment with monoamine oxidase inhibitors (MAOIs). A minimum of 14 days must elapse between discontinuation of MAOIs and initiation of naltrexone/bupropion treatment.
Severe hepatic impairment
End-stage renal disease

DBP: diastolic blood pressure; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; GLP-1: glucagon-like peptide-1; HTN: high blood pressure; LDL-C: low-density lipoprotein cholesterol; SBP: systolic blood pressure; TC: total cholesterol. T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus.

The main objective of dietary intervention is to reduce food intake. Different dietary patterns are effective for weight loss. Plans should be adapted to the patient's clinical characteristics and preferences (Fig. 9). In general, a Mediterranean-type diet should be the basis of treatment in our setting.

A daily caloric reduction of between 500 and 1,000 kcal can produce a weight loss of between .5 and 1 kg/week. Weight reductions of between 7% and 10% produce significant health benefits and metabolic changes.

In addition, it is important to prescribe appropriate physical exercise for each patient and provide psychological support with modification of eating behaviour.

Pharmacological treatment for obesity should be individualised. Drug selection will depend on age, the presence or absence of diabetes mellitus, and contraindications (Table 29).

Surgical treatment for obesity is reserved for a group of patients after the therapeutic failure of other conservative options.¹⁷⁷ Bariatric surgery is indicated in morbid obesity or severe obesity with multiple complications that are not medically controlled and that have failed with other therapeutic strategies. It is an effective treatment, but not without complications. The indications and contraindications are listed in Table 30.

Table 30.

Surgical treatment of obesity.

Indications and contraindications
Indications for bariatric surgery.	BMI ≥ 40 kg/m^2
	BMI ≥35 kg/m^2 with one or more serious comorbidities:
	T2DM
	HTN
	Dyslipidaemia
	Respiratory disorders secondary to obesity
	Steatotic liver disease with metabolic dysfunction
	Osteoarthritis
	Urinary incontinence
Requisites	Age 18–60 years. Individualised treatment is required for older patients.
	Rule out endocrinopathies.
	History of morbid obesity for at least 5 years.
	Failure or insufficient response to medical-nutritional treatment.
	Ability to adhere to recommendations and lifestyle changes after surgery.
	The patient must understand the treatment they will undergo and its long-term consequences.
	Psychiatric evaluation is required in cases of relevant history or suspicion of mental illness.
Contraindications	Severe psychiatric pathology: schizophrenia, major depression, intellectual disability.
	Psychiatric instability.
	Eating disorders (ED).
	Alcohol or other drug abuse.

BMI: body mass index; ED: eating disorders; HTN: hypertension;. T2DM: type 2 diabetes mellitus.

Smoker patients

Smoking

According to the WHO Smoking is a preventable human and economic tragedy.¹⁷⁸ The 2020 European Health Survey found that, in Spain, 16.4% of women and 23.3% of men smoke on a daily basis.¹⁷⁹ More than 7 million people die worldwide each year from tobacco-related causes, and of these, 1.6 million are due to second-hand smoke.¹⁷⁸ Smoking is the leading cause of preventable death, doubling the risk of death by ASVD and increasing it fivefold in those under 50. Smoking contributes to the formation and rupture of atherosclerotic plaques. It also promotes inflammation, oxidation, and dysfunction of the arterial endothelium, which predisposes to arterial spasm, thrombosis, and vascular obstruction. Smoking is harmful in all its forms, in proportion to the amount smoked.¹⁸⁰ Giving up smoking is, among all preventive measures, the most cost-effective in terms of reducing nicotine resistance, with benefits appearing in the first months of abstinence. In Spain, the smoking population decreased by 3.13% between 2009 and 2012, and by 4.81% between 2009 and 2017.¹⁸¹ However, tobacco continues to be promoted,¹⁸² and once a smoking habit is acquired, withdrawing from it is complex, as the number of failed attempts, according to various reports, ranges from 5 to 14.¹⁸³ All smokers should be advised to give up smoking in any interaction with healthcare professionals, which increases the likelihood of success by >50%. A person is considered to have given up smoking when six months have passed since they smoked their last cigarette. Table 31 shows the recommendations on smoking cessation strategies contained in the European guidelines for cardiovascular prevention.¹⁴

Table 31.

Recommendations on strategies for treating smoking.

Recommendation	Class	Level
Any tobacco use should be stopped, as smoking is strongly and independently associated with the development of vascular disease.	I	A
Smokers should be helped to give up by offering nicotine replacement therapy and medications (varenicline and bupropion alone or in combination) when necessary.	IIa	A
Giving up smoking is recommended despite weight gain, as this weight gain does not reduce the vascular benefits of giving up.	I	B
Passive smoking should be avoided.	I	B

Adapted from Ref.¹⁴

Addressing smoking in clinical practice

Every cardiovascular risk assessment visit should include the following sections regarding smoking:

• •

  History of smoking habits:

• none–

  Have you ever smoked (regularly smoked at least 1 cigarette per month)? (No/Yes).

• none–

  How many cigarettes do you smoke per day?

• none–

  If you have given up smoking, how many months have passed since you gave up?

• none–

  How many serious attempts have you made to give up smoking throughout your life?

• •

  Advise the patient firmly on the need to give up smoking. Provide information on the benefits of giving up and strategies to facilitate it. Also, explain the potential weight gain (3−5 kg ​​on average) and its negligibility compared to the vascular prevention benefits and the improvement in overall health.

• •

  Assess the degree of addiction using the Fagerström Test¹⁸⁴ (Annexes) or a shortened questionnaire of only two questions¹⁸⁵ (Annexes) to guide the patient on the need for pharmacological and nicotine replacement therapy. The less time that elapses between the patient waking up in the morning and smoking their first cigarette, and the greater the number of cigarettes they smoke per day, the greater their nicotine dependence.

• •

  Assess the patient's attitude toward smoking. Three key questions can be asked:

• none–

  Do you think tobacco is harmful to you?

• none–

  Would you like to give up smoking?

• none–

  Do you think you can give up?

