Consecutive inclusion will be made of the patients referred to the research unit and who meet the corresponding inclusion criteria, i.e., patients diagnosed with DM2 and aged 20-80 years, with none of the following exclusion criteria: patients unable to comply with the protocol requirements (psychological and/or cognitive disorders, failure to cooperate, educational limitations and problems for understanding written language, failure to sign the informed consent document), patients participating or who will participate in a clinical trial during the study, and patients with serious comorbidities representing a threat to life over the subsequent 12 months.
The sample size has been calculated to determine the time the patients take in suffering an event - the latter being interpreted as morbidity-mortality or the appearance of new target organ damage. To this effect, two groups will be considered, classified according to the median central arterial pressure value. The study accepts an alpha risk of 0.05 and a beta risk of 0.30 in two-sided contrasting for the detection of a minimum difference in relative risk between the two groups of ≥ 2.5 points, and considering an events rate within the high central arterial pressure group (values above the median) of 35% at the end of the study period. A total of 52 patients are required in each group, estimating a loss to follow-up of 10%. A final total of 110 patients therefore will be included.
Sociodemographic variables and cardiovascular risk factors
Patient age, sex, race, educational level and occupational status. Hypertension, dyslipidemia, alcohol consumption, smoking, physical activity and a history of premature cardiovascular disease (before 55 years of age in males and before 65 in females) in first-degree relatives.
Coronary events: Myocardial infarction, unstable angina, stable angina, coronary revascularization. Cerebrovascular events: Ischemic stroke, intracranial hemorrhage, transient brain ischemia. Hospital admissions due to heart failure. Symptomatic peripheral arterial disease: Claudication over a distance of less than 100 m, resting pain, amputation. Heart failure. Atrial fibrillation.
Treatment for diabetes. Antihypertensive treatment. Lipid-lowering treatment. Antiplatelet treatment.
Body weight is to be determined on two occasions using a homologated electronic scale (Seca 770) following due calibration (precision ± 0.1 kg), with the patient wearing light clothing and no shoes. These readings will be rounded to 100 g. Height in turn will be measured with a portable system (Seca 222), recording the average of two readings, and with the patient shoeless in the standing position. The values will be rounded to the closest centimeter. Body mass index (BMI)(kg/m2) will be calculated. Waist circumference will be measured using a flexible graduated measuring tape with the patient in the standing position without clothing. The upper border of the iliac crests are located, and the tape is wrapped around above this point, parallel to the floor, ensuring that it is adjusted without compressing the skin. The reading is taken at the end of a normal breath according to the recommendations of the 2007 SEEDO Conference .
Lipids, creatinine, glucose, high-sensitivity C-reactive protein (CRP), fibrinogen and glycosylated hemoglobin (HbA1c) in blood and microalbuminuria. The parameters will be measured on a blind basis in the reference laboratory after patient fasting for at least 8 hours.
Office or clinical blood pressure
Office blood pressure measurement involves three measurements of systolic (SBP) and diastolic blood pressure (DBP), using the average of the last two, with a validated OMRON model M7 sphygmomanometer (Omron Health Care, Kyoto, Japan), by following the recommendations of the European Society of Hypertension . Pulse pressure (PP) will be estimated with the mean values of the second and third measurements.
Home blood pressure (HBP)
This parameter will be measured using an OMROM model M7 sphygmomanometer (Omron Health Care, Kyoto, Japan). Three measurements will be made in the morning (between 6:00 and 9:00 a.m.), and three in the afternoon/evening (between 18:00 and 21:00 p.m.), over a period of 7 days, with a minimum interval of one minute between measurements, and excluding the first measurement in each case and the values corresponding to the first day of measurement . The investigator will instruct the patients on how to perform the blood pressure recordings at home. Written instructions will be provided, as well as a self-registry sheet, to ensure correct pressure monitoring.
Ambulatory blood pressure monitoring (ABPM)
The ABPM was performed on a day of standard activity, with an adequate cuff for the size of the patient's arm. A control system, SpaceLabs 90207 model (Spacelabs Healthcare, Issaquah, Washington, USA), validated according to the protocol of the British Hypertension Society, was used . The records in which the percentage of valid readings was ≥66% of the total and with valid readings at all times were considered to be valid. Furthermore, for the records to be evaluable, at least 14 measurements were required during the daytime period, or at least seven during the nightime or rest period. The monitor was scheduled for obtaining blood pressure measurements every 20 min during the daytime period and every 30 min during the rest period. The average and dispersión estimators of SBP and DBP were calculated during the 24-h, daytime and nightime periods, defined based on the diary reported by the patient. The patient completes a form specifying bedtime and wake-up time.
Assessment of carotid intima-media thickness
Carotid ultrasonography to assess IMT was performed by two investigators specifically trained for this before starting the study. A Sonosite Micromax ultrasound (Sonosite Inc., Bothell, Washington, USA) device paired with a 5-10 Mhz multifrequency high-resolution linear transducer with Sonocal software was used for performing automatic measurements of IMT for optimising reproducibility. Measurements were made of the primitive carotid after the examination of a longitudinal section of 10 mm at a distance of 1 cm from the bifurcation, performing measurements in the anterior or proximal wall, and in the posterior or distal wall in the lateral, anterior and posterior projections, following an axis perpendicular to the artery to discriminate two lines, one for the intima-blood interface and the other to the media-adventitious interface. A total of 6 measurements were obtained of the right carotid and other 6 of the left carotid, using average values (average IMT) and maximum values (maximum IMT) calculated by the software automatically. The measurements were obtained with the subject lying down, with the head extended and slightly turned opposite to the carotid examined, following the recommendations of the Manheim Carotid Intima-Media Thickness Consensus . Finally, IMT image is frozen in telediastole by means of electrocardiogram triggering to avoid a confounding effect of pulsatile deformation of wall thickness and transferred to a computer. The average IMT was considered to be abnormal if it was above 0.9 mm, or if there were atherosclerotic plaques with a diameter over 1.5 mm, or a focal increase of 0.5 mm, or 50% of the adjacent IMT .