• •

  If the patient answered yes to the three previous questions, they should be assisted with a planned strategy, including setting a date for giving up, behavioural/motivational therapy, and pharmacological support or specific smoking cessation consultations. If they did not answer yes, they should be informed, motivated, and encouraged.

• •

  Establish a follow-up programme.

Treatment of tobacco addiction

Both behavioural and pharmacological treatments are effective and safe for smoking cessation, and this has been demonstrated with the highest quality of evidence. The combination of both treatments is more effective than monotherapy. However, there is insufficient evidence for the effectiveness of hypnosis or acupuncture.¹⁸⁶

Behavioural treatment

Behavioural treatment includes a wide variety of interventions that encourage the patient to reflect on their smoking habit to increase their motivation and confidence in their ability to give up. The aim is to provide skills for managing the urge to smoke and overcoming the negative emotions caused by nicotine withdrawal, promote environmental changes that reduce stimuli that induce smoking, and offer social support. Smoking cessation counselling can be brief and individualised (<5 min) or more extended and involve repeated in-person, virtual, or telephone visits, as well as group meetings or the use of self-help materials. Individualised counselling is the most effective.¹⁸⁷ Behavioural treatment can also promote adherence to pharmacological treatment and help overcome its adverse effects.

Pharmacological treatment

Smoking cessation pharmacotherapy includes nicotine replacement therapy, varenicline, cytisine, and bupropion.¹⁸⁸ Although these products are usually prescribed when a smoker gives up or is about to, various studies suggest that treatment effectiveness increases when it is initiated weeks or even months before smoking cessation.¹⁸⁶

• •

  Nicotine replacement treatment. This can be prescribed as gum, patches, or oral sprays. All of these are effective and increase the likelihood of smoking cessation. Smoking cessation in individuals who respond to nicotine replacement therapy usually occurs within the first four weeks, although extending treatment to eight to twelve weeks increases the likelihood of long-term remission.¹⁸⁹

Smoking one cigarette provides 1–2 mg of nicotine, and the dose of nicotine administered as a substitute must be adjusted to the number of cigarettes smoked. Nicotine patches are applied every 24 h and are available in three strengths: 7, 14, and 21 mg. Peak blood nicotine concentration is reached one hour after application, and its effect lasts for 24 h. Nicotine gum is available in 2 and 4 mg doses, although only about 50% of the dose is absorbed, and the oral spray contains 1 mg of nicotine per spray. With both gum and oral spray, peak nicotine levels are reached within 20–30 min and dissipate over about 2 h. People who smoke fewer than 10 cigarettes a day can use gum or oral spray, while patches are preferable for those who smoke 10 or more cigarettes. In the latter group, patches can be combined with gum or oral spray to combat withdrawal symptoms, achieving somewhat better results than patches alone.¹⁹⁰ Treatment with nicotine replacement therapy is not associated with an increased risk of ADV episodes and has been shown with high-quality evidence to have a significant effect on smoking cessation.¹⁸⁶

• •

  Bupropion. Bupropion is an antidepressant that may inhibit the reuptake of adrenaline and noradrenaline. A large base of clinical trials has shown that it increases the likelihood of smoking cessation by more than 50%. It is administered as one 150 mg extended-release tablet daily for three days, after which the dose is increased to 150 mg twice daily to complete 12 weeks of treatment. Smoking cessation is recommended seven days after starting treatment. Its main drawbacks are a small risk (1/1,000) of seizures and insomnia, which, if it occurs, can be avoided by reducing the dose to one 150 mg tablet daily. It has not been shown to increase the risk of ADV or neuropsychiatric illness. Treatment can be continued for 12 weeks, although it may be extended to 52 weeks in patients at high risk of relapse.¹⁹⁰

• •

  Varenicline. Varenicline is a partial agonist of nicotine receptors, which mediate nicotine dependence through dopamine release. It reduces the symptoms of smoking withdrawal and also the level of satisfaction associated with smoking. A large body of clinical trials has shown that its use more than doubles the likelihood of giving up smoking. It is administered as a .5 mg tablet once daily for three days, a .5 mg tablet every 12 h from day four to day seven, and, from day eight onward, a 1 mg tablet every 12 h until 12 weeks of treatment are completed. As with bupropion, it is recommended to stop smoking on the seventh day of treatment. Its main side effect is nausea, which can be mitigated by gradually increasing the dose and avoiding the highest doses.¹⁹¹ Varenicline has not been shown to be associated with serious cardiovascular or neuropsychiatric adverse effects.¹⁹²

• •

  Cytisinicline (cytisine). Cytisine is a plant alkaloid that, like varenicline, is a partial agonist of nicotine receptors.¹⁹³ Its efficacy in achieving smoking cessation may be similar to that of varenicline, but with somewhat better tolerability.¹⁹⁴ Cytisine is available in 1.5 mg tablets, and its dosage is shown in Table 32.

  Table 32.

  Cytisine dosage.

  Days of treatment	Recommended dose	Maximum daily dose
  From day 1 to day 3	1 tablet every 2 h	6 tablets
  From day 4 to day 12	1 tablet every 2.5 h	5 tablets
  From day 13 to day 16	1 tablet every 3 h	4 tablets
  From day 17 to day 20	1 tablet every 5 h	3 tablets
  From day 21 to day 25	1−2 tablets per day	Up to 2 tablets

The patient must stop smoking no later than the 5th day of treatment, and if they are unsuccessful, they must discontinue treatment, which can be resumed after two or three months.

Combination of pharmacological treatments

Combining nicotine replacement therapy with other drugs, such as varenicline, cytisine, or bupropion, may increase the success rate of smoking cessation. The combination of drugs other than nicotine replacement therapy, such as bupropion with varenicline or cytisine, could only be considered when monotherapy with one of them does not achieve abstinence.¹⁸⁶

Electronic cigarettes (e-cigarettes)

Licensed electronic cigarettes are devices that generate an aerosol, usually containing nicotine, through heating without combustion. Because combustion does not occur, fewer toxins are produced, making them less harmful than conventional cigarettes. A recent Cochrane review concluded that there is high-quality evidence supporting the greater effectiveness of nicotine e-cigarettes compared to other nicotine replacement therapies for smoking cessation.¹⁹⁵ However, evidence is limited regarding their long-term health effects. E-cigarettes can be effective when smokers completely replace conventional cigarettes with e-cigarettes, significantly reducing cardiovascular risk, but this still poses a high risk compared to complete smoking cessation, ¹⁹⁶ which is the therapeutic goal. Among e-cigarettes, the use of heated tobacco products has seen the greatest increase, ¹⁹⁷ which could be explained by their approval in 2020 by the U.S. Food and Drug Administration (FDA) classifies it as a modified risk tobacco product. ¹⁹⁸

Patients with atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia, with its global prevalence increasing from 33.5 million cases in 2010 to more than 59 million today.¹⁹⁹ This figure is likely even higher due to under-diagnosis, especially in the early stages of the disease, as a result of the absence of noticeable symptoms. The increased availability of heart rhythm recording devices, along with growing awareness of AF, has significantly contributed to the overall increase in its detection.¹⁹⁹ The prevalence of AF depends on population characteristics related to age, sex, race, and geographic area.

• •

  Age and sex. AF is closely related to aging, primarily affecting the elderly population.²⁰⁰ The age group with the highest prevalence of atrial fibrillation (AF) is patients over 75 years old, at 9%, doubling to 18% in those over 85.^201,202 In patients between 55 and 75 years old, the prevalence ranges from 1% to 6%, while in patients under 55 years old it is .1%.²⁰² The prevalence is similar in both sexes, but slightly higher in men (1.1% vs. .8%), a figure that adjusts over a lifetime.²⁰²

• •

  Race, ethnicity, and geographic area: Black and Hispanic adults have a lower risk of AF than non-Hispanic whites.²⁰³ This difference becomes more pronounced at older ages. Developed countries have a higher prevalence of AF compared to developing countries, with the highest rates in North America and the lowest in Asia and sub-Saharan Africa.¹⁹⁹

Risk factors that facilitate the onset or recurrence of atrial fibrillation

The lifetime risk of AF increases with the burden of VRFs. Identifying, preventing, and treating these factors is key to reducing the prevalence of AF and its associated morbidity.

Hypertension

High and uncontrolled blood pressure can alter the structure of the myocardial wall, promoting the development of AF and increasing the likelihood of recurrence. The relative risk of developing AF in hypertensive patients is 1.50 compared to normotensive individuals.²⁰⁴ This fact, combined with the high prevalence of hypertension in the general population, makes this cardiovascular risk factor the most frequent underlying cause among patients with AF, and therefore its control should be an integral part of treatment.²⁰⁴ Furthermore, hypertension increases the risk of lacunar and haemorrhagic stroke.

Diabetes mellitus

Diabetes mellitus is present in approximately 25% of patients with AF.²⁰⁵ Although the influence of diabetes mellitus (DM) on myocardial remodelling and its predisposition to the development of atrial fibrillation (AF) is known, intensive glycemic control does not decrease the rate of new-onset AF. Patients with diabetes and greater glycaemic variability have a relative risk of 1.2 of developing AF.²⁰⁶ Conversely, long-standing DM predisposes patients with AF to a higher risk of stroke and thromboembolic events. However, metformin treatment in patients with DM and SGLT2 inhibitors is associated with a lower risk of AF. ²⁰⁶ In this regard, although studies with SGLT2 inhibitors have demonstrated a reduction in left atrial volume, there is conflicting data on whether they reduce the incidence of AF. ²⁰⁷

Obesity and metabolic syndrome

Obesity increases the likelihood of developing atrial fibrillation (AF) in parallel with increasing BMI.²⁰⁸ This may be due to increased left atrial pressure and volume. Weight reduction of 10−15 kg decreases AF recurrence, while a weight loss of >10% in overweight and obese patients with AF reduces symptoms.^205,208 Furthermore, improved cardiorespiratory fitness and exercise can further decrease the AF burden in obese patients with AF. ²⁰⁹ MetS includes hypertension, diabetes mellitus, and obesity, conditions that, as we have seen, are associated with AF; therefore, their combination accentuates the risk.²¹⁰

Heart failure

The prevalence of atrial fibrillation (AF) in patients with heart failure is slightly higher in those with reduced left ventricular ejection fraction (LVEF) compared to preserved LVEF (46% vs. 34%).²¹¹ Patients with AF and both reduced and depressed LVEF benefit from optimisation of HF therapy, particularly SGLT2 inhibitors, to reduce hospitalisations and AF recurrences.²⁰⁵

Obstructive sleep apnoea-hypnoea syndrome

AF is associated with COPD and OSAHS. Atrial remodelling secondary to OSAHS-related hypoxia drives fibrosis and conduction slowing, leading to a higher prevalence of AF.²¹² The risk of AF in these patients increases with increasing OSAHS severity.²¹³ In patients treated with mechanical ventilation, the incidence and recurrence of AF are lower.

Chronic kidney disease

The incidence of AF is more frequent in patients with microalbuminuria and/or a glomerular filtration rate (GFR) below 60 mL/min/1.73 m², and is higher in those in the terminal stages of the disease or on dialysis, leading to increased mortality and thromboembolic events.²¹⁴

Diagnosis of atrial fibrillation and screening strategies

The diagnosis of AF is made by observing irregular RR intervals with absence of P waves on a 12-lead ECG or for at least 30 seconds on an ECG obtained using other single- or multi-lead devices. Four temporal patterns are distinguished based on the presentation, duration, and spontaneous resolution of AF episodes:

• •

  Newly diagnosed AF: AF not previously diagnosed, regardless of symptoms or temporal pattern.

• •

  Paroxysmal AF: AF that resolves spontaneously or with intervention in <7 days.

• •

  Persistent AF: lasts for >7 days and <1 year. Within this category, we can distinguish between long-standing persistent AF: if it lasts for >1 year, but a rhythm control strategy is a viable therapeutic option.