Evaluation of peripheral artery involvement
This was evaluated using the ankle-brachial index (ABI), performed in the morning without having consumed coffee or tobacco for at least 8 hours prior to measuring and an ambient temperature of 22-24°C. With the feet uncovered, in a supine decubitus position after 20 minutes of rest, the pressure in the lower extremities was measured using a portable Doppler system Minidop Es-100Vx (Hadeco, Inc. Arima, Miyamae-ku, Kawasaki, Japan) applying the probe at the anterior or posterior tibial artery at an angle of approximately 60° to the direction of blood flow. The transducer's cuff was quickly inflated in each ankle about 30 mmHg above the systolic pressure and the pressure was allowed to descend (by about 2 mmHg per second) until the first sound corresponding to the systolic pressure was heard. The blood pressure was also measured in both arms (measured twice at 3-5 minute intervals). The ABI was calculated separately for each foot by dividing the higher of the two systolic pressures in the ankle by the highest of the two systolic pressures in the arm . It is considered subclinical organ damage if it is lower than 0.9 .
The electrocardiographic examination was performed with a General Electric MAC 3.500 ECG System (Niskayuna, New York, USA), that measures automatically the voltage and duration of waves and estimates the criteria of the Cornell voltage-duration product (Cornell VDP)  to assess the LVH by the following equation: Men ((RaVL + SV3) * QRS) and women ((RaVL + SV3) * QRS + 6). LVH is defined as the voltage-duration product > 2,440 mm/ms (16). We will estimate left ventricular mass index (LVMI) by Novacode equation .
The kidney damage was assessed by measuring creatinine plasma concentration, the glomerular filtration rate was estimated by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)  and the MDRD-IDMS (Modification of Diet in Renal Disease-Isotopic Dilution Mass Spectrometry)  equation and proteinuria were assessed by the albumin/creatinine ratio following the 2007 European Society of Hypertension/European Society of Cardiology Guidelines criteria . Subclinical organ damage was defined as plasma creatinine between 1.3 - 1.5 mg/dl in men and 1.2 - 1.4 mg/dl in women, glomerular filtration rate below 60 ml/min or albumin/creatinine ratio > 22 mg/gr in men and 31 mg/gr in women. Renal disease was defined as plasma creatinine of 1.5 mg/dl or higher in men and 1.4 mg/l in women or albumin/creatinine ratio > 300 mg/24 h.
Evaluation of retinal involvement
Retinography was performed with a Topcon TRC NW 200 non-mydriatic retinal camera (Topcon Europe B.C. Capelle a/d IJssel The Netherlands), obtaining images centered on the papilla. Once the images were captured, two independent observers classified them according to the Keith-Wagener classification for hypertensive retinopathy , with a third reading being performed in cases where there were discrepancies. Grades III or IV (hemorrhages or exudates, papillary edema) are considered to be associated with cardiovascular disease .
Evaluation of pulse wave velocity and central blood pressure
The pulse wave velocity (PWV) was calculated using the SphygmoCor System (Vx Pulse Wave Velocity), (AtCor Medical Pty Ltd Head Office, West Ryde, Australia) with the patient in the supine decubitus position. The carotid and femoral pulse wave was analyzed, estimating the delay in the electrocardiograma (ECG) wave and calculating the PWV. The space measurements were taken with a measuring tape from the suprasternal notch to the carotid and femoral arteries at the sensor location. A measurement of greater than 12 m/s is considered subclinical organ damage .
Using the SphygmoCor system (Px Pulse Wave Analysis)(Atcor Medical, Australia), with the patient in the sitting position and resting the arm on a rigid surface, pulse wave analysis will be made with a sensor in the radial artery - using mathematical transformation to estimate the aortic pulse wave. From the aortic wave morphology, central (aortic) arterial pressure will be estimated, along with central ventricular load, diastolic perfusion pressure, the subendocardial viability index, the pressure increment, central pulse pressure and the augmentation index (PWA), defined as the percentage increase in central pulse pressure: AIx = pressure increase/pulse pressure * 100 .
All explorations will be carried out on a yearly basis, and due registry will be made of any changes in the sociodemographic variables or cardiovascular risk factors, and of the appearance of events.
A first descriptive analysis will be made of the sociodemographic and clinical characteristics of the study groups. The data will be presented with the mean and 95% confidence interval in the case of quantitative variables, and as frequency distributions for qualitative variables. The Pearson chi-squared test will be used to analyze associations between qualitative variables. The Student t-test for independent samples will be used to compare the means for the two arterial pressure groups. In turn, the analysis of repeated measures will be based on the McNemar test for qualitative data and the Student t-test for paired data in application to quantitative data.
Survival will be analyzed with the Kaplan-Meier and actuarial methods on each visit and at the end of follow-up. The log-rank test will be used for comparing survival in the two groups. Lastly, a Cox regression model will be developed to estimate the event risk between the groups, adjusting for the possible confounding variables analyzed in the study.
Hypothesis contrasting will establish an alpha risk factor of 0.05 as the limit of statistical significance. The SPSS/PC+ version 15.0 statistical package will be used (SPSS Inc., Chicago, Illinois, USA).