• •

  Permanent AF: AF accepted by both the patient and physician, with no further measures taken to restore or maintain sinus rhythm.

The recurrence of AF after a first cardioverted event is around 70%, influenced by several factors such as left ventricular dysfunction and left atrial diameter. Its progression to persistent AF occurs in 8%–25% of cases during the first and fifth years.^215,216 Based on its clinical component, AF can be symptomatic or clinical, asymptomatic or subclinical, when it becomes evident after an acute event, is detected by a device, or after an ECG is performed.

Comprehensive management of patients with atrial fibrillation

The AF Better Care (ABC) approach in previous guidelines has been replaced by the AF-CARE protocol, which promotes multidisciplinary, patient-cantered collaboration organised around four pillars: detection and treatment of comorbidities and cardiovascular risk factors (C), prevention of stroke and thromboembolism (A), symptom reduction through rhythm and rate control strategies (R), and periodic assessment and reassessment (E).²⁰⁵ Recent studies also highlight the importance of healthcare professionals' involvement in understanding the options for multidisciplinary AF management:²¹⁷

• •

  (C) Comorbidities and VRFs: This approach prioritises the treatment of comorbidities and VRFs as the first step in AF patient care, adequately addressing HTN,DM,HF, obesity, sedentary lifestyle, and alcohol consumption.

• •

  (A) Stroke and thromboembolism prevention: Oral anticoagulation (OAC) is recommended in patients at high thromboembolic risk to prevent stroke, following risk factor assessment using the CHA2DS2-VA score.

• •

  (R) Symptom reduction through rhythm or heart rate control: Rhythm control is prioritised in paroxysmal and persistent atrial fibrillation (AF), either pharmacologically with antiarrhythmic drugs or through pulmonary vein ablation, depending on the individual case; heart rate control is prioritised in cases of permanent AF or when a rhythm control strategy is not pursued.

• •

  (E) Periodic evaluation and reassessment: This involves systematically reviewing treatment efficacy, adherence, and disease progression.

Screening

Asymptomatic clinical AF has been independently associated with a higher risk of stroke and mortality compared to symptomatic AF. Therefore, screening is recommended for patients >65 years of age with hypertension, obstructive sleep apnoea, or heart failure, or for those over 75 years of age, using pulse palpation or a 12-lead ECG.²⁰⁵ Although a standard ECG is considered the conventional diagnostic method, the role of new technologies, such as mobile applications and smart watches, has been highlighted in recent years. Studies such as Apple Heart and Huawei Heart have described a high capacity for detecting self-limiting episodes of AF, but these must be confirmed with an ECG.^218,219 The recent 2024 ESC guidelines accept various ECG modalities, including 12-lead ECGs, as well as ECGs from devices that perform single- or multi-lead ECGs. Transthoracic echocardiography is recommended for the initial evaluation and treatment of all patients with atrial fibrillation (AF), allowing for the assessment of cardiac function and structure.

Prevention and non-pharmacological measures

Intense weight loss with comprehensive management of concomitant cardiovascular risk factors results in fewer AF recurrences and symptoms. Excessive alcohol consumption is a risk factor for AF and bleeding in anticoagulated patients, while alcohol abstinence reduces recurrence in regular drinkers with AF.²²⁰ Regular caffeine consumption may be associated with a lower risk of AF, but caffeine intake can increase palpitations unrelated to AF. Physical exercise (>150 min/week of moderate exercise or >75 min/week of vigorous exercise) has demonstrated vascular benefits. While it is true that the incidence of AF appears to have been increased in elite athletes, patients should be advised to perform moderate-intensity exercises to prevent the incidence or recurrence of AF, avoiding excessive endurance exercises (marathons or triathlons) especially in those over 50 years of age.²²¹

Heart rate or rhythm control. Antiarrhythmic drugs, catheter ablation, and atrial fibrillation surgery

Early rhythm control therapy is associated with a lower risk of events in patients with newly diagnosed AF, ²²² while in long-standing AF, rate control is the most recommended therapy.²²³ Both rate control and rhythm control strategies aim to alleviate the pathophysiological consequences of AF and its symptoms. In patients with new-onset AF, spontaneous restoration can be observed in approximately 75% during the first 24–48 h; therefore, withholding treatment for the first 24 h in haemodynamically stable, asymptomatic patients may be an option. The choice of rhythm control therapy will depend on the patient's characteristics, symptoms, and LVEF.

While electrical cardioversion is the preferred approach for unstable patients, treatment for stable patients depends on the time since onset (greater or less than 48 h) and prior anticoagulation. The possibility of electrical cardioversion should be discussed with the patient if it is feasible (in patients on anticoagulant therapy, when the presence of a thrombus in the left atrium and left atrial appendage has been ruled out, or when the onset is less than 24 h old). Alternatively, a wait-and-see approach may be considered.²⁰⁵

Heart rate control

In patients with atrial fibrillation (AF), lax heart rate control (<110 bpm) is recommended, as this strategy has shown non-inferior results to strict control (<80 bpm).²¹⁷

• •

  Beta-blockers: These are the first-line drugs for heart rate control due to their rapid effect, especially in patients with LVEF, inappropriate increase in ventricular rate during exercise, or recent myocardial infarction.

• •

  Non-dihydropyridine calcium channel blockers (verapamil and diltiazem): These are an effective alternative in the absence of heart failure with reduced ejection fraction (HFrEF) or in patients with side effects from beta-blockers or poor tolerance to them. Like beta-blockers, they are effective in reducing heart rate both at rest and during exercise.

• •

  Digoxin: This is considered a useful treatment despite its previously restricted use due to a possible increase in mortality, always with strict monitoring of its levels. ²²⁴

• •

  Amiodarone: This is useful in combination therapy after failure of previous therapy. Its use in this indication is limited to patients with maximum tolerated combination therapy and should be avoided in those with thyroid disease.

Heart rhythm control

Rhythm control is recommended to improve symptoms and quality of life in symptomatic patients with atrial fibrillation.²¹⁷ While synchronised direct electrical cardioversion is the preferred method for patients with atrial fibrillation (AF) and haemodynamic compromise, in stable patients its use is interchangeable with that of pharmacological cardioversion. However, it should be noted that pharmacological cardioversion is less effective than electrical cardioversion, especially the longer the duration of AF. On the other hand, it does not require fasting, sedation, or anaesthesia.

• •

  Flecainide and propafenone (class Ic): These are indicated in patients without structural heart disease or Brugada syndrome and should be used with caution due to their proarrhythmic effect (less pronounced with propafenone). They should be used in combination with an AV node inhibitor due to the risk of inducing class IC atrial flutter, and QRS and QT interval monitoring should be performed the first time they are used. Their effect is rapid (3–5 h) in more than 50% of cases. The use of the "pill-in-the-pocket" with flecainide or propafenone is safe and recommended in patients with paroxysmal atrial fibrillation after training and prior safety testing in the hospital.²²⁵

• •

  Amiodarone: Intravenous amiodarone is the preferred choice for patients with HF with reduced LVEF. It is the drug associated with the lowest recurrence rate, but it has a delayed cardioverter effect (8−12 h), shorter than other antiarrhythmics, and requires monitoring.²²⁶ Caution should be exercised when it is combined with another drug that prolongs the QT interval, and it should be discontinued when the QT interval exceeds 500 ms. In contrast, dronedarone has demonstrated very low conversion rates.

• •

  Vernakalant: has a faster cardioverter effect than amiodarone (1 h).²¹⁷ It should not be used in hypotensive patients, those with recent coronary artery disease, heart failure in functional class III-IV, reduced ejection fraction, severe aortic stenosis, or QT prolongation, and should be used with caution concomitantly with dabigatran.

Catheter ablation of the pulmonary veins is an effective rhythm control technique indicated for symptomatic patients with paroxysmal atrial fibrillation, persistent atrial fibrillation in whom antiarrhythmic drugs have failed, or atrial fibrillation that has led to tachycardiomyopathy with ventricular dysfunction. Ablation could be considered in asymptomatic patients in very specific cases where it has been shown to reduce morbidity and mortality. Another technique for pulmonary vein ablation is surgical, which is indicated when the patient is going to undergo cardiac surgery, especially if it involves the mitral valve, and rhythm control is thought to be achievable.

Anticoagulant therapy for stroke prevention

Anticoagulation is the treatment of choice for the prevention of ischaemic stroke, regardless of whether it is permanent, persistent, or paroxysmal atrial fibrillation.^217,227 Most guidelines and systematic reviews recommend oral anticoagulants, with a preference for direct oral anticoagulants (DOACs) in all patients except those considered at low risk of stroke (CHA2DS2-VA 0). In patients with mechanical heart valves, severe mitral stenosis, or advanced renal disease, vitamin K antagonists (VKAs) would be the preferred choice. The indication for oral anticoagulation is established by prognostic models that incorporate the patient's age and comorbidities. The most widely used scale is the chronic heart failure, hypertension, age >75, diabetes, previous stroke, vascular disease, age 65−74 (CHA₂DS₂-VA) (Table 33), which excludes gender. The HAS-BLED bleeding risk assessment was also excluded, in accordance with previous guidelines. Anticoagulation is indicated in patients with a CHA₂DS₂-VA ≥ 2 (Class I indication) and in those with a CHA₂DS₂-VA 1 score ≥ 1 (Class IIA indication), level of evidence C. Table 34 summarises the Class I recommendations for oral anticoagulation in atrial fibrillation, according to the European guidelines.²¹⁷ It is important to note that stroke risk is not fixed, but dynamic and can fluctuate with age, the development of new comorbidities, and changes in polypharmacy, all of which must be considered for appropriate dosing.

Table 33.

CHA₂DS₂-VA thrombotic risk score in atrial fibrillation.

VRF	Weighted value
Congestive HF	1
Hypertension	1
Age ≥75 years	2
DM	1
Previous stroke/TIA/peripheral embolism	2
Vascular disease (peripheral artery disease, coronary artery disease, aortic plaque)	1
Age between 65 and 74 years	1
Maximum score	9
Interpretation: low risk = 0; moderate risk = 1; high risk ≥2

AF: atrial fibrillation; CHA₂DS₂-VA: chronic heart failure, hypertension, age >75, diabetes, previous stroke, vascular disease, age 65−74; DM: diabetes mellitus; HF: heart failure; ICD: ischaemic heart disease; TIA: Transient ischaemic attack; VRF: vascular risk factors.

Table 34.

Class I recommendations for oral anticoagulation in atrial fibrillation (AF).

	Class	Level of evidence
Oral anticoagulation is recommended in patients with clinical AF and a high thromboembolic risk.	I	A
A CHA2DS2-VA score ≥2 is an indicator of high thromboembolic risk requiring anticoagulation.	I	C
Oral anticoagulation is recommended in all patients with AF and hypertrophic cardiomyopathy or cardiac amyloidosis, regardless of CHA2DS2-VA score, for the prevention of stroke and thromboembolism.	I	B
Periodic individualised assessment of thrombotic risk is recommended to ensure optimal anticoagulation. DOACs are preferred over VKAs for the prevention of stroke or thromboembolism, except in patients with mechanical heart valves or moderate to severe mitral stenosis.	I	B
An INR of 2–3 is recommended in patients with AF receiving VKAs for stroke prevention.	I	A
Oral anticoagulation is recommended in patients with clinical AF and a high thromboembolic risk.	I	B

CHA2DS2-VA: chronic heart failure, hypertension, age >75, diabetes, previous stroke, vascular disease, age 65−74; DOACs: direct oral anticoagulants; INR: international normalized ratio; VKAs: vitamin K antagonists.

Patients treated with vitamin K antagonists (VKAs) (warfarin or acenocoumarol) require frequent monitoring of the international normalised ratio (INR) to ensure safe anticoagulation levels. The quality of laboratory control, as measured by time in therapeutic range (TTR), is crucial for optimising treatment efficacy and safety, since a TTR greater than 65% is correlated with a reduced incidence of stroke.²²⁸

Four large randomised controlled trials have been conducted with DOACs: dabigatran (RELY), rivaroxaban (ROCKET-AF), apixaban (ARISTOTLE), and edoxaban (ENGAGE-AF). Meta-analyses of pivotal and real-world studies have demonstrated efficacy equal to or better than VKAs, with a lower incidence of bleeding complications. DOACs offer clear advantages over VKAs, such as a stable anticoagulant effect, rapid onset of action, few drug or dietary interactions, and no need for monitoring. However, while patients using DOACs generally do not require monitoring, they should be regularly evaluated to ensure there are no drug interactions and to adjust the dose if necessary, depending on renal function and other factors.²¹⁷ A meta-analysis of pivotal studies showed a 19% reduction in stroke or systemic embolism, an 8% reduction in mortality, and a 65% reduction in intracranial hemorrhage with DOACs compared to VKAs.²²⁹ Similarly, real-world meta-analyses have demonstrated that apixaban and dabigatran are associated with a lower risk of bleeding complications.²³⁰

DOACs are contraindicated in pregnancy, in patients with mechanical heart valves, and in patients with moderate or severe mitral stenosis. Recommended DOAC doses for atrial fibrillation are shown in Table 35.

Table 35.

Recommended doses of direct oral anticoagulants (DOACs) in atrial fibrillation (AF).

DAOC	Standard dose	Dose reduction criteria	Reduced dose
Apixaban	5 mg/12 h/day	At least 2: Age ≥80 years Weight ≤60 kg Creatinine ≥135 μmol/L	2.5 mg/12 h/day
Dabigatran	150 mg/12 h/day	At least 1: Age ≥80 years Treatment with verapamilo	110 mg/12 h/day
Edoxaban	60 mg/day	At least 1: Moderate or severe renal impairment (creatinine clearance 15−50 mL/min) Weight ≤60 kg Concomitant use of cyclosporine, dronedarone, erythromycin, or ketoconazole	30 mg/day
Rivaroxaban	20 mg/day	Creatinine Clearance 15–49 mL/min	15 mg/day

While VKAs are the preferred choice in patients with advanced renal disease, DOACs show efficacy and safety compared to VKAs in patients with moderate renal impairment (creatinine clearance >30 mL/min), although dose adjustment is required (Table 35). In Europe, reduced doses of rivaroxaban, apixaban, and edoxaban have been approved for patients with severe renal impairment (creatinine clearance 15–29 mL/min), but few subjects have been included in randomised controlled trials. American guidelines recommend VKAs (INR 2–3) or apixaban in patients with atrial fibrillation (AF) and creatinine clearance <15 mL/min or on dialysis.²³¹ Finally, in patients with contraindications to DOACs, left atrial appendage closure is promising alternative for the prevention of ischaemic stroke.^217,227

It is important to involve the patient in the decision-making process regarding different anticoagulation options and to consider polypharmacy and comorbidities that may predispose them to bleeding. Age, frailty, weight, and renal function must be taken into account, as these can influence the choice of anticoagulant and dosage. Patients should also be educated about the signs of potential complications and the importance of treatment adherence to prevent adverse events.

Among the emerging anticoagulation options for atrial fibrillation (AF) is the use of coagulation factor XI inhibitors, such as monoclonal antibodies, antisense oligonucleotides, and small molecules. Some phase 2 studies, such as PACIFIC-AF, and others in phase 3, such as OCEANIC-AF, indicate a significant reduction in bleeding complications, making them a promising alternative for anticoagulation in patients with AF.²³²

Anticoagulation in patients requiring cardioversion

It is important to initiate anticoagulation early in patients scheduled for cardioversion, given that this procedure is associated with a risk of thromboembolism. Patients who have been in atrial fibrillation (AF) for more than 48 h should begin anticoagulation at least three weeks before cardioversion and then continue for four weeks (unless they require indefinite anticoagulation). Current guidelines recommend adequate anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), which are the preferred choice for both electrical and pharmacological cardioversion due to their efficacy and lower risk of complications compared to VKAs.^227,231

Organisation and functioning of the vascular risk clinic: Professionals and equipment. Quality criteria

In recent years, several important national and international studies have confirmed poor overall control of cardiovascular risk factors (CVRFs), especially in patients with high and very high cardiovascular risk.^233–241 The poor achievement of therapeutic goals can be attributed to various factors, including lack of adherence to treatment, therapeutic inertia, the socioeconomic status of the population, and also organisational models.^242–245 The current trend is to create integrated multidisciplinary models, which allow fluid and bidirectional collaboration between levels of care, positioning the patient as the centre of the process, unlike the classic, isolated care models, with little interaction between levels and usually unidirectional.^245,246

Multidisciplinary control of CVR has clear advantages²⁴⁵:

• •

  Standardise the approach to and treatment of vascular risk factors (VRFs) across different levels of care, thus ensuring continuity of care in vascular prevention.

• •

  Improve the detection of all VRFs in patients with high cardiovascular risk, facilitating the most appropriate and earliest therapeutic intervention for each patient.

• •

  Optimise healthcare resources by avoiding duplicate visits and additional tests.

• •

  Define and agree upon referral criteria to create a bidirectional flow that, in most cases, facilitates the patient's return to primary care after the assessments and interventions that required referral to specialist care. This ensures that this information reaches the primary care physician and that the patient receives unified healthcare messages from both levels of care.

• •

  Promote teaching and research in cardiovascular risk.

A vascular risk clinic, as an organisational unit within the scheduled care setting, requires the following²⁴⁵:

• •

  Professionals from various specialties (Internal Medicine, Endocrinology, Cardiology, Nephrology, Neurology, Clinical Biochemistry), in coordination with other primary care professionals (Family Medicine, Nursing, Nutrition) and other professionals such as smoking cessation units or mental health professionals, to facilitate the implementation of comprehensive vascular prevention strategies.

• •

  Standardised protocols based on clinical practice guidelines for the comprehensive management of the main cardiovascular risk factors.

• •

  Basic structural requirements.²⁴⁷ This includes the ability to perform accurate blood pressure measurement with validated devices (Table 36).^247,248

  Table 36.

  Resources from a hospital consultation for the global control of the main vascular risk factors.

  Set up	Material resources	IT resources
  Consultation room for each healthcare professional	Complete consultation room furnishings (desk and examination table) and basic equipment: stethoscope, ophthalmoscope, flashlight, scale, stadiometer, and measuring tape	Digital medical record, accessible to the referral healthcare area
  Space for nursing staff to measure blood pressure, provide health education, and review treatment adherence	Validated blood pressure measurement devices^248	Online Access to risk scales and questionnaires
  It is desirable that the consultation rooms of the professionals participating in the vascular risk consultation (VRC) be located in the same area	It is advisable to have:	Electronic prescription, according to the health service model
  Ambient temperature control	A semi-automatic blood pressure measurement device so that several automatic measurements (generally 3) can be taken automatically in both arms without an observer. It is recommended that on the first visit, the 3 automatic measurements be taken simultaneously in both arms.	Option for online consultation with primary care
  	Access to ABPM	Option for video consultation
  	Portable Doppler for ABI determination
  	Electrocardiograph

  ABI: ankle-brachial index; ABPM: ambulatory blood pressure monitoring; BP: blood pressure.

  Adapted from Ref.²⁴⁷

As a basic tool for measuring the quality of care, indicators must be established (Table 37) that identify areas for potential improvement in order to optimise the overall management of VRFs. These indicators should be used as a self-assessment system.^245,247,249

Table 37.

Indicators for measuring the quality of care in the overall management of patients with high vascular risk.

Indicators
Structure or activity	Process or quality	Outcome
Total number of patients referred to the VR consultation	Number of referrals to the VR clinic that meet predefined and agreed-upon referral criteria / total number of referrals	Number of patients seen who meet vascular risk factor control targets according to their risk category / total number of patients seen
Number of VR team sessions	Number of patients with their first VR clinic visit and a response time within the established parameters / total number of first visits	Appropriateness of resource use (additional tests) / total number of patients seen
Number of consultation sessions conducted with primary care	Number of patients seen with diagnosis coding (according to ICD-10) / total number of patients seen	Number of VR consultation episodes closed through referral to primary care with a consensual care report / number of VR consultation discharges
Number of telehealth visits conducted by VR clinic members: virtual consultations, consultation sessions, telemedicine	Number of patients in primary prevention and without diabetes mellitus (DM) whose risk has been estimated using a scale / total number of patients in primary prevention and without DM seen in the VR clinic
Scientific output: communications and publications shared by several members of the group

CD-10: International Classification of Diseases, 10th Revision; CVD: cardiovascular risk; DM: diabetes mellitus; VRF: vascular risk factors.

Adapted from Ref.²⁴⁵

Consultations where patients with cardiovascular risk factors are treated must be adapted to the organisational system of the corresponding public or private health service. The incorporation in recent years of elements such as the digitisation of medical records, with the possibility of adding indicators and extracting information, electronic prescribing, which facilitates understanding the degree of adherence to treatment, and telemedicine options (both for patient-physician and physician-physician interaction) can facilitate access to the patient's clinical information and better management of VRFs.

In this regard, the creation of alerts in clinical laboratories can also contribute to improving the detection, treatment, and monitoring of certain VRFs (dyslipidaemia, diabetes mellitus) in primary care, as well as facilitating effective contact between primary and hospital care professionals through teleconsultations based on agreed-upon referral criteria.²⁵⁰

The COVID-19 pandemic brought about substantial changes in healthcare, including a growing prominence of telehealth consultations, which have been incorporated alongside in-person consultations in multiple healthcare settings. Criteria for choosing between in-person and telehealth consultations have been proposed for cardiovascular clinics, as described in Table 38.²⁵¹ To facilitate the diagnosis and management of dyslipidaemias through e-consultations in cardiovascular clinics, minimum necessary parameters have also been proposed.¹³

Table 38.

Consultation type selection criteria.

Preference for in-person consultation	Preference for telematic consultation
Suspected potentially serious or urgent problems, need to deliver bad news. Clinical changes, decompensation or worsening of the patient's condition, need for an interview with accompanying persons, first visit	Clinically stable
Communication difficulties with the patient (language barrier, hearing loss, cognitive problems)	No communication difficulties
Requires physical examination	Does not require a physical examination
Requires training in physical self-examination:	Trained in self-examination
Weight
BP measurement
HBPM
Requires additional short-term testing:	Requires medium- to long-term additional tests (manage requests through administrative channels)
Blood tests
ECG
Radiology
Ankle-brachial index
PWV
ABPM
Requires more personalised health education or significant changes in treatment, or treatment titration	Will not require treatment changes a priori
Uncontrolled CVD	No CVD or in stable condition
Presence of multiple comorbidities	No significant comorbidities

ABPM: ambulatory blood pressure monitoring; BP: blood pressure; CVD: cardiovascular disease; ECG: electrocardiogram; HBPM: home blood pressure monitoring; PWV: pulse wave velocity.

Adapted from Ref.²⁵¹

Referral and discharge criteria for patients with vascular risk

Referral criteria for patients with vascular risk

Patients with high vascular risk are generally referred to clinics for the management of one or morevascular risk factors (VRFs), primarily hypertension, diabetes mellitus, and dyslipidaemia, either for primary or secondary prevention. In this regard, it is common for patients with established ASVD (coronary, cerebrovascular, or peripheral arterial) to be referred to vascular risk clinics. These patients, sometimes young, may not have identified any VRFs (for thrombophilia testing) or may be unaware of or not adequately controlling the VRFs detected during their hospital assessment.

It is uncommon to receive patients for smoking cessation, even though this is a major VRF. This task usually falls to specialised pulmonology or primary care units. Each public health service usually establishes its own referral criteria to specialised units, based on its own schedules, resource availability, and level of care (district hospitals versus tertiary referral hospitals).

The main reasons for referral for patients DM are shown in Table 39.

Table 39.

Reasons for referral of patients with diabetes mellitus.

Diabetes mellitus
T1DM
Gestational diabetes
Diabetes of unknown origin
Poor glycaemic control, unstable diabetes, hypoglycaemia
Comorbidities (e.g., morbid obesity)
Severe microvascular disease (polyneuropathy, diabetic foot, CKD, advanced retinopathy)

CKD: chronic kidney disease; DM: diabetes mellitus; T1DM: type 1 diabetes mellitus.

In the context of the RV (Regional Health Network), the main type of DM to consider is type 2, associated with dyslipidaemia, obesity, hypertension (HTN), and metabolic syndrome (MetS). Therefore, the most common reason will be inadequate glycaemic control, despite the enormous therapeutic arsenal available for type 2 DM in recent years.^252,253

The referral criteria for patients with HTN, according to the practical guide of the Spanish Society of Hypertension-Spanish League Against Arterial Hypertension (SEH-LELHA) published in 2022, are as follows²⁵⁴:

• •

  Suspected secondary HTN.

• •

  Age of onset <40 years with stage 2−3 hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).

• •

  Recurrent hypertensive crises in patients with previously normal blood pressure or well-controlled hypertension.

• •

  Indication for complementary studies not available in primary care, particularly advanced vascular examinations that may influence therapeutic decisions.

• •

  Resistant hypertension (uncontrolled hypertension with three complementary drugs at adequate doses, one of which is a diuretic), especially after ruling out pseudoresistance due to the white coat effect with ambulatory blood pressure monitoring (ABPM) and ruling out non-pharmacological or pharmacological treatment non-adherence.

• •

  Difficult-to-control hypertension related to multiple drug intolerances, multiple contraindications, persistent non-adherence, or extreme variability in blood pressure readings.

The SEA has published the referral criteria for patients with dyslipidaemia to its lipid units (Table 40).²⁵⁵

Table 40.

Referral criteria to lipid units of the Spanish Society of Atherosclerosis.

Dyslipidaemia	Thresholds	Clinical context	Diagnosis	Treatment
Hypercholesterolaemia	TC > 300 mg/dL	Tendon xanthomas	Cascade screening for FH	Triple therapy
	LDL-C > 200 mg/dL	Corneal arcus <45 years old	Cascade screening for severe lupus anticoagulant (Lp(a)) elevation	New treatments (PCSK9 inhibitors/inclisiran)
	Lp(a) > 150 mg/dL (300 nmol/L)	FH +++	Genetic testing	Drug intolerance
		Premature coronary artery disease or pulmonary enema	Imaging techniques to detect SVD	Treatment resistance
		Recurrent coronary artery disease		Apheresis
		Vascular disease without obvious cardiovascular risk factors
		Suspected familial hypercholesterolemia
		Steatosis and/or cirrhosis
Hypertriglyceridaemia	Fasting TG > 1,000 mg/dL	Xanthomas	Evaluation of primary causes	Exclude primary cause
	TG > 500 mg/dL despite treatment	Hepatomegaly	Biochemical tests	Ineffective treatment
	Hypertriglyceridemia and TC > 350 mg/dL	Splenomegaly	Molecular diagnosis	Special diets
		Lipemia retinalis
		Childhood onset
		Pancreatitis
HDL-C	HDL -C< 20 mg/dL	Hepatomegaly	Exclude primary causes	Control of primary causes
	HDL-C > 100 mg/dL	Splenomegaly	Biochemical tests
		Tonsillar hypertrophy	Molecular diagnosis
		Corneal opacity
		Renal insufficiency
Hypocholesterolaemia	LDL-C < 50 mg/dL without treatment	Malabsorption	Exclude primary causes
		Steatosis	Biochemical tests
			Molecular diagnosis

FH: family history; FH: familial hypercholesterolemia; HDL-C: high-density lipoprotein cholesterol; IHD: ischaemic heart disease; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); PCSK9 inhibitor: proprotein convertase subtilisin/kexin type 9 inhibitor; PAD: peripheral arterial disease; SVD: subclinical vascular disease; TC: total cholesterol; TG: triglycerides; +++: positive.

Adapted from Ref.²⁵⁵

In the case of dyslipidaemia, the most common reasons for referring patients are poor control of serum cholesterol or triglyceride levels, treatment and diagnosis of FH, adverse effects of medication, especially statin intolerance (primarily due to muscle toxicity), or the need for combination therapies or hospital administration, particularly with PCSK9 inhibitors/inclisiran.²⁵⁵

Discharge criteria for patients with vascular risk

It is obvious that, once a definitive diagnosis has been reached and the vascular risk factor that prompted the consultation is controlled, patients should be referred from the specialised unit for follow-up in primary care. However, it is not uncommon for patients to be reviewed in outpatient clinics for various reasons. These include failure to achieve therapeutic goals; the need for non-conventional procedures (bariatric surgery; LDL-C apheresis, or lysosomal replacement therapy infusion in day hospitals); the need to prescribe and dispense certain medications through the hospital pharmacy (such as PCSK9 inhibitors and inclisiran); polypharmacy with a high risk of drug interactions (e.g., in patients with HIV infection and transplant recipients), and those who experience adverse effects from medication, such as hypoglycaemia. Patients with monogenic hyperlipidaemia should maintain contact (at least annually, in the absence of complications or comorbidities) with lipid units for shared follow-up with primary care. This reinforces adherence to medication and healthy lifestyles, and facilitates the rapid incorporation of new therapies for this patient group. Some patients with secondary hypertension remain hypertensive despite aetiological treatment of their disease, suggesting the prolonged effect of hypertension on the vascular system (remodelling) or that some of them may also have essential hypertension.²⁵⁶

It would in any case be advisable for each unit to establish its own referral criteria, based on its clinical activity and its relationship with primary care.

Funding

This study was partially funded by Ferrer Laboratories. The authors of the document are responsible for its content. Ferrer Laboratories was not involved in its design, writing, or content.